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

Abstract

An anti-Nectin-4 antibody-drug conjugate for treating a tumor, and a method and medical use for treating a tumor with the anti-Nectin-4 antibody-drug conjugate.

Description

Anti-Nectin-4 Antibody-Drug Conjugates for Tumor Treatment

[0001] This disclosure claims priority to the following patent applications: Chinese Patent Application No. 2024103772252, filed on March 29, 2024; Chinese Patent Application No. 2024114078081 and No. 2024114058548, filed on October 10, 2024; Chinese Patent Application No. 2024117719773, filed on December 4, 2024; Chinese Patent Application No. 202510142456X, filed on February 10, 2025; and Chinese Patent Application No. 2025102770536, filed on March 10, 2025. The entire contents of the foregoing patent applications are incorporated into this disclosure by reference. Technical Field

[0002] The present disclosure belongs to the field of medicine and relates to a method for treating tumors with an anti-nectin-4 antibody-drug conjugate and its medical uses. Background Art

[0003] Nectin-4 (gene name PVRL4, poliovirus receptor 4) protein belongs to the nectin family of the immunoglobulin superfamily. The nectin family works together with cadherins to have a significant impact on the generation and maintenance of adherens junctions (AJs) and tight junctions (TJs), regulating a variety of cellular behaviors, including cell adhesion, growth, differentiation, migration, and apoptosis. Unlike nectins 1-3, which are widely expressed in normal adult tissues, nectin-4 protein is specifically expressed in the embryo and placenta, expressed in a few normal adult tissues (including skin), and overexpressed in tumor tissues (in addition to AJs, it is also distributed at the cell apex and released into the plasma). Nectin-4 is specifically and highly expressed in tumor tissues and is closely related to tumor prognosis. The potential mechanisms by which nectin-4 promotes tumor occurrence and metastasis include: 1) promoting tumor angiogenesis: 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, reshape the actin cytoskeleton, and enhance the driving force of pseudopodia extension in tumor cells, ultimately leading to tumor development and spread.

[0004] Antibody-drug conjugates (ADCs) are small molecule cytotoxic drugs covalently attached to antibodies via a chemical link. Using the antibody as a carrier, the small molecule drug is delivered to target cells. They combine the highly targeted properties of antibodies with the potent killing power of cytotoxic drugs against target cells and are considered a new generation of antibody-targeted therapeutics. The antibody in the Nectin-4 ADC specifically recognizes and binds to the Nectin-4 receptor on the surface of target cells. It then enters the target cell through endocytosis, where it is broken down and releases the cytotoxic drug. The cytotoxic drug then exerts its anti-tumor effect by damaging DNA or acting on microtubules, preventing cell division and inducing apoptosis.

[0005] Currently, there is a need to develop safe and effective drug treatment options targeting Nectin-4. Summary of the Invention

[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 any of the following uses:

[0008] (1) Use of anti-nectin-4 antibody-drug conjugates in the preparation of drugs for treating tumors;

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

[0010] (3) Use of a combination of an anti-nectin-4 antibody-drug conjugate and an immunotherapeutic agent in the preparation of a medicament for treating tumors;

[0011] (4) anti-nectin-4 antibody-drug conjugates for treating tumors;

[0012] (5) Anti-Nectin-4 antibody-drug conjugates combined with immunotherapeutic agents for the treatment of tumors;

[0013] (6) An 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;

[0014] (7) An immunotherapeutic agent for treating a tumor, wherein the immunotherapeutic agent is administered to a subject in combination with an anti-nectin-4 antibody drug conjugate;

[0015] (8) A pharmaceutical composition, a kit or a product for treating a tumor, wherein the pharmaceutical composition, kit or product comprises an anti-nectin-4 antibody-drug conjugate;

[0016] (9) A pharmaceutical composition, kit or product for treating tumors, wherein the pharmaceutical composition, kit or product comprises an anti-nectin-4 antibody drug conjugate and an immunotherapeutic agent;

[0017] (10) Use of a pharmaceutical composition, a kit, or a product in the preparation of a drug for treating tumors, wherein the pharmaceutical composition, kit, or product comprises an anti-nectin-4 antibody-drug conjugate;

[0018] (11) Use of a pharmaceutical composition, a kit or a product in the preparation of a drug for treating tumors, wherein the pharmaceutical composition, kit or product comprises an anti-nectin-4 antibody drug conjugate and an immunotherapeutic agent.

[0019] In some embodiments, the treatment of the tumor includes perioperative treatment of the tumor. In some embodiments, the perioperative treatment of the tumor includes neoadjuvant therapy before surgical treatment and / or adjuvant therapy after surgical treatment. In some embodiments, the adjuvant therapy includes combined administration of an anti-nectin-4 antibody drug conjugate and an immunotherapeutic agent, and immunotherapeutic agent monotherapy. In some embodiments, the adjuvant therapy includes first administering a combined administration of an anti-nectin-4 antibody drug conjugate and an immunotherapeutic agent, followed by immunotherapeutic agent monotherapy.

[0020] In some embodiments, the use described in any of the above items comprises:

[0021] (1) Use of an anti-nectin-4 antibody-drug conjugate in the preparation of a neoadjuvant therapy drug for a tumor patient before surgical treatment, and / or use of an anti-nectin-4 antibody-drug conjugate in the preparation of an adjuvant therapy drug for a tumor patient after surgical treatment;

[0022] (2) Use of an anti-nectin-4 antibody-drug conjugate combined with an immunotherapeutic agent in the preparation of a neoadjuvant therapy for a tumor patient prior to surgical treatment, and / or use of an anti-nectin-4 antibody-drug conjugate combined with an immunotherapeutic agent in the preparation of an adjuvant therapy for a tumor patient after surgical treatment;

[0023] (3) Use of a combination of an anti-nectin-4 antibody-drug conjugate and an immunotherapeutic agent in the preparation of a neoadjuvant therapy for a tumor patient prior to surgical treatment, and / or use of a combination of an anti-nectin-4 antibody-drug conjugate and an immunotherapeutic agent in the preparation of an adjuvant therapy for a tumor patient after surgical treatment;

[0024] (4) anti-nectin-4 antibody-drug conjugates for use as neoadjuvant therapy before surgical treatment of cancer patients and / or as adjuvant therapy after surgical treatment of cancer patients;

[0025] (5) an anti-nectin-4 antibody-drug conjugate combined with an immunotherapeutic agent for use as a neoadjuvant therapy before surgical treatment of a tumor patient and / or as an adjuvant therapy after surgical treatment of a tumor patient;

[0026] (6) An anti-nectin-4 antibody-drug conjugate is used for neoadjuvant therapy before surgical treatment of a tumor patient, and / or for adjuvant therapy after surgical treatment of a tumor patient, wherein the anti-nectin-4 antibody-drug conjugate is administered to a subject in combination with an immunotherapeutic agent;

[0027] (7) An immunotherapeutic agent is used for neoadjuvant therapy before surgical treatment of a tumor patient, and / or for adjuvant therapy after surgical treatment of a tumor patient, wherein the immunotherapeutic agent is administered to a subject in combination with an anti-nectin-4 antibody drug conjugate;

[0028] (8) A pharmaceutical composition, a kit or a product for neoadjuvant therapy before surgical treatment of a tumor patient, and / or for adjuvant therapy after surgical treatment of a tumor patient, wherein the pharmaceutical composition, kit or product comprises an anti-nectin-4 antibody drug conjugate;

[0029] (9) A pharmaceutical composition, a kit or a product for neoadjuvant therapy before surgical treatment of a tumor patient and / or for adjuvant therapy after surgical treatment of a tumor patient, wherein the pharmaceutical composition, kit or product comprises an anti-nectin-4 antibody drug conjugate and an immunotherapeutic agent;

[0030] (10) Use of a pharmaceutical composition, kit or product for the preparation of a neoadjuvant drug for a tumor patient prior to surgical treatment, and / or for the preparation of a post-operative adjuvant drug for a tumor patient, wherein the pharmaceutical composition, kit or product comprises an anti-nectin-4 antibody drug conjugate;

[0031] (11) Use of a pharmaceutical composition, a kit or a product for preparing a neoadjuvant drug for a tumor patient before surgical treatment, and / or for preparing a post-operative adjuvant drug for a tumor patient, wherein the pharmaceutical composition, kit or product comprises an anti-nectin-4 antibody drug conjugate and an immunotherapeutic agent.

[0032] In some embodiments, the present disclosure provides a method as shown in any of the following:

[0033] (1) A method for treating a tumor, comprising administering a therapeutically effective amount of an anti-nectin-4 antibody-drug conjugate to a subject in need thereof;

[0034] (2) a method for treating a tumor, comprising administering a therapeutically effective amount of an anti-nectin-4 antibody drug conjugate and an immunotherapeutic agent to a subject in need thereof;

[0035] (3) A method for treating a tumor, comprising administering a therapeutically effective amount of an immunotherapeutic agent to a subject in need thereof;

[0036] (4) A method for treating a tumor, comprising administering a pharmaceutical composition, a kit, or a product to a subject in need thereof; wherein the pharmaceutical composition, kit, or product comprises an anti-nectin-4 antibody-drug conjugate;

[0037] (5) A method for treating a tumor, comprising administering a pharmaceutical composition, a kit, or a product to a subject in need thereof; wherein the pharmaceutical composition, kit, or product comprises an anti-nectin-4 antibody drug conjugate and an immunotherapeutic agent.

[0038] In some embodiments, the method of any of the foregoing items comprises:

[0039] (1) A method for perioperative treatment of tumors, comprising administering a therapeutically effective amount of an anti-nectin-4 antibody-drug conjugate to a subject in need thereof as a neoadjuvant therapy before surgical treatment of the subject and / or as an adjuvant therapy after surgical treatment of the subject;

[0040] (2) A method for perioperative treatment of tumors, comprising administering a therapeutically effective amount of an anti-nectin-4 antibody drug conjugate and an immunotherapeutic agent to a subject in need thereof as neoadjuvant therapy before surgical treatment of the subject and / or as adjuvant therapy after surgical treatment of the subject;

[0041] (3) A method for perioperative treatment of tumors, comprising administering a therapeutically effective amount of an immunotherapy agent to a subject in need thereof as a neoadjuvant therapy before the subject undergoes surgical treatment, and / or as an adjuvant therapy after the subject undergoes surgical treatment;

[0042] (4) A method for perioperative treatment of tumors, comprising administering a pharmaceutical composition, a kit, or a product to a subject in need thereof as a neoadjuvant therapy before surgical treatment and / or an adjuvant therapy after surgical treatment; wherein the pharmaceutical composition, kit, or product comprises an anti-nectin-4 antibody drug conjugate;

[0043] (5) A method for perioperative treatment of tumors, comprising administering a pharmaceutical composition, a drug kit or a product to a subject in need thereof as a neoadjuvant therapy before surgical treatment and / or an adjuvant therapy after surgical treatment; wherein the pharmaceutical composition, drug kit or product comprises an anti-nectin-4 antibody drug conjugate and an immunotherapeutic agent.

[0044] In some embodiments, the adjuvant therapy comprises a combination of an anti-nectin-4 antibody drug conjugate and an immunotherapeutic agent, followed by immunotherapeutic agent monotherapy. In some embodiments, the adjuvant therapy comprises a combination of an anti-nectin-4 antibody drug conjugate and an immunotherapeutic agent, followed by immunotherapeutic agent monotherapy.

[0045] In some embodiments, the present disclosure provides a product as shown in any of the following:

[0046] (1) A pharmaceutical composition comprising an anti-nectin-4 antibody-drug conjugate;

[0047] (2) a pharmaceutical kit comprising an anti-nectin-4 antibody drug conjugate;

[0048] (3) a product comprising an anti-nectin-4 antibody-drug conjugate;

[0049] (4) a pharmaceutical composition comprising an anti-nectin-4 antibody-drug conjugate and an immunotherapeutic agent;

[0050] (5) a pharmaceutical kit comprising an anti-nectin-4 antibody drug conjugate and an immunotherapeutic agent;

[0051] (6) a product comprising an anti-nectin-4 antibody drug conjugate and an immunotherapeutic agent;

[0052] In some embodiments, the kit or article of manufacture further comprises one or more containers independently comprising an anti-nectin-4 antibody drug conjugate. In some embodiments, the kit or article of manufacture further comprises one or more containers independently comprising an anti-nectin-4 antibody drug conjugate and an immunotherapeutic agent.

[0053] In some embodiments, in the pharmaceutical composition, the anti-nectin-4 antibody drug conjugate is present in a separately packaged form. In some embodiments, in the pharmaceutical composition, the anti-nectin-4 antibody drug conjugate and the immunotherapeutic agent are present in a separately packaged form.

[0054] In some embodiments, the tumor is a solid tumor. In some embodiments, the tumor is an advanced solid tumor.

[0055] In some embodiments, the tumor is urothelial carcinoma. In some embodiments, the tumor is advanced urothelial carcinoma. In some embodiments, the tumor is locally advanced or metastatic urothelial carcinoma. In some embodiments, the tumor is locally advanced unresectable or metastatic urothelial carcinoma.

[0056] 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 urothelial carcinoma. In some embodiments, the tumor is a Nectin-4 positive advanced urothelial carcinoma. In some embodiments, the tumor is a Nectin-4 positive locally advanced or metastatic urothelial carcinoma. In some embodiments, the tumor is a Nectin-4 positive locally advanced unresectable or metastatic urothelial carcinoma.

[0057] In some embodiments, the tumor is a urothelial carcinoma that is negative for Nectin-4 expression. In some embodiments, the tumor is an advanced urothelial carcinoma that is negative for Nectin-4 expression. In some embodiments, the tumor is a locally advanced or metastatic urothelial carcinoma that is negative for Nectin-4 expression. In some embodiments, the tumor is a locally advanced unresectable or metastatic urothelial carcinoma that is negative for Nectin-4 expression.

[0058] In some embodiments, the tumor has not been previously treated, or the tumor has failed or is intolerant to previous treatment.

[0059] In some embodiments, the tumor is advanced urothelial carcinoma and has not received systemic anti-tumor treatment for advanced urothelial carcinoma. In some embodiments, the tumor is locally advanced or metastatic urothelial carcinoma and has not received systemic anti-tumor treatment for locally advanced or metastatic urothelial carcinoma. In some embodiments, the tumor is locally advanced unresectable or metastatic urothelial carcinoma and has not received systemic anti-tumor treatment for locally advanced unresectable or metastatic urothelial carcinoma.

[0060] In some embodiments, the tumor is urothelial carcinoma that has failed or is intolerant to standard therapy, has no standard therapy, or has refused standard therapy. In some embodiments, the tumor is advanced urothelial carcinoma that has failed or is intolerant to standard therapy, has no standard therapy, or has refused standard therapy. In some embodiments, the tumor is locally advanced or metastatic urothelial carcinoma that has failed or is intolerant to standard therapy, has no standard therapy, or has refused standard therapy. In some embodiments, the tumor is locally advanced unresectable or metastatic urothelial carcinoma that has failed or is intolerant to standard therapy, has no standard therapy, or has refused standard therapy.

[0061] In some embodiments, the tumor is a urothelial carcinoma that has previously received first-line (1L), second-line (2L), third-line (3L), and / or fourth-line (4L) systemic anti-tumor therapy. In some embodiments, the tumor is an advanced urothelial carcinoma that has previously received first-line (1L), second-line (2L), third-line (3L), and / or fourth-line (4L) systemic anti-tumor therapy. In some embodiments, the tumor is a locally advanced or metastatic urothelial carcinoma that has previously received first-line (1L), second-line (2L), third-line (3L), and / or fourth-line (4L) systemic anti-tumor therapy. In some embodiments, the tumor is a locally advanced unresectable or metastatic urothelial carcinoma that has previously received first-line (1L), second-line (2L), third-line (3L), and / or fourth-line (4L) systemic anti-tumor therapy.

[0062] In some embodiments, the tumor is urothelial carcinoma that has previously received first-line (1L) systemic anti-cancer therapy. In some embodiments, the tumor is advanced urothelial carcinoma that has previously received first-line (1L) systemic anti-cancer therapy. In some embodiments, the tumor is locally advanced or metastatic urothelial carcinoma that has previously received first-line (1L) systemic anti-cancer therapy. In some embodiments, the tumor is locally advanced unresectable or metastatic urothelial carcinoma that has previously received first-line (1L) systemic anti-cancer therapy.

[0063] In some embodiments, the tumor is urothelial carcinoma that has previously received second-line (2L) systemic anti-cancer therapy. In some embodiments, the tumor is advanced urothelial carcinoma that has previously received second-line (2L) systemic anti-cancer therapy. In some embodiments, the tumor is locally advanced or metastatic urothelial carcinoma that has previously received second-line (2L) systemic anti-cancer therapy. In some embodiments, the tumor is locally advanced unresectable or metastatic urothelial carcinoma that has previously received second-line (2L) systemic anti-cancer therapy.

[0064] In some embodiments, the tumor is urothelial carcinoma that has previously received third-line (3L) systemic anti-cancer therapy. In some embodiments, the tumor is advanced urothelial carcinoma that has previously received third-line (3L) systemic anti-cancer therapy. In some embodiments, the tumor is locally advanced or metastatic urothelial carcinoma that has previously received third-line (3L) systemic anti-cancer therapy. In some embodiments, the tumor is locally advanced unresectable or metastatic urothelial carcinoma that has previously received third-line (3L) systemic anti-cancer therapy.

[0065] In some embodiments, the tumor is urothelial carcinoma that has previously received four lines (4L) of systemic anti-cancer therapy. In some embodiments, the tumor is advanced urothelial carcinoma that has previously received four lines (4L) of systemic anti-cancer therapy. In some embodiments, the tumor is locally advanced or metastatic urothelial carcinoma that has previously received four lines (4L) of systemic anti-cancer therapy. In some embodiments, the tumor is locally advanced unresectable or metastatic urothelial carcinoma that has previously received four lines (4L) of systemic anti-cancer therapy.

[0066] In some embodiments, the tumor is urothelial carcinoma with a previous line of systemic anti-tumor treatment of ≥1 line (≥1L), ≥2 lines (≥2L), ≥3 lines (≥3L) or ≥4 lines (≥4L). In some embodiments, the tumor is advanced urothelial carcinoma with a previous line of systemic anti-tumor treatment of ≥1 line (≥1L), ≥2 lines (≥2L), ≥3 lines (≥3L) or ≥4 lines (≥4L). In some embodiments, the tumor is locally advanced or metastatic urothelial carcinoma with a previous line of systemic anti-tumor treatment of ≥1 line (≥1L), ≥2 lines (≥2L), ≥3 lines (≥3L) or ≥4 lines (≥4L). In some embodiments, the tumor is locally advanced unresectable or metastatic urothelial carcinoma with a previous line of systemic anti-tumor treatment of ≥1 line (≥1L), ≥2 lines (≥2L), ≥3 lines (≥3L) or ≥4 lines (≥4L).

[0067] In some embodiments, the tumor is urothelial carcinoma that has received ≥1 line (≥1L) of previous systemic anti-tumor treatment. In some embodiments, the tumor is advanced urothelial carcinoma that has received ≥1 line (≥1L) of previous systemic anti-tumor treatment. In some embodiments, the tumor is locally advanced or metastatic urothelial carcinoma that has received ≥1 line (≥1L) of previous systemic anti-tumor treatment. In some embodiments, the tumor is locally advanced unresectable or metastatic urothelial carcinoma that has received ≥1 line (≥1L) of previous systemic anti-tumor treatment.

[0068] In some embodiments, the tumor is urothelial carcinoma that has received 1 line (1L) of systemic anti-cancer treatment. In some embodiments, the tumor is advanced urothelial carcinoma that has received 1 line (1L) of systemic anti-cancer treatment. In some embodiments, the tumor is locally advanced or metastatic urothelial carcinoma that has received 1 line (1L) of systemic anti-cancer treatment. In some embodiments, the tumor is locally advanced unresectable or metastatic urothelial carcinoma that has received 1 line (1L) of systemic anti-cancer treatment.

[0069] In some embodiments, the tumor is urothelial carcinoma with ≥2 lines (≥2L) of previous systemic anti-tumor treatment. In some embodiments, the tumor is advanced urothelial carcinoma with ≥2 lines (≥2L) of previous systemic anti-tumor treatment. In some embodiments, the tumor is locally advanced or metastatic urothelial carcinoma with ≥2 lines (≥2L) of previous systemic anti-tumor treatment. In some embodiments, the tumor is locally advanced unresectable or metastatic urothelial carcinoma with ≥2 lines (≥2L) of previous systemic anti-tumor treatment.

[0070] In some embodiments, the tumor is urothelial carcinoma that has received 2 lines (2L) of systemic anti-cancer treatment. In some embodiments, the tumor is advanced urothelial carcinoma that has received 2 lines (2L) of systemic anti-cancer treatment. In some embodiments, the tumor is locally advanced or metastatic urothelial carcinoma that has received 2 lines (2L) of systemic anti-cancer treatment. In some embodiments, the tumor is locally advanced unresectable or metastatic urothelial carcinoma that has received 2 lines (2L) of systemic anti-cancer treatment.

[0071] In some embodiments, the tumor is urothelial carcinoma that has received ≥3 lines (≥3L) of previous systemic anti-tumor treatment. In some embodiments, the tumor is advanced urothelial carcinoma that has received ≥3 lines (≥3L) of previous systemic anti-tumor treatment. In some embodiments, the tumor is locally advanced or metastatic urothelial carcinoma that has received ≥3 lines (≥3L) of previous systemic anti-tumor treatment. In some embodiments, the tumor is locally advanced unresectable or metastatic urothelial carcinoma that has received ≥3 lines (≥3L) of previous systemic anti-tumor treatment.

[0072] In some embodiments, the tumor is urothelial carcinoma that has received 3 lines (3L) of systemic anti-cancer treatment. In some embodiments, the tumor is advanced urothelial carcinoma that has received 3 lines (3L) of systemic anti-cancer treatment. In some embodiments, the tumor is locally advanced or metastatic urothelial carcinoma that has received 3 lines (3L) of systemic anti-cancer treatment. In some embodiments, the tumor is locally advanced unresectable or metastatic urothelial carcinoma that has received 3 lines (3L) of systemic anti-cancer treatment.

[0073] In some embodiments, the tumor is urothelial carcinoma that has received ≥4 lines of systemic anti-tumor treatment (≥4L). In some embodiments, the tumor is advanced urothelial carcinoma that has received ≥4 lines of systemic anti-tumor treatment (≥4L). In some embodiments, the tumor is locally advanced or metastatic urothelial carcinoma that has received ≥4 lines of systemic anti-tumor treatment (≥4L). In some embodiments, the tumor is locally advanced unresectable or metastatic urothelial carcinoma that has received ≥4 lines of systemic anti-tumor treatment (≥4L).

[0074] In some embodiments, the tumor is urothelial carcinoma that has received 4 lines of systemic anti-cancer treatment (4L). In some embodiments, the tumor is advanced urothelial carcinoma that has received 4 lines of systemic anti-cancer treatment (4L). In some embodiments, the tumor is locally advanced or metastatic urothelial carcinoma that has received 4 lines of systemic anti-cancer treatment (4L). In some embodiments, the tumor is locally advanced unresectable or metastatic urothelial carcinoma that has received 4 lines of systemic anti-cancer treatment (4L).

[0075] In some embodiments, the tumor is a urothelial carcinoma that has been previously treated with platinum-containing chemotherapy, immunotherapy, and / or antibody drug conjugate (ADC). In some embodiments, the tumor is an advanced urothelial carcinoma that has been previously treated with platinum-containing chemotherapy, immunotherapy, and / or antibody drug conjugate (ADC). In some embodiments, the tumor is a locally advanced or metastatic urothelial carcinoma that has been previously treated with platinum-containing chemotherapy, immunotherapy, and / or antibody drug conjugate (ADC). In some embodiments, the tumor is a locally advanced unresectable or metastatic urothelial carcinoma that has been previously treated with platinum-containing chemotherapy, immunotherapy, and / or antibody drug conjugate (ADC).

[0076] In some embodiments, the tumor is urothelial carcinoma that has been previously treated with an antibody drug conjugate (ADC). In some embodiments, the tumor is advanced urothelial carcinoma that has been previously treated with an antibody drug conjugate (ADC). In some embodiments, the tumor is locally advanced or metastatic urothelial carcinoma that has been previously treated with an antibody drug conjugate (ADC). In some embodiments, the tumor is locally advanced unresectable or metastatic urothelial carcinoma that has been treated with an antibody drug conjugate (ADC).

[0077] In some embodiments, the tumor is urothelial carcinoma that has been previously treated with an HRE2 antibody drug conjugate (ADC). In some embodiments, the tumor is advanced urothelial carcinoma that has been previously treated with an HRE2 antibody drug conjugate (ADC). In some embodiments, the tumor is locally advanced or metastatic urothelial carcinoma that has been previously treated with an HRE2 antibody drug conjugate (ADC). In some embodiments, the tumor is locally advanced unresectable or metastatic urothelial carcinoma that has been treated with an HRE2 antibody drug conjugate (ADC).

[0078] In some embodiments, the tumor is urothelial carcinoma that has been previously treated with platinum-containing chemotherapy and / or immunotherapy. In some embodiments, the tumor is advanced urothelial carcinoma that has been previously treated with platinum-containing chemotherapy and / or immunotherapy. In some embodiments, the tumor is locally advanced or metastatic urothelial carcinoma that has been previously treated with platinum-containing chemotherapy and / or immunotherapy. In some embodiments, the tumor is locally advanced unresectable or metastatic urothelial carcinoma that has been previously treated with platinum-containing chemotherapy and / or immunotherapy.

[0079] In some embodiments, the tumor is urothelial carcinoma that has been previously treated with platinum-containing chemotherapy and / or immune checkpoint inhibitors. In some embodiments, the tumor is advanced urothelial carcinoma that has been previously treated with platinum-containing chemotherapy and / or immune checkpoint inhibitors. In some embodiments, the tumor is locally advanced or metastatic urothelial carcinoma that has been previously treated with platinum-containing chemotherapy and / or immune checkpoint inhibitors. In some embodiments, the tumor is locally advanced unresectable or metastatic urothelial carcinoma that has been previously treated with platinum-containing chemotherapy and / or immune checkpoint inhibitors.

[0080] In some embodiments, the tumor is urothelial carcinoma that has been previously treated with platinum-containing chemotherapy and / or PD-(L)1 inhibitors. In some embodiments, the tumor is advanced urothelial carcinoma that has been previously treated with platinum-containing chemotherapy and / or PD-(L)1 inhibitors. In some embodiments, the tumor is locally advanced or metastatic urothelial carcinoma that has been previously treated with platinum-containing chemotherapy and / or PD-(L)1 inhibitors. In some embodiments, the tumor is locally advanced unresectable or metastatic urothelial carcinoma that has been previously treated with platinum-containing chemotherapy and / or PD-(L)1 inhibitors.

[0081] In some embodiments, the tumor is urothelial carcinoma that has been previously treated with platinum-containing chemotherapy. In some embodiments, the tumor is advanced urothelial carcinoma that has been previously treated with platinum-containing chemotherapy. In some embodiments, the tumor is locally advanced or metastatic urothelial carcinoma that has been previously treated with platinum-containing chemotherapy. In some embodiments, the tumor is locally advanced unresectable or metastatic urothelial carcinoma that has been previously treated with platinum-containing chemotherapy.

[0082] In some embodiments, the tumor is urothelial carcinoma that has been previously treated with one line of systemic anti-cancer therapy and platinum-containing chemotherapy. In some embodiments, the tumor is advanced urothelial carcinoma that has been previously treated with one line of systemic anti-cancer therapy and platinum-containing chemotherapy. In some embodiments, the tumor is locally advanced or metastatic urothelial carcinoma that has been previously treated with one line of systemic anti-cancer therapy and platinum-containing chemotherapy. In some embodiments, the tumor is locally advanced unresectable or metastatic urothelial carcinoma that has been previously treated with one line of systemic anti-cancer therapy and platinum-containing chemotherapy.

[0083] In some embodiments, the tumor is urothelial carcinoma that has been previously treated with platinum-containing chemotherapy and a PD-(L)1 inhibitor. In some embodiments, the tumor is advanced urothelial carcinoma that has been previously treated with platinum-containing chemotherapy and a PD-(L)1 inhibitor. In some embodiments, the tumor is locally advanced or metastatic urothelial carcinoma that has been previously treated with platinum-containing chemotherapy and a PD-(L)1 inhibitor. In some embodiments, the tumor is locally advanced unresectable or metastatic urothelial carcinoma that has been previously treated with platinum-containing chemotherapy and a PD-(L)1 inhibitor.

[0084] In some embodiments, the tumor is bladder cancer. In some embodiments, the tumor is muscle-invasive bladder cancer. In some embodiments, the tumor is non-metastatic bladder cancer. In some embodiments, the tumor is non-metastatic muscle-invasive bladder cancer.

[0085] In some embodiments, the tumor is urothelial carcinoma of the bladder. In some embodiments, the tumor is muscle-invasive urothelial carcinoma of the bladder. In some embodiments, the tumor is non-metastatic urothelial carcinoma of the bladder. In some embodiments, the tumor is non-metastatic muscle-invasive urothelial carcinoma of the bladder.

[0086] In some embodiments, the tumor is a bladder cancer that is amenable to surgery. In some embodiments, the tumor is a bladder urothelial carcinoma that is amenable to surgery. In some embodiments, the tumor is a muscle-invasive bladder urothelial carcinoma that is amenable to surgery. In some embodiments, the tumor is a non-metastatic muscle-invasive bladder urothelial carcinoma that is amenable to surgery.

[0087] In some embodiments, the surgical treatment is radical cystectomy (RC) and pelvic lymph node dissection (PLND).

[0088] In some embodiments, the tumor is bladder cancer with a TNM stage combination of (T2-T4a)N0M0 or (T1-T4a)N1M0. In some embodiments, the tumor is bladder urothelial carcinoma with a TNM stage combination of (T2-T4a)N0M0 or (T1-T4a)N1M0. In some embodiments, the tumor is muscle-invasive bladder urothelial carcinoma with a TNM stage combination of (T2-T4a)N0M0 or (T1-T4a)N1M0. In some embodiments, the tumor is non-metastatic muscle-invasive bladder urothelial carcinoma with a TNM stage combination of (T2-T4a)N0M0 or (T1-T4a)N1M0.

[0089] In the present disclosure, standard treatment, systemic anti-tumor treatment (including first-line treatment, second-line treatment, third-line treatment, fourth-line treatment) refers to treatment regimens for urothelial carcinoma (including advanced urothelial carcinoma, locally advanced or metastatic urothelial carcinoma, locally advanced unresectable or metastatic urothelial carcinoma) well known to those skilled in the art. For example, treatment regimens disclosed in treatment guidelines approved by regulatory authorities. For example, detailed and up-to-date information on standard treatment regimens for various cancers and systemic anti-tumor treatment regimens (including first-line treatment, second-line treatment, third-line treatment, and fourth-line treatment) provided in the NCCN guidelines and CSCO guidelines is included but is not limited to.

[0090] In some embodiments, the anti-nectin-4 antibody-drug conjugate provided by the present disclosure is used to treat patients with advanced urothelial carcinoma who have received ≥1 line of previous systemic anti-tumor treatment, and can significantly improve the patient's tumor objective response rate and progression-free production time, particularly at a dosage of 6 mg / kg, it can achieve a cORR of 41.9% and an mPFS of 5.8 months. At a dosage of 8 mg / kg, it can achieve a cORR of 50% and an mPFS of 5.8 months. Compared with other ADC drugs with the same target and other standard treatment options, it has significant therapeutic advantages and provides a positive and effective clinical treatment option for patients with advanced urothelial carcinoma.

[0091] In some embodiments, the anti-nectin-4 antibody drug conjugate provided by the present disclosure is used to treat patients with advanced urothelial carcinoma who have been treated with an antibody drug conjugate (ADC) before (patients who have previously received antibody drug conjugate treatment and have received ≥1 line of systemic anti-tumor treatment), and can significantly improve the patient's tumor objective response rate, particularly at a dosage of 6 mg / kg, achieving a cORR of 54.5%, and at a dosage of 8 mg / kg, achieving a cORR of 42.9%, providing a positive and effective clinical treatment plan for patients with advanced urothelial carcinoma who have been treated with an ADC before.

[0092] In some embodiments, the anti-nectin-4 antibody drug conjugates provided herein were administered to subjects, and 44.4% of all subjects experienced Grade ≥3 TRAEs, of which the incidence rates of Grade ≥3 TRAEs were 38.7% and 65.6% in the 6 mg / kg and 8 mg / kg dose groups, respectively, demonstrating a tolerable and controllable clinical safety profile.

[0093] In some embodiments, the anti-nectin-4 antibody-drug conjugate provided herein is combined with an immunotherapy agent for the treatment of patients with advanced urothelial carcinoma who have failed standard treatment (patients who have received ≥1 line of previous systemic anti-tumor treatment), and can significantly improve the patient's tumor objective response rate. In the 6 mg / kg dose group, the uORR can reach 50.0%, and at a dose of 8 mg / kg, the disease control rate (DCR) can reach 90.9%. Compared with the anti-nectin-4 antibody-drug conjugate of the present disclosure alone, it has therapeutic advantages and provides a positive and effective clinical treatment plan for patients with advanced urothelial carcinoma who have failed standard treatment.

[0094] In some embodiments, the anti-nectin-4 antibody-drug conjugate provided herein is combined with an immunotherapeutic agent for the treatment of patients with advanced urothelial carcinoma who have failed standard treatment and have received prior immunotherapy (ICI). The uORR can reach 46.2% in the 6 mg / kg dose group, providing an active and effective clinical treatment option for patients with advanced urothelial carcinoma who have failed standard treatment and have previously received immunotherapy (ICI).

[0095] In some embodiments, the anti-nectin-4 antibody-drug conjugate provided herein is combined with an immunotherapeutic agent for the treatment of patients with advanced urothelial carcinoma who have failed standard treatment and have not received immunotherapy (ICI). The uORR can reach 52.6% in the 6 mg / kg dose group, providing an active and effective clinical treatment option for patients with advanced urothelial carcinoma who have failed standard treatment and have not received immunotherapy (ICI) before.

[0096] In some embodiments, the anti-nectin-4 antibody-drug conjugate provided herein is combined with an immunotherapy agent for the treatment of patients with advanced urothelial carcinoma who have not previously received systemic anti-tumor treatment. The uORR can reach 47.2% in the 8 mg / kg dose group, and the disease control rate (DCR) is 94.4%. Compared with other ADC drugs with the same target and other standard treatment options, it has therapeutic advantages and provides an active and effective clinical treatment option for patients with advanced urothelial carcinoma who have never been treated.

[0097] In some embodiments, the anti-nectin-4 antibody-drug conjugate provided herein is administered to subjects in combination with an immunotherapy agent. The incidence of grade ≥3 TRAEs in all subjects (6 mg / kg and 8 mg / kg dose groups) is 40% (Ib 6 mg / kg: 41%, Ib 8 mg / kg: 41%, Phase II 8 mg / kg: 39%). Even in the higher dose 8 mg / kg dose group, the incidence of grade ≥3 TRAEs in previously treated patients with advanced urothelial carcinoma (≥1 line of previous systemic anti-tumor treatment) is 41%, and the incidence of grade ≥3 TRAEs in treatment-naive patients with advanced urothelial carcinoma (no previous systemic anti-tumor treatment) is 39%. Compared with the anti-nectin-4 antibody-drug conjugate monotherapy in the present disclosure, the combination therapy does not significantly increase drug toxicity, and this combination regimen has a significant safety advantage.

[0098] Immunotherapeutic agents

[0099] In some embodiments, the immunotherapeutic agent comprises either one or a combination of anti-PD-L1 antibody and anti-CTLA-4 antibody.

[0100] In some embodiments, the immunotherapeutic agent includes any of the following: 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.

[0101] <Anti-PD-L1 Antibody>

[0102] 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 shown in SEQ ID NOs: 11-13, and the light chain variable region comprises LCDR1, LCDR2, and LCDR3 as shown in SEQ ID NOs: 14-16.

[0103] The CDR sequences mentioned above are shown in Table 1 below:

[0104] Table 1. CDR sequences of anti-PD-L1 antibodies (Kabat scheme)

[0105] In some embodiments, the anti-PD-L1 antibody comprises any one of the aforementioned HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3, or a combination of any two, three, four, five, or six of them.

[0106] 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 of the amino acid sequence set forth in SEQ ID NO: 17, and the VL comprises LCDR1, LCDR2, and LCDR3 of the amino acid sequence set forth in SEQ ID NO: 18. The above CDRs are defined according to the Kabat, IMGT, Chothia, AbM, or Contact definitions. In some specific embodiments, the CDRs are defined according to the Kabat definition.

[0107] In some embodiments, the anti-PD-L1 antibody is a chimeric, humanized, fully human antibody or an antigen-binding fragment thereof.

[0108] 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 shown in SEQ ID NO: 17, or at least 80%, 90% identical thereto, and the VL comprises an amino acid sequence as shown in SEQ ID NO: 18, or at least 80%, 90% identical thereto.

[0109] Heavy chain variable region:

[0110] Light chain variable region:

[0111] Note: The underlined part is the CDR region determined according to the Kabat numbering convention.

[0112] In some embodiments, the anti-PD-L1 antibody comprises any one or both of the aforementioned VH and VL.

[0113] 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 regions of human IgG1, 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 into which F234A and L235A mutations have been introduced. In some embodiments, the light chain constant region can be selected from the light chain constant region of human κ, λ chains, or variants thereof.

[0114] In some embodiments, the anti-PD-L1 antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises an amino acid sequence as shown in SEQ ID NO: 19, or at least 80%, at least 90% identical thereto; and / or the light chain comprises an amino acid sequence as shown in SEQ ID NO: 20, or at least 80%, at least 90% identical thereto.

[0115] In some embodiments, the anti-PD-L1 antibody comprises a heavy chain having an amino acid sequence as shown in SEQ ID NO: 19, and a light chain having an amino acid sequence as shown in SEQ ID NO: 20.

[0116] Heavy chain sequence of anti-PD-L1 antibody:

[0117] Light chain sequence of anti-PD-L1 antibody:

[0118] Note: The underlined portion is the variable region sequence of the antibody heavy chain or light chain, and the ununderlined portion is the antibody constant region sequence.

[0119] In some embodiments, the preparation of the above-mentioned anti-PD-L1 antibodies or antigen-binding fragments thereof can refer to WO2017084495A1 and WO2018210230A1. The present disclosure incorporates the relevant contents of the antibody sequences, preparation methods, and compositions in WO2017084495A1 and WO2018210230A1 into the present disclosure by reference.

[0120] 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 therebetween.

[0121] In some embodiments, the dosage of the anti-PD-L1 antibody can be 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 range therebetween.

[0122] In some embodiments, the anti-PD-L1 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. g, 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 ranges therebetween.

[0123] In some embodiments, the anti-PD-L1 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, 800mg, 850mg, 900mg, 950mg, 1000mg, 1050mg, 1100mg, 1150mg, 1200mg, 1250mg, 1300mg, 1350mg, 1400mg, 1450mg, 1500mg, 1550mg, 1600mg, 1650mg, 1700mg, 1750mg, 1800mg, 1850mg, 1900mg, 195 0mg, 2000mg, 2050mg, 2100mg, 2150mg, 2200mg, 2250mg, 2300mg, 2350mg, 2400mg, 2450mg, 2500mg , 2550mg, 2600mg, 2650mg, 2700mg, 2750mg, 2800mg, 2850mg, 2900mg, 2950mg, 3000mg, 3050mg, 31 3900 mg, 3950 mg, 4000 mg, 4500 mg, or 5000 mg; and any range therebetween.

[0124] In some embodiments, the anti-PD-L1 antibody is administered at a dose of about 1200 mg.

[0125] In some embodiments, the anti-PD-L1 antibody is administered 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 anti-PD-L1 antibody is administered once every 3 weeks.

[0126] In some embodiments, the anti-PD-L1 antibody is administered at a dose of about 1200 mg, and the administration frequency is once every 3 weeks.

[0127] In some embodiments, the anti-PD-L1 antibody is administered orally, parenterally, or transdermally; parenteral administration includes, but is not limited to, intravenous injection, subcutaneous injection, and intramuscular injection. In some embodiments, the anti-PD-L1 antibody is administered by intravenous injection.

[0128] <Anti-CTLA-4 Antibody>

[0129] 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.

[0130] The CDR sequences mentioned above are shown in Table 2 below:

[0131] Table 2. CDR sequences of anti-CTLA-4 antibodies

[0132] In some embodiments, the anti-CTLA-4 antibody comprises any one of the aforementioned HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3, or a combination of any two, three, four, five, or six of them.

[0133] In some embodiments, an 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 of the amino acid sequence set forth in SEQ ID NO: 27, and the VL comprises LCDR1, LCDR2, and LCDR3 of the amino acid sequence set forth in SEQ ID NO: 28. The CDRs are defined according to the Kabat, IMGT, Chothia, AbM, or Contact definitions. In specific embodiments, the CDRs are defined according to the Kabat definition.

[0134] In some embodiments, the anti-CTLA-4 antibody is a chimeric, humanized, fully human antibody or an antigen-binding fragment thereof.

[0135] 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 set forth in SEQ ID NO: 27, or at least 80%, 90% identical thereto, and the VL comprises an amino acid sequence as set forth in SEQ ID NO: 28, or at least 80%, 90% identical thereto.

[0136] Heavy chain variable region:

[0137] Light chain variable region:

[0138] In some embodiments, the anti-CTLA-4 antibody comprises any one or both of the aforementioned VH and VL.

[0139] In some embodiments, the anti-CTLA-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 regions of human IgG1, IgG2, IgG3, IgG4, and variants thereof. In some embodiments, the light chain constant region can be selected from the light chain constant regions of human κ, λ chains, or variants thereof.

[0140] In some embodiments, an anti-CTLA-4 antibody comprises a heavy chain comprising an amino acid sequence as set forth in SEQ ID NO:29, or at least 80%, at least 90% identical thereto; and / or a light chain comprising an amino acid sequence as set forth in SEQ ID NO:30, or at least 80%, at least 90% identical thereto.

[0141] In some embodiments, the anti-CTLA-4 antibody comprises a heavy chain having an amino acid sequence as shown in SEQ ID NO:29, and a light chain having an amino acid sequence as shown in SEQ ID NO:30.

[0142] Heavy chain sequence of anti-CTLA-4 antibody:

[0143] Light chain sequence of anti-CTLA-4 antibody:

[0144] Note: The underlined portion is the variable region sequence of the antibody heavy chain or light chain, and the ununderlined portion is the antibody constant region sequence.

[0145] 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 therebetween.

[0146] In some embodiments, the anti-CTLA-4 antibody is administered at a dosage 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, From about 1 mg / kg to about 50 mg / kg, from about 1 mg / kg to about 20 mg / kg, from about 1 mg / kg to about 10 mg / kg, from about 1 mg / kg to about 9 mg / kg, from about 1 mg / kg to about 8 mg / kg, from about 1 mg / kg to about 7 mg / kg, from about 1 mg / kg to about 6 mg / kg, from about 1 mg / kg to about 5 mg / kg, from about 2 mg / kg to about 10 mg / kg, from about 2 mg / kg to about 9 mg / kg, from about 2 mg / kg to about 8 mg / kg, from about 2 mg / kg to about 7 mg / kg, from about 2 mg / kg to about 6 mg / kg, from about 2 mg / kg to about 5 mg / kg, from about 3 mg / kg to about 10 mg / kg, from about 3 mg / kg to about 9 mg / kg, from about 3 mg / kg to about 8 mg / kg, from about 3 mg / kg to about 7 mg / kg, from about 3 mg / kg to about 6 mg / kg, from about 3 mg / kg to about 5 mg / kg, or any range therebetween.

[0147] In some embodiments, the anti-CTLA-4 antibody is administered at a dose of 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, about 2. 3mg / kg, about 2.4mg / kg, about 2.5mg / kg, about 2.6mg / kg, about 2.7mg / kg, about 2.8mg / kg, about 2.9mg / kg, about 3.0mg / kg, about 3.1mg / kg, about 3.2mg / kg, about 3.3mg / kg, about 3.4mg / kg, about 3.5mg / kg, about 3.6mg / kg, about 3.7mg / kg, about 3.8mg / kg, about 3.9mg / kg, about 4.0mg / kg, about 4.1mg / kg, about 4.2mg / kg, about 4.3mg / kg, about 4.4mg / kg, about 4.5mg / kg, about 4.6mg / kg, about 4.7mg / kg, about 4. 8mg / kg, about 4.9mg / kg, about 5.0mg / kg, about 5.1mg / kg, about 5.2mg / kg, about 5.3mg / kg, about 5.4mg / kg, about 5.5mg / kg, about 5.6mg / kg, about 5.7mg / kg, about 5.8mg / kg, about 5.9mg / kg, about 6.0mg / kg, about 6.1mg / kg, about 6.2mg / kg, about 6.3mg / kg, about 6.4mg / kg, about 6.5mg / kg, about 6.6mg / kg, about 6.7mg / kg, about 6.8mg / kg, about 6.9mg / kg, about 7.0mg / kg, about 7.1mg / kg, about 7.2mg / kg, about 7. 3mg / kg, about 7.4mg / kg, about 7.5mg / kg, about 7.6mg / kg, about 7.7mg / kg, about 7.8mg / kg, about 7.9mg / kg, about 8.0mg / kg, about 8.1mg / kg, about 8.2mg / kg, about 8.3mg / kg, about 8.4mg / kg, about 8.5mg / kg, about 8.6mg / kg, about 8.7mg / kg, about 8.8mg / kg, about 8.9mg / kg, about 9.0mg / kg, about 9.1mg / kg, about 9.2mg / kg, about 9.3mg / kg, about 9.4mg / kg, about 9.5mg / kg, about 9.6mg / kg, about 9.7mg / kg, about 9.8mg / kg, about 9.9mg / kg, about 10.0mg / kg, about 10.5mg / kg, about 11mg / kg, about 11.5mg / kg, about 12mg / kg, about 12.5mg / kg, about 13mg / kg, about 13.5mg / kg, about 14mg / kg, about 14.5mg / kg, about 15mg / kg, about 15mg / kg, about 16mg / kg, about 17mg / kg, about 18mg / 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 ​​therebetween.

[0148] In some embodiments, the dosing amount of the anti-CTLA-4 antibody is 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, 13.5mg / kg, 14mg / kg, 14.5mg / kg, 15mg / kg, 15mg / kg, 16mg / kg, 17mg / kg, 18mg / kg, 19mg / kg, 20mg / kg, 21mg / kg, 22mg / kg, 23mg / kg, 24mg / kg, 25mg / kg, 26mg / kg, 27mg / kg, 28mg / kg, 29mg / kg, 30mg / kg, 35mg / kg, 40mg / kg, 45mg / kg, 50mg / kg, 100mg / kg, or any range of values ​​between these points.

[0149] In some embodiments, the anti-CTLA-4 antibody is administered at a dose of about 4.0 mg / kg.

[0150] In some embodiments, the anti-CTLA-4 antibody may be administered at a dosage of about 1-1000 mg, about 1-800 mg, about 1-700 mg, about 1-600 mg, about 1-500 mg, about 5-500 mg, about 10-500 mg, about 20-500 mg, about 30-500 mg, about 40-500 mg, about 50-500 mg, about 60-500 mg, about 10-400 mg, about 20-400 mg, about 30-400 mg, about 40-400 mg, about 50-400 mg, about 60-400 mg, about 10-350 mg, about 20-350 mg, about 30-350 mg, about 40-3 30-100 mg, about 40-100 mg, about 50-100 mg, about 60-100 mg, about 60-100 mg, about 10-150 mg, about 20-150 mg, about 30-150 mg, about 40-150 mg, about 50-150 mg, about 60-150 mg, about 10-100 mg, about 20-100 mg, about 30-100 mg, about 40-100 mg, about 50-100 mg, about 60-100 mg, about 60-90 mg, about 60-80 mg, or any range between these point values.

[0151] 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 51mg, about 52mg, about 53mg, about 54mg, about 55mg, about 56mg, about 57mg, about 58mg, about 59mg, about 60mg, about 61mg, about 62mg, about 63mg, about 64mg, about 65mg, about 66mg, about 67mg, about 68mg, about 69mg, about 70mg, about 71mg, about 72mg, about 73mg, about 74mg, about 75mg, about 76mg, about 77mg, about 78mg, about 79mg, about 80mg, about 81mg, about 8 2mg, about 83mg, about 84mg, about 85mg, about 86mg, about 87mg, about 88mg, about 89mg, about 90mg, about 91mg, about 92mg, about 93mg, about 94mg, about 95mg, about 96mg, about 97mg, about 98mg, about 99mg, about 100mg, about 110mg, about 120mg, about 130mg, about 140mg, about 150mg, about 160mg, about 180mg, about 200mg, about 210mg, about 220mg, about 230 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 therebetween, or any range therebetween.

[0152] 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, 51mg, 52mg, 53mg, 54mg, 55mg, 56mg, 57mg, 58mg, 59mg, 60mg, 61mg, 62mg, 63mg, 64mg, 65mg, 66mg , 67mg, 68mg, 69mg, 70mg, 71mg, 72mg, 73mg, 74mg, 75mg, 76mg, 77mg, 78mg, 79mg, 80mg, 81mg, 82mg , 83mg, 84mg, 85mg, 86mg, 87mg, 88mg, 89mg, 90mg, 91mg, 92mg, 93mg, 94mg, 95mg, 96mg, 97mg, 98m g, 99mg, 100mg, 110mg, 120mg, 130mg, 140mg, 150mg, 160mg, 180mg, 200mg, 210mg, 220mg, 230mg, 2 40mg, 250mg, 260mg, 270mg, 280mg, 290mg, 300mg, 310mg, 320mg, 330mg, 340mg, 350mg, 360mg, 370mg, 380mg, 390mg, 400mg, 450mg, 500mg, 600mg, 700mg, 800mg, 900mg, 1000mg, or any range between these point values.

[0153] In some embodiments, the anti-CTLA-4 antibody is administered at a dose of about 70 mg.

[0154] In some embodiments, the anti-CTLA-4 antibody is administered at a dose of about 280 mg or 210 mg.

[0155] In some embodiments, the anti-CTLA-4 antibody is administered 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 a single administration. In some embodiments, the anti-CTLA-4 antibody is administered once every 12 weeks.

[0156] In some embodiments, the anti-CTLA-4 antibody is administered once every 6 weeks or as a single dose. In some embodiments, the anti-CTLA-4 antibody is administered as a single dose in week 1 at a dose of about 280 mg, is not administered from week 2 to week 12, and is administered at a dose of about 70 mg starting from week 13 at a frequency of once every 6 weeks.

[0157] In some embodiments, with 21 days as one cycle, a single dose of 280 mg or 210 mg is administered on Day 1 of Cycle 1, no administration is given in Cycles 2-4, and starting from Day 1 of Cycle 5, the dose is administered at a frequency of 70 mg once every 6 weeks (C1D1 280 mg or 210 mg is administered once, no administration is given in C2-C4, and 70 mg Q6W in C5 and subsequent cycles).

[0158] In some embodiments, the anti-CTLA-4 antibody is administered orally, parenterally, or transdermally; parenteral administration includes, but is not limited to, intravenous injection, subcutaneous injection, and intramuscular injection. In some embodiments, the anti-CTLA-4 antibody is administered by intravenous injection.

[0159] <Anti-Nectin-4 Antibody Drug Conjugate>

[0160] In some embodiments, the anti-nectin-4 antibody drug conjugate is derived from an antibody drug conjugate of any structure in WO2022228406A and WO2023221971A. The present disclosure incorporates the structures, preparation methods, and other related contents of the immunoconjugates in the above patents into the present disclosure by reference.

[0161] In some embodiments, the anti-nectin-4 antibody drug conjugate has a structure as shown in the following formula:

[0162] wherein n is 1 to 10, and 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 values. In some embodiments, n is an integer or decimal from 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.

[0163] In some embodiments, the anti-nectin-4 antibody is derived from any type of anti-nectin-4 antibody or antigen-binding fragment thereof in WO2022228406A. The present disclosure incorporates the antibody sequences, preparation methods and other related contents in the above patents into the present disclosure by reference.

[0164] 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 NOs: 1-3, and the light chain variable region comprises LCDR1, LCDR2, and LCDR3 as shown in SEQ ID NOs: 4-6.

[0165] The CDR sequences mentioned above are shown in Table 3 below:

[0166] Table 3. CDR sequences of anti-nectin-4 antibodies (Kabat scheme)

[0167] In some embodiments, the anti-nectin-4 antibody comprises any one of the aforementioned HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3, or a combination of any two, three, four, five, or six of them.

[0168] 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 of the amino acid sequence set forth in SEQ ID NO: 7, and the VL comprises LCDR1, LCDR2, and LCDR3 of the amino acid sequence set forth in SEQ ID NO: 8. The CDRs are defined according to the Kabat, IMGT, Chothia, AbM, or Contact definitions. In some specific embodiments, the CDRs are defined according to the Kabat definition.

[0169] In some embodiments, the anti-nectin-4 antibody is a chimeric, humanized, fully human antibody or an antigen-binding fragment thereof.

[0170] 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 as shown in SEQ ID NO: 7, or at least 80%, 90% identical thereto, and the VL comprises an amino acid sequence as shown in SEQ ID NO: 8, or at least 80%, 90% identical thereto.

[0171] Heavy chain variable region:

[0172] Light chain variable region:

[0173] In some embodiments, the anti-nectin-4 antibody comprises any one or both of the aforementioned VH and VL.

[0174] 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 regions of human IgG1, IgG2, IgG3, IgG4, and variants thereof. In some embodiments, the light chain constant region can be selected from the light chain constant regions of human κ, λ, or variants thereof.

[0175] In some embodiments, the anti-nectin-4 antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises an amino acid sequence as shown in SEQ ID NO:9, or a sequence having at least 80%, at least 90% sequence identity thereto; and / or the light chain comprises an amino acid sequence as shown in SEQ ID NO:10, or a sequence having at least 80%, at least 90% sequence identity thereto.

[0176] In some embodiments, the anti-nectin-4 antibody comprises a heavy chain having an amino acid sequence as shown in SEQ ID NO:9, and a light chain having an amino acid sequence as shown in SEQ ID NO:10.

[0177] Heavy chain sequence of anti-nectin-4 antibody:

[0178] Light chain sequence of anti-nectin-4 antibody:

[0179] Note: The underlined portion is the variable region sequence of the antibody heavy chain or light chain, and the ununderlined portion is the antibody constant region sequence.

[0180] 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 therebetween.

[0181] In the context of this disclosure, "antibody" is used in the broadest sense to encompass 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 referred to 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

[0182] In some embodiments, the anti-nectin-4 antibody drug conjugate is prepared as described in Example 1.

[0183] In some embodiments, the dosage of the anti-nectin-4 antibody drug conjugate can be selected from 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 16 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 g, 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 6.0 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 g / 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 therebetween.

[0184] 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. 1mg / kg, about 3.2mg / kg, about 3.4mg / kg, about 3.5mg / kg, about 3.6mg / kg, about 3.7mg / kg, about 3.8mg / kg, about 3.9mg / kg, about 4.0mg / kg, about 4.1mg / kg, about 4.2mg / kg, about 4.3mg / kg, about 4.4mg / kg, about 4.5mg / kg, about 4.6mg / kg, about 4.7mg / kg, about 4.8mg / kg, about 4.9mg / kg, about 5.0mg / kg, about 5.1mg / kg, about 5.2mg / kg, about 5.3mg / kg, about 5.4mg / kg, about 5.5mg / kg, about 5.6mg / kg, about 5.7mg / kg, about 5.8mg / kg, about 5.9mg / kg, about 6.0mg / kg, about 6.1mg / kg, about 6.2mg / kg, about 6.3mg / kg, about 6.4mg / kg, about 6.5mg / kg, about 6.6mg / kg, about 6.7mg / kg, about 6.8mg / kg, about 6.9mg / kg, about 7.0mg / kg, about 7.1mg / kg, about 7.2mg / kg, about 7.3mg / kg, about 7.4mg / kg, about 7.5mg / kg, about 7.6mg / kg, about 7.7mg / kg, about 7.8mg / kg, about 7.9mg / kg, about 8.0mg / kg, about 8.1mg / 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 therebetween.

[0185] 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, 3.3 mg / kg, 3.4 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, 4.9 mg / kg, 4.1 mg / kg, 4.3 mg / kg, 4.4 mg / kg, 4.5 mg / kg, 4.6 mg / kg, 4.7 mg / kg, 4.8 mg / kg, 4.9 mg / kg, 5.1 mg / kg, 5. .4mg / kg, 3.5mg / kg, 3.6mg / kg, 3.7mg / kg, 3.8mg / kg, 3.9mg / kg, 4.0mg / kg, 4.1mg / kg, 4.2mg / kg, 4.3mg / kg, 4.4mg / kg, 4.5mg / kg, 4.6mg / kg, 4.7mg / kg, 4.8mg / kg, 4.9mg / kg, 5.0mg / kg, 5.1mg / kg, 5.2mg / kg, 5.3mg / kg, 5.4mg / kg, 5.5mg / kg, 5.6mg / kg, 5.7mg / kg, 5.8mg / kg, 5.9mg / kg, 6.0mg / kg, 6 .1mg / kg, 6.2mg / kg, 6.3mg / kg, 6.4mg / kg, 6.5mg / kg, 6.6mg / kg, 6.7mg / kg, 6.8mg / kg, 6.9mg / kg, 7.0mg / kg, 7.1mg / kg, 7.2mg / kg, 7.3mg / kg, 7.4mg / kg, 7.5mg / kg, 7.6mg / kg, 7.7mg / kg, 7.8mg / kg, 7.9mg / kg, 8.0mg / kg, 8.1mg / kg, 8.2mg / kg, 8.3mg / kg, 8.4mg / kg, 8.5mg / kg, 8.6mg / kg, 8.7mg / kg, 8.8mg / kg, 8.9mg / kg, 9.0mg / kg, 9.1mg / kg, 9.2mg / kg, 9.3mg / kg, 9.4mg / kg, 9.5mg / kg, 9.6mg / kg, 9.7mg / kg, 9.8mg / kg, 9.9mg / kg, 10.0mg / kg, 10.5mg / kg, 11mg / kg, 12mg / kg, 12.5mg / kg, 13mg / kg, 13.5mg / kg, 14mg / kg, 15mg / kg, 16mg / kg, 18mg / kg, 19mg / kg, 20mg / kg, 50mg / kg, or any range therebetween.

[0186] In some embodiments, the anti-nectin-4 antibody drug conjugate is administered 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. In some embodiments, the anti-nectin-4 antibody drug conjugate is administered 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. In some embodiments, the anti-nectin-4 antibody drug conjugate is administered once every 3 weeks or twice every 3 weeks.

[0187] In some embodiments, the dosage 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 dosage is once every 3 weeks. In some embodiments, the dosage of the anti-nectin-4 antibody drug conjugate is about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, or about 4 mg / kg, and the dosage is twice every 3 weeks. In some embodiments, the dosage of the anti-nectin-4 antibody drug conjugate is about 4 mg / kg, and the dosage is twice every 3 weeks. In some embodiments, the dosage of the anti-nectin-4 antibody drug conjugate is about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, or about 4 mg / kg, and the dosage is twice every 3 weeks, and is administered on days D1 and D8 of each cycle. In some embodiments, the dosage of the anti-nectin-4 antibody drug conjugate is about 4 mg / kg, and the frequency of administration is twice every 3 weeks, and the administration is done on days D1 and D8 of each cycle. In some embodiments, the dosage of the anti-nectin-4 antibody drug conjugate is about 6 mg / kg or about 8 mg / kg, and the frequency of administration is once every 3 weeks.

[0188] In some embodiments, the anti-nectin-4 antibody drug conjugate is administered orally, parenterally, or transdermally; parenteral administration includes, but is not limited to, intravenous injection, subcutaneous injection, and intramuscular injection. In some specific embodiments, the anti-nectin-4 antibody drug conjugate is administered by intravenous injection.

[0189] In some embodiments, the anti-nectin-4 antibody drug conjugate is configured in an injectable form. Exemplarily, the injectable form of the anti-nectin-4 antibody drug conjugate is an injection or a lyophilized powder injection, which comprises the anti-nectin-4 antibody drug conjugate and one or more pharmaceutically acceptable excipients. In some embodiments, the anti-nectin-4 antibody drug conjugate is formulated as any composition selected from WO2023221971A.

[0190] Dosage regimen

[0191] In some embodiments, any of the foregoing uses, methods, or compositions is selected from the group consisting of:

[0192] (1) Anti-nectin-4 antibody drug conjugate monotherapy,

[0193] (2) Anti-nectin-4 antibody drug conjugates combined with anti-PD-L1 antibodies,

[0194] (3) first administer the anti-nectin-4 antibody drug conjugate and anti-PD-L1 antibody in combination, and then administer the anti-PD-L1 antibody alone;

[0195] (4) Anti-nectin-4 antibody drug conjugates combined with anti-CTLA-4 antibodies,

[0196] (5) Anti-nectin-4 antibody-drug conjugates are administered in combination with anti-PD-L1 antibodies and anti-CTLA-4 antibodies.

[0197] In some embodiments, the anti-nectin-4 antibody drug conjugate is administered as a single agent in a regimen of:

[0198] a) the anti-nectin-4 antibody drug conjugate is administered at a dose of 0.1-50 mg / kg at 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;

[0199] a) the anti-nectin-4 antibody drug conjugate is administered at a dose of 0.1-20 mg / kg at 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;

[0200] a) the dose of the 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;

[0201] a) the dose of the anti-nectin-4 antibody drug conjugate is 1-10 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;

[0202] a) administering the anti-nectin-4 antibody drug conjugate 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, at 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;

[0203] a) administering the anti-nectin-4 antibody drug conjugate 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, once every 3 weeks or twice every 3 weeks;

[0204] a) administering the anti-nectin-4 antibody drug conjugate 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 three weeks; or

[0205] a) The anti-nectin-4 antibody drug conjugate is administered at a dosage of about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, or about 4 mg / kg, with a frequency of twice every three weeks.

[0206] In some embodiments, the anti-nectin-4 antibody drug conjugate and anti-PD-L1 antibody are administered in a regimen of:

[0207] a) The dosage of the 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; b1) The dosage of the anti-PD-L1 antibody is 5-5000 mg, and the dosing frequency is once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 5 weeks, or once every 6 weeks;

[0208] a) The dosage of the anti-nectin-4 antibody drug conjugate is 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 dosage of the anti-PD-L1 antibody is 5-5000 mg, and the frequency of administration is once every 3 weeks;

[0209] a) The dosage of the anti-nectin-4 antibody drug conjugate is 1-10 mg / kg, with a frequency of twice every 3 weeks or once every 3 weeks; b1) The dosage of the anti-PD-L1 antibody is 5-5000 mg, with a frequency of once every 3 weeks;

[0210] 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 administration frequency 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, and the administration frequency is once every 3 weeks;

[0211] 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 frequency of administration once every three weeks; b1) the anti-PD-L1 antibody is administered at a dose of 5-5000 mg, with a frequency of administration once every three weeks;

[0212] 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, and the frequency of administration is twice every 3 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;

[0213] 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 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 frequency of once every 3 weeks;

[0214] 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;

[0215] 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;

[0216] 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 three 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, or about 3000 mg, with a dosing frequency of once every three weeks;

[0217] a) The dosage of the anti-nectin-4 antibody drug conjugate is approximately 4 mg / kg, with a frequency of twice every 3 weeks, administered on D1 and D8 of each cycle; b1) The dosage of the anti-PD-L1 antibody is approximately 1200 mg, with a frequency of once every 3 weeks;

[0218] a) the anti-nectin-4 antibody drug conjugate is administered at a dose of about 6 mg / kg, once every 3 weeks; b1) the anti-PD-L1 antibody is administered at a dose of about 1200 mg, once every 3 weeks; or

[0219] a) The dosage of the anti-nectin-4 antibody drug conjugate is approximately 8 mg / kg, and the dosage is once every 3 weeks; b1) The dosage of the anti-PD-L1 antibody is approximately 1200 mg, and the dosage is once every 3 weeks.

[0220] In some embodiments, the dosing regimen of the anti-PD-L1 antibody monotherapy is:

[0221] b1) The dose of the anti-PD-L1 antibody is 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;

[0222] b1) The dose of anti-PD-L1 antibody is 5-5000 mg, and the frequency of administration is once every 3 weeks;

[0223] b1) the anti-PD-L1 antibody is administered at a dose of 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, or about 2000 mg, once every 3 weeks; or

[0224] b1) The dosage of the anti-PD-L1 antibody is about 1200 mg, and the administration frequency is once every 3 weeks.

[0225] In some embodiments, any of the aforementioned anti-nectin-4 antibody-drug conjugates is combined with an anti-PD-L1 antibody as a neoadjuvant therapy for cancer patients before surgical treatment, and / or as an adjuvant therapy for cancer patients after surgical treatment.

[0226] In some embodiments, the adjuvant therapy comprises administering to the patient any of the aforementioned anti-nectin-4 antibody-drug conjugates and anti-PD-L1 antibodies in combination, and administering to the patient any of the aforementioned PD-L1 antibody monotherapy regimens. In some embodiments, the adjuvant therapy comprises first administering to the patient any of the aforementioned anti-nectin-4 antibody-drug conjugates and anti-PD-L1 antibodies in combination, and then administering to the patient any of the aforementioned anti-PD-L1 antibody monotherapy regimens.

[0227] In some embodiments, the cycle of neoadjuvant therapy is 2-8 cycles, each cycle is 21 days or 28 days; preferably 4 cycles, each cycle is 21 days.

[0228] In some embodiments, the adjuvant therapy has a cycle of 1-26 cycles, each cycle is 21 days or 28 days; preferably 13 cycles, each cycle is 21 days.

[0229] In some embodiments, the adjuvant therapy cycle includes a combination therapy cycle of an anti-nectin-4 antibody drug conjugate and an anti-PD-L1 antibody and a monotherapy cycle of an anti-PD-L1 antibody; the combination therapy cycle is 1-10 cycles, each cycle is 21 days or 28 days; preferably 5 cycles, each cycle is 21 days; the anti-PD-L1 antibody monotherapy cycle is 2-16 cycles, each cycle is 21 days or 28 days; preferably 8 cycles, each cycle is 21 days.

[0230] In some embodiments, after 4 cycles of neoadjuvant therapy, the tumor patient undergoes surgical treatment, followed by adjuvant therapy, which includes 5 cycles of combined administration of an anti-nectin-4 antibody drug conjugate and an anti-PD-L1 antibody, followed by 8 cycles of anti-PD-L1 antibody monotherapy, with each cycle lasting 21 days.

[0231] In some embodiments, the interval between neoadjuvant therapy and surgical treatment is ≤1000 weeks, ≤900 weeks, ≤800 weeks, ≤700 weeks, ≤600 weeks, ≤500 weeks, ≤400 weeks, ≤300 weeks, ≤200 weeks, ≤100 weeks, ≤90 weeks, ≤80 weeks, ≤70 weeks, ≤60 weeks, ≤50 weeks, ≤40 weeks, ≤35 weeks, ≤30 weeks, ≤25 weeks, ≤20 weeks, ≤19 weeks, ≤18 weeks, ≤17 weeks, ≤16 weeks, ≤15 weeks, ≤14 weeks, ≤13 weeks, ≤12 weeks, ≤11 weeks, ≤10 weeks, ≤9 weeks, ≤8 weeks, ≤7 weeks, ≤6 weeks, ≤5 weeks, ≤4 weeks, ≤3 weeks, ≤2 weeks, or ≤1 week. In some embodiments, the interval between neoadjuvant therapy and surgical treatment is ≤15 weeks. In some embodiments, the interval between neoadjuvant therapy and surgical treatment is ≤6 weeks or ≤12 weeks.

[0232] In some embodiments, the interval between surgical treatment and adjuvant therapy is ≤1000 weeks, ≤900 weeks, ≤800 weeks, ≤700 weeks, ≤600 weeks, ≤500 weeks, ≤400 weeks, ≤300 weeks, ≤200 weeks, ≤100 weeks, ≤90 weeks, ≤80 weeks, ≤70 weeks, ≤60 weeks, ≤50 weeks, ≤40 weeks, ≤35 weeks, ≤30 weeks, ≤25 weeks, ≤20 weeks, ≤19 weeks, ≤18 weeks, ≤17 weeks, ≤16 weeks, ≤15 weeks, ≤14 weeks, ≤13 weeks, ≤12 weeks, ≤11 weeks, ≤10 weeks, ≤9 weeks, ≤8 weeks, ≤7 weeks, ≤6 weeks, ≤5 weeks, ≤4 weeks, ≤3 weeks, ≤2 weeks, or ≤1 week. In some embodiments, the interval between neoadjuvant therapy and surgical treatment is ≤15 weeks. In some embodiments, the interval between the neoadjuvant therapy and the surgical treatment is more preferably 3 weeks to 10 weeks.

[0233] In some embodiments, the neoadjuvant treatment is 4 cycles, followed by surgical treatment at an interval of ≤6 weeks, ≤15 weeks, or ≤12 weeks, and adjuvant treatment is performed at an interval of 3 to 10 weeks after surgical treatment. The adjuvant treatment includes 5 cycles of combined administration of an anti-nectin-4 antibody drug conjugate and an anti-PD-L1 antibody, followed by 8 cycles of anti-PD-L1 antibody monotherapy, each cycle lasting 21 days. In some embodiments, the surgical treatment is radical cystectomy and pelvic lymph node dissection.

[0234] In some embodiments, the anti-nectin-4 antibody drug conjugate and anti-CTLA-4 antibody are administered in a regimen of:

[0235] 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 a single dose;

[0236] 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; b2) The anti-CTLA-4 antibody is administered at a dose of 1-1000 mg, with a frequency of once every 6 weeks or a single dose;

[0237] a) The dosage of the anti-nectin-4 antibody drug conjugate is 1-10 mg / kg, with a frequency of twice every 3 weeks or once every 3 weeks; b2) The dosage of the anti-CTLA-4 antibody is 1-1000 mg, with a frequency of once every 6 weeks or a single dose;

[0238] 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 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 frequency of once every 6 weeks or a single dose;

[0239] 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 frequency of once every three weeks; b2) the anti-CTLA-4 antibody is administered at a dose of 1-1000 mg, with a frequency of once every six weeks or a single dose;

[0240] 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, and the frequency of administration is twice every 3 weeks; b2) the anti-CTLA-4 antibody is administered at a dose of 1-1000 mg, and the frequency of administration is once every 6 weeks or a single dose;

[0241] 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; 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 frequency of once every 6 weeks or a single dose;

[0242] 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, and the frequency of administration is 2 times 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;

[0243] a) the anti-nectin-4 antibody drug conjugate is administered at a dose of about 3 mg / kg, or about 4 mg / kg, twice every three 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, once every six weeks or as a single dose;

[0244] 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 is administered once every three 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, and is administered once every six weeks or as a single dose;

[0245] a) The anti-nectin-4 antibody drug conjugate is administered at a dose of approximately 4 mg / kg twice every three weeks, with administration on D1 and D8 of each cycle; b2) The anti-CTLA-4 antibody is administered as a single dose in week 1 at a dose of approximately 280 mg or 210 mg, with no administration from weeks 2 to 12. Starting from week 13, the dose is administered at a dose of approximately 70 mg, with a frequency of administration once every six weeks;

[0246] a) the anti-nectin-4 antibody drug conjugate is administered at a dose of about 6 mg / kg once every three 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, with no administration from week 2 to week 12, and starting from week 13, the dose is administered at a dose of about 70 mg once every six weeks; or

[0247] a) The anti-nectin-4 antibody drug conjugate is administered at a dose of approximately 8 mg / kg once every three weeks; b2) The anti-CTLA-4 antibody is administered as a single dose in week 1 at a dose of approximately 280 mg or 210 mg, with no administration from week 2 to week 12. Starting from week 13, the dose is approximately 70 mg once every six weeks.

[0248] In some embodiments, the anti-nectin-4 antibody drug conjugate, combined with anti-PD-L1 antibody and anti-CTLA-4 antibody, is administered as follows:

[0249] a) The dosage of the anti-nectin-4 antibody drug conjugate is 0.1-50 mg / kg, and the dosage 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 dosage of the anti-PD-L1 antibody is 5-5000 mg, and the dosage is once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 5 weeks, or once every 6 weeks; b2) The dosage of the anti-CTLA-4 antibody is 1-1000 mg, and the dosage is 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 a single dose;

[0250] a) The dosage of the anti-nectin-4 antibody drug conjugate is 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 dosage of the anti-PD-L1 antibody is 5-5000 mg, with a dosing frequency of once every 3 weeks; b2) The dosage of the anti-CTLA-4 antibody is 1-1000 mg, with a dosing frequency of once every 6 weeks or a single dose;

[0251] a) The dosage of the anti-nectin-4 antibody drug conjugate is 1-10 mg / kg, with a frequency of twice every 3 weeks or once every 3 weeks; b1) The dosage of the anti-PD-L1 antibody is 5-5000 mg, with a frequency of once every 3 weeks; b2) The dosage of the anti-CTLA-4 antibody is 1-1000 mg, with a frequency of once every 6 weeks or a single dose;

[0252] a) the dosage 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; the dosage is twice every 3 weeks or once every 3 weeks; b1) the dosage of the anti-PD-L1 antibody is 5-5000 mg, and the dosage is once every 3 weeks; b2) the dosage of the anti-CTLA-4 antibody is 1-1000 mg, and the dosage is once every 6 weeks or a single dose;

[0253] a) The dosage 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 dosage is once every 3 weeks; b1) The dosage of the anti-PD-L1 antibody is 5-5000 mg, and the dosage is once every 3 weeks; b2) The dosage of the anti-CTLA-4 antibody is 1-1000 mg, and the dosage is once every 6 weeks or a single dose;

[0254] a) The dosage 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 dosage is twice every 3 weeks; b1) The dosage of the anti-PD-L1 antibody is 5-5000 mg, and the dosage is once every 3 weeks; b2) The dosage of the anti-CTLA-4 antibody is 1-1000 mg, and the dosage is once every 6 weeks or a single dose;

[0255] a) The dosage of the anti-nectin-4 antibody drug conjugate is 1-10 mg / kg, and the dosage is twice every 3 weeks or once every 3 weeks; b1) The dosage 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 dosage is once every 3 weeks. times; 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 frequency of once every 6 weeks or a single dose;

[0256] 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 g, 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;

[0257] 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. times; 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 frequency of once every 6 weeks or a single dose;

[0258] 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 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, administered once every 6 weeks or as a single dose;

[0259] a) The anti-nectin-4 antibody drug conjugate is administered at a dose of approximately 4 mg / kg twice every three weeks, on D1 and D8 of each cycle; b1) The anti-PD-L1 antibody is administered at a dose of approximately 1200 mg once every three weeks; b2) The anti-CTLA-4 antibody is administered as a single dose in week 1 at a dose of approximately 280 mg or 210 mg, with no administration from weeks 2 to 12. Starting from week 13, the dose is approximately 70 mg, with a frequency of once every six weeks;

[0260] a) an anti-nectin-4 antibody drug conjugate is administered at a dose of about 6 mg / kg once every three weeks; b1) an anti-PD-L1 antibody is administered at a dose of about 1200 mg once every three weeks; b2) an anti-CTLA-4 antibody is administered as a single dose in week 1 at a dose of about 280 mg or 210 mg, with no administration from week 2 to week 12, and starting from week 13, at a dose of about 70 mg once every six weeks; or

[0261] a) The dosage of the anti-nectin-4 antibody drug conjugate is approximately 8 mg / kg, and the dosing frequency is once every 3 weeks; b1) The dosage of the anti-PD-L1 antibody is approximately 1200 mg, and the dosing frequency is once every 3 weeks; b2) The anti-CTLA-4 antibody is administered as a single dose in week 1 at a dosage of approximately 280 mg or 210 mg, and no dosing is performed in weeks 2-12. Starting from week 13, the dosage is approximately 70 mg, and the dosing frequency is once every 6 weeks.

[0262] In some embodiments, the order of administration of the anti-nectin-4 antibody-drug conjugate combined with the anti-PD-L1 antibody is as follows: the anti-nectin-4 antibody-drug conjugate is recommended to be administered first, followed by the anti-PD-L1 antibody. The interval between administration of the two drugs should be greater than 30 minutes, and administration should be completed on the same day if possible.

[0263] In some embodiments, the order of administration of an anti-nectin-4 antibody-drug conjugate combined with an anti-PD-L1 antibody and an anti-CTLA-4 antibody is as follows: The anti-nectin-4 antibody-drug conjugate is recommended first, followed by the anti-PD-L1 antibody, and finally the anti-CTLA-4 antibody. The interval between administration of the two drugs should be greater than 30 minutes, and administration should be completed on the same day if possible.

[0264] Nectin-4 targeted therapy and combined therapy strategies have shown certain clinical benefits in advanced solid tumors, bringing patients clinical benefits that are superior to existing treatments, and the disease is controlled or alleviated. BRIEF DESCRIPTION OF THE DRAWINGS

[0265] Figure 1 shows the statistical results of the therapeutic efficacy evaluation of subjects enrolled in the Phase I clinical study of ADC-4.

[0266] the term

[0267] In order to make the present disclosure more easily understood, certain technical and scientific terms are specifically defined below. Unless otherwise explicitly defined herein, all other technical and scientific terms used herein have the meanings commonly understood by those skilled in the art to which the present disclosure belongs.

[0268] Unless the context clearly requires otherwise, throughout the specification and claims, the words "comprising," "having," "including," etc. should be construed to have an inclusive sense rather than an exclusive or exhaustive sense; that is, in the sense of "including but not limited to."

[0269] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not.

[0270] "About" and "approximately" refer to values ​​within an acceptable error range for a particular value as determined by one of ordinary skill in the art, which value depends in part on how it is measured or determined (i.e., the limits of the measurement system). For example, "about" can mean within 1 or more than 1 standard deviation. Alternatively, "about" or "substantially comprising" can mean a range of up to 20%, such as between 1% and 15%, between 1% and 10%, between 1% and 5%, between 0.5% and 5%, between 0.5% and 1%, and in this disclosure, each instance of a number or numerical range preceded by the term "about" also includes embodiments of the given number. Unless otherwise stated, when a specific value appears in the application and claims, the meaning of "about" or "substantially comprising" should be assumed to be within an acceptable error range for that specific value.

[0271] The term "and / or," such as "X and / or Y," should be understood to mean "X and Y" or "X or Y" and should be used to provide clear support for both meanings or either meaning.

[0272] In some embodiments, the present disclosure defines:

[0273] Antibody-drug conjugates (ADCs) link antibodies or antibody fragments to biologically active cytotoxins or small molecule drugs with cell-killing activity via a stable chemical linker. These ADCs leverage the antibody's specificity for tumor cell-specific or highly expressed antigens and the high efficacy of the cytotoxin, while avoiding toxic side effects on normal cells. Compared to traditional chemotherapy drugs, ADCs can precisely bind to tumor cells while minimizing their effects on normal cells.

[0274] An antibody drug conjugate "retains its chemical stability" in a pharmaceutical formulation if the antibody drug conjugate shows no significant chemical changes. Chemical stability can be assessed by detecting and quantifying chemically altered forms of the protein. Degradation processes that often change the chemical structure of a protein include hydrolysis or truncation (assessed by methods such as size exclusion chromatography and CE-SDS), oxidation (assessed by methods such as peptide mapping in combination with mass spectrometry or MALDI / TOF / MS), deamidation (assessed by methods such as ion exchange chromatography, capillary isoelectric focusing, peptide mapping, isoaspartate measurement), and isomerization (assessed by measuring isoaspartate content, peptide mapping, etc.).

[0275] 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 when the pharmaceutical formulation is prepared.

[0276] The three letter and one letter codes for amino acids used in this disclosure are as described in J. biol. chem, 243, p3558 (1968).

[0277] As used herein, the term "antibody" is used in the broadest sense to encompass 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), as long as they exhibit the desired antigen-binding activity. An antibody may refer to an immunoglobulin, which is a tetrapeptide chain structure composed 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 regions of immunoglobulins' heavy chains differ, resulting in different antigenicity. Accordingly, immunoglobulins can be divided into five classes, or so-called immunoglobulin isotypes: IgM, IgD, IgG, IgA, and IgE, with their corresponding heavy chains being μ, δ, γ, α, and ε, respectively. Igs of the same class can be further divided into different subclasses based on differences in the amino acid composition of their hinge regions and the number and location of heavy chain disulfide bonds. For example, IgG can be divided into IgG1, IgG2, IgG3, and IgG4. Light chains are classified as either kappa or lambda chains based on differences in their constant regions. Each of the five classes of Ig can have either kappa or lambda chains. The approximately 110 amino acids near the N-terminus of both the heavy and light chains of antibodies vary greatly in sequence and constitute the variable region (V region); the remaining amino acid sequences near the C-terminus are relatively stable and constitute the constant region (C region). The variable region consists of three hypervariable regions (CDRs) and four framework regions (FRs) whose sequences are relatively conserved. These three hypervariable regions determine the specificity of the antibody and are also known as complementarity-determining regions (CDRs). Each light chain variable region (VL) and heavy chain variable region (VH) consists of three CDRs and four FRs, arranged from the amino terminus to the carboxyl terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The three CDRs of the light chain are referred to as LCDR1, LCDR2, and LCDR3; the three CDRs of the heavy chain are referred to as HCDR1, HCDR2, and HCDR3.

[0278] For the determination or definition of CDRs, the definitive delineation of CDRs and the identification of residues comprising the binding site of the antibody can be accomplished by resolving the structure of the antibody and / or resolving the structure of the antibody-ligand complex. This can be accomplished by any of the various techniques known to those skilled in the art, such as X-ray crystallography. A variety of 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 definitions, and conformational definitions.

[0279] The amino acid sequence boundaries of CDRs can be determined by various well-known schemes, for example: "Kabat" numbering convention (see Kabat et al. (1991), "Sequences of Proteins of Immunological Interest", 5th edition, Public Health Service, National Institutes of Health, Bethesda, MD), "Chothia" numbering convention, "ABM" numbering convention, "contact" numbering convention (see Martin, ACR. Protein Sequence and Structure Analysis of Antibody Variable Domains [J]. 2001) and ImMunoGenTics (IMGT) numbering convention (Lefranc, MP et al., Dev. Comp. Immunol., 27, 55-77 (2003); Front Immunol. 2018 Oct 16; 9: 2278), etc.

[0280] The term "antigen-binding fragment" or "functional fragment" or "antigen-binding portion" refers to one or more fragments of an intact antibody that retains the ability to specifically bind to an antigen. It has been shown that fragments of a full-length antibody can be used to perform the antigen-binding function of an antibody. Exemplary 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) an 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 an interchain disulfide bond between VH and VL; (vi) scFv; (vii) diabodies, bispecific antibodies, and multispecific antibodies comprising fragments such as scFv, dsFv, and Fab.

[0281] The terms "specific binding", "selective binding", "selectively binds" and "specifically binds" refer to the binding of an antibody to a predetermined epitope on an antigen. -8 M, for example, less than approximately 10 -9 M, 10 -10 M, 10 -11 Binds with an affinity (KD) of M or less.

[0282] The term "KD" refers to the dissociation equilibrium constant for a particular antibody-antigen interaction. Typically, the antibodies of the present disclosure exhibit dissociation equilibrium constants of less than about 10-7 M, for example, less than about 10-7 M. -8 M, 10 -9 M or 10 -10 The IL-5 binding protein binds to IL-5 with a dissociation equilibrium constant (KD) of M or less, e.g., as determined using surface plasmon resonance (SPR) technology in a BIACORE instrument.

[0283] "Homology" refers to the sequence similarity between two polynucleotide sequences or between two polypeptides. When a position in the two compared sequences is occupied by the same base or amino acid monomer subunit, for example, if every position in two DNA molecules is occupied by adenine, then the molecules are homologous at that position. The percentage 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 compared × 100. For example, if 6 out of 10 positions in the two sequences match or are homologous when the sequences are optimally aligned, then the two sequences are 60% homologous; if 95 out of 100 positions in the two sequences match or are homologous, then the two sequences are 95% homologous. Typically, when aligning two sequences, the comparison is performed to give the maximum percentage homology. For example, the comparison can be performed using the BLAST algorithm, where the parameters of the algorithm are selected to give the maximum match between each sequence over the entire length of each reference sequence. The following references relate to the BLAST algorithm commonly used for sequence analysis: BLAST ALGORITHMS: Altschul, SF et al., (1990) J. Mol. Biol. 215: 403-410; Gish, W. et al., (1993) Nature Genet. 3: 266-272; Madden, TL et al., (1996) Meth. Enzymol. 266: 131-141; Altschul, SF et al., (1997) Nucleic Acids Res. 25: 3389-3402; Zhang, J. et al., (1997) Genome Res. 7: 649-656. Other conventional BLAST algorithms, such as those provided by NCBI BLAST, are also well known to those skilled in the art.

[0284] "Administering" and "treating" as applied to an animal, a human, a laboratory subject, a cell, a tissue, an organ or a biological fluid, refers to the contacting of an exogenous drug, therapeutic agent, diagnostic agent or composition with an animal, a human, a subject, a cell, a tissue, an organ or a biological fluid. "Administering" and "treating" can refer to, for example, therapeutic, pharmacokinetics, diagnostics, research and experimental procedures. Treatment of cells includes contacting an agent with a cell, and contacting an agent with a fluid, wherein the fluid is in contact with the cell. "Administering" and "treating" also mean treating, for example, a cell in vitro and ex vivo, by an agent, a diagnostic, a binding composition or by another cell. "Treatment" as applied to a human, veterinary or research subject, refers to therapeutic treatment, prophylactic or preventative measures, research and diagnostic applications.

[0285] "Treatment" means administering an internal or external therapeutic agent, such as a composition comprising any of the binding compounds of the present disclosure, to a patient who has one or more symptoms of a disease for which the therapeutic agent is known to have a therapeutic effect. Typically, the therapeutic agent is administered in an amount effective to alleviate one or more symptoms of the disease in the patient or population being treated, to induce regression of such symptoms or to inhibit the progression of such symptoms to any clinically measurable degree. The amount of a therapeutic agent effective to alleviate any specific disease symptom (also referred to as a "therapeutically effective amount") can vary according to a variety of factors, such as the patient's disease state, age, and weight, and the ability of the drug to produce the desired therapeutic effect in the patient. Whether the symptoms of the disease have been alleviated can be assessed by any clinical test method commonly used by a physician or other health care professional to assess the severity or progression of the symptoms. Although embodiments of the present disclosure (e.g., methods of treatment or articles of manufacture) may not be effective in alleviating every symptom of the target disease, they should alleviate the target disease symptoms in a statistically significant number of patients as determined by 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.

[0286] An "effective amount" encompasses an amount sufficient to ameliorate or prevent the symptoms or conditions of a medical condition. An effective amount also means an amount sufficient to permit or facilitate diagnosis. The effective amount for a particular patient or veterinary subject may vary depending on factors such as the condition to be treated, the patient's overall health, the route and dosage of administration, and the severity of side effects. An effective amount can be the maximum dose or dosage regimen that avoids significant side effects or toxic effects.

[0287] The terms "subject" and "patient" refer to mammals, particularly primates, and especially humans.

[0288] The "combination" described in the present disclosure is a mode of administration, which refers to the administration of at least one dose of an anti-Nectin-4 antibody drug conjugate and at least one dose of an immunotherapeutic agent and / or a chemotherapeutic agent within a certain time period, wherein both drugs show a pharmacological effect. The time period can be within a dosing cycle, such as within 4 weeks, within 3 weeks, within 2 weeks, within 1 week, or within 24 hours, or within 12 hours, etc. The anti-Nectin-4 antibody drug conjugate and other types of drugs can be administered simultaneously or sequentially. This period includes treatments in which the anti-Nectin-4 antibody drug conjugate and other types of drugs are administered by the same route of administration or different routes of administration. The combined administration mode described in the present disclosure is selected from simultaneous administration, independent formulation and co-administration, or independent formulation and sequential administration.

[0289] In the antibody-drug conjugates disclosed herein, "n" refers to the average number of cytotoxic drugs loaded on each antibody or antigen-binding fragment thereof in the antibody-drug conjugate molecule, and can also be expressed as the ratio of the amount of drug to the amount of antibody, which is the average number of drugs per ADC molecule after the coupling reaction as determined by hydrophobic chromatography (HIC) mass spectrometry.

[0290] A "pharmaceutical composition" refers to a mixture containing one or more compounds described herein, or their physiologically / pharmaceutically acceptable salts or prodrugs, together 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, facilitating absorption of the active ingredient and thereby exerting its biological activity. DETAILED DESCRIPTION

[0291] The present disclosure is further described below with reference to the following examples, but these examples are not intended to limit the scope of the present disclosure. Experimental methods in the examples herein where specific conditions are not specified generally follow conventional conditions, such as those in the Cold Spring Harbor Laboratory's "Antibody Techniques Laboratory Manual" and "Molecular Cloning Manual," or according to the conditions recommended by the raw material or product manufacturer. Reagents where the specific source is not specified are commercially available.

[0292] Example 1. Preparation of anti-nectin-4 antibody drug conjugates

[0293] The anti-nectin-4 antibody drug conjugate is ADC-4 prepared in Example 3-4 of WO2023221971A (incorporated herein by reference in its entirety), and has the following structure:

[0294] The average value calculated by reverse phase chromatography was: n=3.5-4.7.

[0295] The anti-nectin-4 antibody is derived from the antibody NEC49, and its CDR sequence is shown in Table 3. The full length of the heavy chain of the antibody NEC49 is shown in SEQ ID NO: 9, and the full length of the light chain is shown in SEQ ID NO: 10.

[0296] Example 2. Phase I clinical study of anti-nectin-4 antibody drug conjugates in the treatment of patients with advanced solid tumors

[0297] 1. Trial Drug

[0298] Anti-nectin-4 antibody drug conjugate: ADC-4 prepared in Example 1. The dosage form is injection (sterile powder for injection), specification: 80 mg / bottle.

[0299] 2. Enrollment of subjects

[0300] 1) Aged 18 and above, regardless of gender;

[0301] 2) Eastern Cooperative Oncology Group (ECOG) performance status score of 0-1;

[0302] 3) expected survival time ≥ 3 months;

[0303] 4) Pathologically confirmed locally advanced or metastatic urothelial carcinoma;

[0304] 5) Ability to provide preserved or fresh tumor tissue for nectin-4 expression detection (based on immunohistochemistry [IHC] testing in a central laboratory); for subjects who are unable to provide tumor tissue samples that meet the above requirements, discussion with the sponsor is required to determine whether to enroll.

[0305] 6) There is at least one measurable lesion that meets the RECIST 1.1 criteria;

[0306] 3. Clinical plan

[0307] 3.1 Research Design

[0308] Dose escalation phase:

[0309] 1) Receive 1 mg / kg, 2 mg / kg, 4 mg / kg, 6 mg / kg, 8 mg / kg, Q3W for the treatment of locally advanced unresectable or metastatic urothelial carcinoma;

[0310] 2) Receive 4 mg / kg twice every 3 weeks, administered on D1 and D8 respectively, for the treatment of locally advanced unresectable or metastatic urothelial carcinoma;

[0311] Efficacy expansion stage

[0312] Receive 6mg / kg, 8mg / kg for the treatment of locally advanced unresectable or metastatic urothelial carcinoma.

[0313] 3.2 Administration

[0314] ADC-4: intravenous infusion, 2 mg / kg, 4 mg / kg, 6 mg / kg, 8 mg / kg, 10 mg / kg, Q3W or other doses explored / determined.

[0315] 4. Test results

[0316] 1) Effectiveness indicators:

[0317] Tumor assessments were performed using RECIST v1.1, and all subjects underwent baseline tumor imaging during the screening period. Efficacy was evaluated using RECIST v1.1, with investigator-assessed ORR, DCR, DoR, and PFS as indicators.

[0318] As of November 14, 2023, a total of 20 subjects with advanced urothelial carcinoma were enrolled in a Phase I clinical study of an anti-nectin-4 antibody-drug conjugate, with 1, 3, 3, 7, and 6 subjects enrolled in the 1mg / kg, 2mg / kg, 4mg / kg, 6mg / kg, and 8mg / kg dose groups, respectively. Five and three subjects in the 6mg / kg and 8mg / kg dose groups, respectively, had baseline target lesions and completed at least one efficacy assessment, with unconfirmed ORRs of 40% (3 / 5) and 66.7% (2 / 3), respectively.

[0319] In a Phase I clinical study of an anti-nectin-4 antibody-drug conjugate, 73 subjects with locally advanced, unresectable or metastatic urothelial carcinoma were enrolled (median age: 65 years; 57.5% had received ≥2 lines of systemic anti-tumor therapy; 42.5% had received ADC prior therapy). Based on the full analysis set, the confirmed objective response rate (ORR) was 38.4% (28 / 73; 95% CI, 27.2–50.5) among all subjects. The confirmed ORRs for the 6 mg / kg and 8 mg / kg dose groups were 32.3% (10 / 31, 95% CI, 16.7–51.4) and 50.0% (16 / 32, 95% CI, 31.9–68.1), respectively. Among all subjects, the proportion of subjects with a 6-month duration of response (DoR%) was 59.3% (95% CI, 23.1–83.0); the 6-month DoR% for the 6 mg / kg and 8 mg / kg dose groups were 66.7% [95% CI, 5.4–94.5] and 54.0% [95% CI, 12.7–83.2], respectively. Among them, 31 subjects had ADC treatment, and 12 subjects (38.7%; 95% CI, 21.9–57.8) had a confirmed partial response (PR).

[0320] In a Phase I clinical study of an anti-nectin-4 antibody-drug conjugate, a total of 81 subjects with locally advanced unresectable or metastatic urothelial carcinoma were enrolled. The baseline characteristics of the enrolled subjects are shown in Table 4.

[0321] Table 4. Baseline characteristics of the subjects

[0322] *ADC is disitamab vedotin (HER2 ADC)

[0323] #Failure or intolerance of standard treatment, no standard treatment or refusal of standard treatment

[0324] In a Phase I clinical study of an anti-nectin-4 antibody-drug conjugate, 81 patients with locally advanced, unresectable, or metastatic urothelial carcinoma were enrolled. The statistical results of the treatment efficacy evaluation for these enrolled subjects are shown in Tables 5-7 and Figure 1. Based on the full analysis set, the confirmed objective response rate (ORR) among all subjects was 38.3% (31 / 81, 95% CI, 27.7–49.7). The confirmed ORRs for the 6 mg / kg and 8 mg / kg dose groups were 41.9% (13 / 31, 95% CI, 24.5–60.9) and 50.0% (16 / 32, 95% CI, 31.9–68.1), respectively. Among all subjects, the confirmed disease control rate (DCR) was 76.5% (62 / 81, 95% CI, 65.8–85.3); the confirmed DCRs were 90.3% (28 / 31, 95% CI, 74.3–98.0) and 84.4% (27 / 32, 95% CI, 67.2–94.7) in the 6 mg / kg and 8 mg / kg dose groups, respectively. The 6-month duration of response (DoR%) among all subjects was 53.1% (95% CI, 27.8–73.1); the 6-month DoR% was 59.5% (95% CI, 23.5–83.0) and 43.5% (95% CI, 8.3–75.7) in the 6 mg / kg and 8 mg / kg dose groups, respectively. The median progression-free survival (PFS) was 5.8 months (95% CI, 3.9-9.0) for the 6 mg / kg and 5.8 months (95% CI, 3.4-8.2) for the 8 mg / kg dose groups, respectively. Of the 31 subjects who had previously received ADC therapy, 13 achieved a confirmed partial response (PR), resulting in an ORR of 41.9% (95% CI, 24.6–60.9); a DCR of 74.2% (95% CI, 55.4–88.1); and a 6-month DoR of 52.4% (95% CI, 20.1–77.0). Among 31 subjects treated with ADC, the ORRs for the 6 mg / kg and 8 mg / kg dose groups were 54.5% (95% CI, 23.4–83.3) and 42.9% (95% CI, 17.7–71.1), respectively. The DCRs were 90.9% (95% CI, 58.7–99.8) and 78.6% (95% CI, 49.2–95.3), respectively. The 6-month DoR%s were 41.7% (95% CI, 5.6–76.7) and 75.0% (95% CI, 12.8–96.1), respectively.

[0325] Table 5. Efficacy evaluation (ORR and DCR)

[0326] Table 6. Evaluation of efficacy (DoR)

[0327] Table 7. Efficacy evaluation of ADC-treated subjects (ORR, DCR and DoR)

[0328] 2) Safety evaluation:

[0329] After all subjects are enrolled in the study, safety assessments will be conducted during each treatment cycle. This includes the incidence and grade of AEs, serious adverse events (SAEs) (assessed according to NCI-CTCAE v5.0 criteria), 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.

[0330] In a Phase I clinical study of an anti-nectin-4 antibody-drug conjugate, 20 subjects with advanced urothelial carcinoma were enrolled, with 1, 3, 3, 7, and 6 patients enrolled in the 1 mg / kg, 2 mg / kg, 4 mg / kg, 6 mg / kg, and 8 mg / kg dose groups, respectively. The incidence of Grade ≥ 3 TRAEs in the 6 mg / kg and 8 mg / kg dose groups was 29% (2 / 7) and 33% (2 / 6), respectively. DLTs occurred in all 1 mg / kg, 2 mg / kg, 4 mg / kg, and 6 mg / kg dose groups.

[0331] In a Phase I clinical study of an anti-nectin-4 antibody-drug conjugate, 73 subjects with locally advanced, unresectable, or metastatic urothelial carcinoma were enrolled. Dose-limiting toxicity (DLT) observations were completed in all dose groups, and 32 subjects (43.8%) experienced Grade 3 or higher TRAEs. The most common TRAEs included anemia (23.3%), decreased white blood cell count (19.2%), and decreased neutrophil count (17.8%). The incidence of Grade 3 or higher TRAEs in the 6 mg / kg and 8 mg / kg dose groups was 32.3% (10 / 31) and 65.6% (21 / 32), respectively.

[0332] In a Phase I clinical study of an anti-nectin-4 antibody-drug conjugate, 81 subjects with locally advanced, unresectable, or metastatic urothelial carcinoma were enrolled. Safety evaluation results are shown in Table 8. Dose-limiting toxicity (DLT) observations were completed in all dose groups. A total of 36 subjects (44.4%) experienced Grade 3 or higher TRAEs. The incidence of Grade 3 or higher TRAEs was 38.7% (12 / 31) in the 6 mg / kg and 65.6% (21 / 32) dose groups, respectively. The most common TRAEs included anemia (22.2%), decreased white blood cell count (18.5%), and decreased neutrophil count (16%). The incidence of TRAEs leading to dose reduction (8.6%) and discontinuation (2.5%) was relatively low.

[0333] Table 8. Safety evaluation

[0334] In summary, the ADC-4 antibody conjugate exhibited a tolerable and manageable safety profile and showed promising antitumor activity in urothelial carcinoma.

[0335] Example 3. A randomized, open-label, controlled, multicenter phase III clinical study of an anti-nectin-4 antibody drug conjugate versus investigator's choice of chemotherapy for the treatment of locally advanced or metastatic urothelial carcinoma who have previously received platinum-containing chemotherapy and PD-(L)1 inhibitors

[0336] 1. Trial Drug

[0337] (1) Anti-Nectin-4 Antibody Drug Conjugate: ADC-4 prepared in Example 1. The dosage form is injection (sterile powder for injection), specification: 80 mg / bottle;

[0338] (2)Docetaxel injection;

[0339] (3) Paclitaxel injection;

[0340] (4) Gemcitabine hydrochloride injection;

[0341] (5) Pemetrexed disodium injection.

[0342] 2. Enrollment of subjects

[0343] 1) Aged 18 to 75, regardless of gender;

[0344] 2) Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1;

[0345] 3) expected survival time ≥ 3 months;

[0346] 4) Pathologically confirmed urothelial carcinoma, with imaging or other methods confirming locally advanced unresectable or metastatic disease;

[0347] 5) For locally advanced or metastatic disease, patients who have previously received platinum-containing chemotherapy and PD-(L)1 inhibitors; patients who have received platinum-containing chemotherapy and / or PD-(L)1 inhibitors during neoadjuvant / adjuvant treatment and have relapsed or progressed during treatment or within 12 months after treatment are also eligible for inclusion;

[0348] 6) Imaging-confirmed disease progression during or after the most recent treatment regimen;

[0349] 7) Ability to provide preserved or fresh tumor tissue for nectin-4 expression detection (based on immunohistochemistry [IHC] testing in a central laboratory); for subjects who are unable to provide tumor tissue samples that meet the above requirements, discussion with the sponsor is required to determine whether to enroll.

[0350] 8) There is at least one measurable lesion that meets the RECIST 1.1 criteria;

[0351] 3. Clinical plan

[0352] 3.1 Clinical Design

[0353] The experimental group received ADC-4 6.0 mg / kg to treat locally advanced unresectable or metastatic urothelial carcinoma who had previously received platinum-containing chemotherapy and PD-(L)1 inhibitors.

[0354] Control group: The treatment regimen selected by the investigator (if used in the previous treatment regimen, it cannot be selected), as follows:

[0355] Received docetaxel injection 75mg / m 2 or paclitaxel injection 175 mg / m 2 Or gemcitabine hydrochloride alone 1000 mg / m 2 or pemetrexed disodium alone 500 mg / m 2 For the treatment of locally advanced unresectable or metastatic urothelial carcinoma who have previously received platinum-containing chemotherapy and PD-(L)1 inhibitors.

[0356] 3.2 Administration

[0357] Experimental group: ADC-4 6 mg / kg intravenous drip, administered on the first day of each cycle, with one dosing cycle every 3 weeks (Q3W).

[0358] Control group:

[0359] Paclitaxel alone 175 mg / m 2 , intravenous drip, administered on the first day of each cycle, Q3W;

[0360] Docetaxel alone 75 mg / m 2 , intravenous drip, administered on the first day of each cycle, Q3W;

[0361] Gemcitabine hydrochloride alone 1000 mg / m 2 , intravenous drip, administered on the 1st and 8th day of each cycle, Q3W;

[0362] Pemetrexed disodium alone 500 mg / m 2 , intravenous drip, administered on the first day of each cycle, Q3W.

[0363] Both groups received medication until disease progression confirmed by blinded independent central review (BICR), intolerable toxicity, initiation of new anti-tumor treatment, subject's voluntary request to withdraw from the study, loss to follow-up, death, or the investigator's judgment that the subject needed to withdraw from the study.

[0364] 4. Results Evaluation

[0365] 4.1 Effectiveness Indicators

[0366] Tumor assessment was performed using RECIST v1.1, and all subjects underwent baseline tumor imaging during the screening period. Efficacy measures included investigator-assessed ORR, DCR, DoR, PFS, and OS.

[0367] 4.2 Safety evaluation

[0368] After all subjects are enrolled in the study, safety assessments will be conducted during each treatment cycle, including the incidence and grade of TRAEs, serious adverse events (SAEs) (assessed according to NCI-CTCAE v5.0 criteria), 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.

[0369] Example 4. A multicenter, open-label, phase IB / II clinical study of the safety, tolerability, and efficacy of an anti-nectin-4 antibody drug conjugate with or without anti-tumor therapy in subjects with advanced solid tumors

[0370] 1. Trial Drug

[0371] (1) Anti-Nectin-4 Antibody Drug Conjugate: ADC-4 prepared in Example 1. The dosage form is injection (lyophilized powder).

[0372] (2) Anti-PD-L1 antibody, whose heavy chain is shown in SEQ ID NO: 19 and whose light chain is shown in SEQ ID NO: 20. The dosage form is an injection.

[0373] 2. Enrollment of subjects

[0374] 1) Aged 18 and above, regardless of gender;

[0375] 2) Eastern Cooperative Oncology Group (ECOG) performance status score of 0-1;

[0376] 3) expected survival ≥ 12 weeks;

[0377] 4) Patients with pathologically confirmed locally advanced unresectable or metastatic solid tumors who have failed, are intolerant to, or refuse standard treatment in the Phase Ib dose-escalation phase. The criteria for other phases are as follows:

[0378] A Phase Ib PK expansion phase enrolled patients with pathologically confirmed locally advanced unresectable or metastatic urothelial carcinoma who had failed standard therapy for locally advanced unresectable or metastatic disease.

[0379] Phase II enrolls patients with pathologically confirmed locally advanced unresectable or metastatic urothelial carcinoma who have not received systemic antineoplastic therapy for locally advanced unresectable or metastatic disease.

[0380] 5) Ability to provide archived or fresh tumor tissue for nectin-4 expression and PD-L1 testing, with positive nectin-4 expression in the tumor tissue (based on immunohistochemistry [IHC] testing performed by a central laboratory; urothelial carcinoma patients are not required to have positive expression). For subjects who are unable to provide tumor tissue samples that meet the above requirements, inclusion in the study must be determined after discussion with the sponsor.

[0381] 6) At least one measurable lesion according to RECIST v1.1 criteria.

[0382] 3. Clinical plan

[0383] 3.1 Research Design

[0384] Phase Ib stage

[0385] (1) Stage IB urothelial carcinoma, Part 1 (IB-UC-Part 1), ADC-4 combined with anti-PD-L1 antibody:

[0386] o UC-Part 1 dose level 1: ADC-4 6 mg / kg Q3W + anti-PD-L1 antibody 1200 mg Q3W;

[0387] o UC-Part 1 dose level 2: ADC-4 8 mg / kg Q3W + anti-PD-L1 antibody 1200 mg Q3W;

[0388] o UC-Part 1 dose level 3: ADC-4 4 mg / kg D1, D8 Q3W + anti-PD-L1 antibody 1200 mg Q3W.

[0389] Phase II (Efficacy Expansion)

[0390] Cohort 1: SHR-A2102 6mg / kg Q3W + SHR-1316 1200mg Q3W

[0391] Cohort 2: SHR-A2102 8mg / kg Q3W + SHR-1316 1200mg Q3W

[0392] Cohort 3: SHR-A2102 6 mg / kg Q3W. Each cohort will enroll 20-40 patients. The sponsor will determine the cohort and number of patients to be enrolled at the time of enrollment. The sponsor may also increase or decrease the number of cohorts and / or the number of patients in each cohort, and / or add a dose option to Cohort 3 (e.g., 8 mg / kg), based on subsequent development strategies.

[0393] 3.2 Administration

[0394] ADC-4: intravenous infusion, 6 mg / kg, 8 mg / kg, Q3W; 4 mg / kg D1, D8, Q3W or other doses explored / determined.

[0395] Anti-PD-L1 antibody: intravenous drip, 1200 mg, administered once every 3 weeks, each drip time is 30-60 minutes, and one cycle is 21 days (Q3W).

[0396] Dosing sequence: It is recommended to administer ADC-4 first, followed by anti-PD-L1 antibody. The interval between the two drugs should be greater than 30 minutes, and administration should be completed on the same day if possible.

[0397] 4. Results Evaluation

[0398] 4.1 Effectiveness Indicators

[0399] Tumor assessment was based on RECIST v1.1 criteria, and all subjects underwent baseline tumor imaging during the screening period. Efficacy measures included investigator-assessed ORR and DCR.

[0400] Table 9. Baseline characteristics of subjects

[0401] *ADC is disitamab vedotin (HER2 ADC)

[0402] A total of 90 subjects were enrolled, and their baseline characteristics are shown in Table 9. In Phase Ib, 32 subjects were enrolled in the 6 mg / kg and 22 subjects were enrolled in the 8 mg / kg dose groups; in Phase II, Cohort 2 (8 mg / kg dose group), 36 subjects were enrolled. The statistical results of the treatment efficacy evaluation for the enrolled subjects are as follows:

[0403] 1) Phase IB included 53 subjects who completed at least one efficacy evaluation, and 1 subject who did not undergo treatment evaluation:

[0404] The objective response rate (uORR) for all subjects in the 6 mg / kg group was 50.0% (16 / 32), and the disease control rate (DCR) was 90.6% (20 / 22), including 2 subjects (6.3%) with complete disease response (CR), 14 subjects (43.8%) with partial response (PR), and 13 subjects (40.7%) with stable disease (SD). The disease control rate (DCR) for all subjects in the 8 mg / kg group was 90.9% (20 / 22).

[0405] In the 6 mg / kg group, the objective response rate (uORR) in subjects who had previously received immunotherapy (ICI) was 46.2% (6 / 13), and the objective response rate (uORR) in subjects who had not previously received immunotherapy (ICI) was 52.6% (10 / 19).

[0406] 2) Cohort 2 of Phase II enrolled 36 subjects. The objective response rate (uORR) of all subjects in the 8 mg / kg group was 47.2% (17 / 36), and the disease control rate (DCR) was 94.4% (34 / 36).

[0407] 4.2 Safety evaluation

[0408] After all subjects are enrolled in the study, safety assessments will be conducted during each treatment cycle. This includes the incidence and grade of AEs, serious adverse events (SAEs) (assessed according to NCI-CTCAE v5.0 criteria), 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.

[0409] A total of 90 subjects were enrolled, and 77 (86%) experienced at least one study drug-related adverse event (TRAE). Grade 3 or higher TRAEs occurred in 36 (40%) subjects, including 14 (41%) subjects at 6.0 mg / kg in Phase Ib, 9 (41%) subjects at 8.0 mg / kg, and 14 (39%) subjects at 8 mg in Phase II. The most common TRAEs included decreased neutrophil count (16%), anemia (12%), and decreased white blood cell count (10%). TRAEs led to drug suspension in 30 (33%) subjects, dose reduction in 3 (3.3%) subjects, and permanent discontinuation in 2 (2.2%) subjects. This suggests that the combination therapy did not significantly increase drug toxicity compared to monotherapy, demonstrating a significant safety advantage for this combination regimen.

[0410] Table 10. Safety evaluation

[0411] Example 5. A multicenter, open-label, phase IB / II clinical study of the safety, tolerability, and efficacy of an anti-nectin-4 antibody drug conjugate combined with other anti-tumor therapies in subjects with advanced urothelial carcinoma

[0412] 1. Trial Drug

[0413] (1) Anti-Nectin-4 Antibody Drug Conjugate: ADC-4 prepared in Example 1. The dosage form is injection (lyophilized powder).

[0414] (2) Anti-PD-L1 antibody, whose heavy chain is shown in SEQ ID NO: 19 and whose light chain is shown in SEQ ID NO: 20. The dosage form is an injection.

[0415] (3) Anti-CTLA-4 antibody, whose heavy chain is shown in SEQ ID NO: 29 and whose light chain is shown in SEQ ID NO: 30. The dosage form is an injection.

[0416] 2. Enrollment of subjects

[0417] 1) Aged 18 and above, regardless of gender;

[0418] 2) Eastern Cooperative Oncology Group (ECOG) performance status score of 0-1;

[0419] 3) expected survival ≥ 12 weeks;

[0420] 4) Patients with pathologically confirmed locally advanced unresectable or metastatic solid tumors (locally advanced unresectable or metastatic urothelial carcinoma). Phase Ib subjects must have failed standard treatment, are intolerant to standard treatment, or refuse standard treatment. Phase II subjects must not have received systemic anti-tumor treatment for locally advanced unresectable or metastatic urothelial carcinoma.

[0421] 5) Ability to provide archived or fresh tumor tissue for Nectin-4 expression and PD-L1 testing (based on immunohistochemistry [IHC] testing in a central laboratory). For subjects who are unable to provide tumor tissue samples that meet the above requirements, the decision on whether to enroll in the study must be made after discussion with the sponsor.

[0422] 6) At least one measurable lesion according to RECIST v1.1 criteria.

[0423] 3. Clinical plan

[0424] 3.1 Research Design

[0425] Phase Ib stage

[0426] Two doses are preset and dose exploration is performed as follows:

[0427] Dose level 1:

[0428] (a) ADC-4, 6 mg / kg Q3W;

[0429] (b) anti-PD-L1 antibody, 1200 mg Q3W; and

[0430] (c) Anti-CTLA-4 antibody, with a 21-day cycle, a single dose of 280 mg is administered on the first day of the first cycle, no administration is given in cycles 2-4, and starting from the first day of the fifth cycle, a dose of 70 mg is administered every 6 weeks (C1D1 280 mg is administered once, no administration is given in C2-C4, and 70 mg Q6W in C5 and subsequent cycles).

[0431] Dose Level 2:

[0432] (a) ADC-4, 8 mg / kg Q3W;

[0433] (b) anti-PD-L1 antibody, 1200 mg Q3W; and

[0434] (c) Anti-CTLA-4 antibody, with a 21-day cycle, a single dose of 280 mg is administered on the first day of the first cycle, no administration is given in cycles 2-4, and starting from the first day of the fifth cycle, a dose of 70 mg is administered every 6 weeks (C1D1 280 mg is administered once, no administration is given in C2-C4, and 70 mg Q6W in C5 and subsequent cycles).

[0435] During the study, other dose levels or intermediate doses of ADC-4 (e.g., 7 mg / kg Q3W, 5 mg / kg Q3W, 4 mg / kg D1, D8 Q3W, 3 mg / kg D1, D8 Q3W) may also be explored based on overall assessment.

[0436] Phase II (Efficacy Expansion)

[0437] Cohort 1: Received ADC-4 8mg / kg Q3W + anti-PD-L1 antibody 1200mg Q3W + anti-CTLA-4 antibody treatment, the anti-CTLA-4 antibody was administered in a 21-day cycle, with a single dose of 280mg on the first day of cycle 1, no administration in cycles 2-4, and a dose of 70mg every 6 weeks starting from day 1 of cycle 5 (C1D1 280mg administered once, no administration in C2-C4, C5 and subsequent cycles 70mg Q6W).

[0438] Cohort 2: Received ADC-4 Q3W 6mg / kg + anti-PD-L1 antibody 1200mg Q3W + anti-CTLA-4 antibody treatment, the anti-CTLA-4 antibody was administered in a 21-day cycle, with a single dose of 280mg on the first day of cycle 1, no administration in cycles 2-4, and a dose of 70mg every 6 weeks starting from day 1 of cycle 5 (C1D1 280mg administered once, no administration in C2-C4, C5 and subsequent cycles 70mg Q6W).

[0439] Each cohort will enroll 20–40 patients. The sponsor will determine the initial cohort and number of patients to be enrolled at the time of enrollment. The sponsor may add or remove cohorts and adjust the number of patients in each cohort based on subsequent development strategies.

[0440] 3.2 Administration

[0441] ADC-4: Intravenous infusion: 6 mg / kg, 8 mg / kg, 7 mg / kg Q3W, 5 mg / kg Q3W, Q3W; 4 mg / kg D1, D8, Q3W; 3 mg / kg D1, D8, Q3W, or other doses explored / determined. The total dose should be calculated based on the subject's body weight before each dose.

[0442] Anti-PD-L1 antibody: Intravenous drip, 1200 mg, once every 3 weeks, each drip lasting 30-60 minutes, 21 days per cycle (Q3W). Cumulative use should not exceed 35 times.

[0443] Anti-CTLA-4 antibody: Intravenous infusion: a single dose of 280 mg on day 1 of cycle 1. No dose is given in cycles 2-4. Starting on day 1 of cycle 5, a 70 mg dose is administered every 6 weeks (280 mg once on C1D1, no dose is given on cycles C2-C4, and 70 mg every 6 weeks on cycles C5 and thereafter). Each intravenous infusion lasts 30 ± 10 minutes, and a cycle is 21 days. The cumulative dose should not exceed 18 times.

[0444] Dosage sequence: It is recommended to administer ADC-4 first, then anti-PD-L1 antibody, and finally anti-CTLA-4 antibody. The interval between the two drugs should be greater than 30 minutes, and if possible, the two drugs should be administered on the same day.

[0445] 4. Results Evaluation

[0446] 4.1 Effectiveness Indicators

[0447] Tumor assessment was performed using RECIST v1.1, and all subjects underwent baseline tumor imaging during the screening period. Efficacy measures included investigator-assessed ORR, DCR, DoR, PFS, and OS.

[0448] A total of 14 subjects were enrolled (50% with urothelial bladder cancer, 92.9% with prior ICI treatment). In the 6 mg / kg group, the objective response rate (uORR) was 50% (4 / 8) and the confirmed disease control rate (DCR) was 87.5% (7 / 8).

[0449] 4.2 Safety evaluation

[0450] After all subjects are enrolled in the study, safety assessments will be conducted during each treatment cycle. This includes the incidence and grade of AEs, serious adverse events (SAEs) (assessed according to NCI-CTCAE v5.0 criteria), 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.

[0451] A total of 14 subjects were enrolled, and dose-limiting toxicity (DLT) observations were completed in all dose groups. Twelve (85.7%) subjects reported treatment-related adverse events (TRAEs). Four (28.6%) subjects experienced Grade 3 or higher TRAEs. The incidence of TRAEs leading to dose reduction (0%) and TRAE-induced discontinuation (7.1%) was relatively low.

[0452] Example 6. Randomized, open, multicenter phase II / III clinical study of anti-nectin-4 antibody drug conjugate combined with anti-PD-L1 antibody and surgical treatment for patients with muscle-invasive bladder cancer

[0453] 1. Trial Drug

[0454] (1) Anti-Nectin-4 Antibody Drug Conjugate: ADC-4 prepared in Example 1. The dosage form is injection (lyophilized powder).

[0455] (2) Anti-PD-L1 antibody, whose heavy chain is shown in SEQ ID NO: 19 and whose light chain is shown in SEQ ID NO: 20. The dosage form is an injection.

[0456] 2. Enrollment of subjects

[0457] 1) Aged 18 and above, regardless of gender;

[0458] 2) Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1;

[0459] 3) expected survival period ≥ 2 years;

[0460] 4) Pathologically and radiologically confirmed non-metastatic muscle-invasive bladder cancer (MIBC) (T2-T4a)N0M0 or (T1-T4a)N1M0), with predominantly urothelial transitional epithelium.

[0461] 5) Metastatic lesions (N≤1, M0) were excluded by imaging (computed tomography (CT) or magnetic resonance imaging (MRI) of the chest / abdomen / pelvis) (assessed by the investigator for stage II and by BICR for stage III).

[0462] 6) Ability to provide archived or fresh tumor tissue for Nectin-4 expression and PD-L1 testing (based on immunohistochemistry [IHC] testing in a central laboratory). For subjects who are unable to provide tumor tissue samples that meet the above requirements, the decision on whether to enroll in the study must be made after discussion with the sponsor.

[0463] 7) Suitable for and agree to undergo radical cystectomy (RC) + pelvic lymph node dissection (PLND).

[0464] 6) The subject has evaluable lesions that meet the RECIST 1.1 criteria (Phase II is assessed by the investigator, and Phase III is assessed by BICR).

[0465] 3. Clinical plan

[0466] 3.1 Research Design

[0467] Phase II

[0468] After four cycles (21 days per cycle) of neoadjuvant treatment with an anti-nectin-4 antibody-drug conjugate (6 mg / kg Q3W or 8 mg / kg Q3W) combined with an anti-PD-L1 antibody (1200 mg Q3W), patients underwent radical cystectomy (RC) and pelvic lymph node dissection (PLND). In the postoperative adjuvant treatment phase, patients received five cycles (21 days per cycle) of the anti-nectin-4 antibody-drug conjugate (6 mg / kg Q3W) combined with an anti-PD-L1 antibody (1200 mg Q3W), followed by eight cycles (21 days per cycle) of monotherapy with the anti-PD-L1 antibody (1200 mg Q3W).

[0469] Phase III

[0470] In this phase, eligible subjects were randomly assigned to the experimental group and the control group in a 1:1 ratio. Randomization stratification factors were: ECOG (0 vs 1); pathological stage (T2N0 vs T3 / 4aN0 vs T1-4aN1); PD-L1 (CPS ≥ 10 vs CPS < 10). The treatment regimens for the experimental group and the control group (existing standard perioperative treatment regimen) were as follows:

[0471] 1. Experimental Group (Group A): Received 4 cycles (one cycle of 21 days) of neoadjuvant treatment with an anti-nectin-4 antibody-drug conjugate (6 mg / kg, Q3W) combined with an anti-PD-L1 antibody (1200 mg, Q3W), followed by radical cystectomy (RC) and pelvic lymph node dissection (PLND). In the postoperative adjuvant treatment phase, patients received 5 cycles (one cycle of 21 days) of anti-nectin-4 antibody-drug conjugate (6 mg / kg, Q3W) combined with an anti-PD-L1 antibody (1200 mg, Q3W), followed by 8 cycles (one cycle of 21 days) of monotherapy with an anti-PD-L1 antibody (1200 mg, Q3W).

[0472] Subjects in both the experimental and control groups will complete 4 cycles of neoadjuvant therapy and then have their imaging reviewed (in the same manner as during the screening period) ≤ 5 weeks (35 days + 7 days) before planned RC+PLND surgery to exclude disease progression (confirmed by BICR). Subjects whose imaging examinations show no distant metastases will undergo surgery within 6 weeks after the last neoadjuvant treatment. If the surgery is delayed due to AEs, the subject can undergo surgery outside this time window (up to 12 weeks. If it exceeds 12 weeks, the decision must be made in consultation with the sponsor). If the subject's surgery is delayed for any reason other than AEs (i.e., more than 6 weeks after the last neoadjuvant treatment), the decision can be made in consultation with the sponsor. Suspected distant disease progression (based on imaging findings assessed by the research center) occurring at any pre-operative time point (or during the neoadjuvant treatment period) should be verified as disease progression by BICR as soon as possible.

[0473] Subjects in Group A without radiographic disease progression will continue to receive anti-nectin-4 antibody-drug conjugate (6 mg / kg, Q3W) combined with anti-PD-L1 antibody (1200 mg, Q3W) combination therapy (adjuvant treatment period, starting 8 weeks ± 14 days after radical cystectomy), up to 5 cycles of anti-nectin-4 antibody-drug conjugate (6 mg / kg, Q3W) combined with anti-PD-L1 antibody (1200 mg, Q3W) combination therapy, and then 8 cycles (one cycle of 21 days) of anti-PD-L1 antibody (1200 mg, Q3W) monotherapy to complete a total of approximately 1 year of treatment.

[0474] 3.2 Administration

[0475] ADC-4: intravenous infusion, 6 mg / kg, every 3 weeks; or other doses to be explored / determined.

[0476] Anti-PD-L1 antibody: intravenous drip, 1200 mg, administered once every 3 weeks, each drip time is 30-60 minutes, and one cycle is 21 days (Q3W).

[0477] 4. Results Evaluation

[0478] 4.1 Effectiveness Indicators

[0479] Tumor assessment was performed using RECIST v1.1, and all subjects underwent baseline tumor imaging during the screening period. Efficacy measures included investigator-assessed ORR, DCR, DoR, PFS, and OS.

[0480] 4.2 Safety evaluation

[0481] After all subjects are enrolled in the study, safety assessments will be conducted during each treatment cycle. This includes the incidence and grade of AEs, serious adverse events (SAEs) (assessed according to NCI-CTCAE v5.0 criteria), 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.

Claims

1. Use of an anti-nectin-4 antibody-drug conjugate in the preparation of a drug for treating tumors, wherein the anti-nectin-4 antibody-drug conjugate comprises the following structure: in: 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; and the tumor is a urinary system tumor.

2. The use according to claim 1, wherein The subject with the urinary system tumor has previously received anti-tumor treatment, wherein the anti-tumor treatment is selected from chemotherapy, antibody-drug conjugate (ADC) treatment, and / or immunotherapy, and the chemotherapy is preferably platinum-containing treatment.

3. The use according to claim 1 or 2, wherein The subject with the urinary system tumor has failed or is intolerant to previous anti-tumor treatment, preferably is a subject who has failed or is intolerant to chemotherapy, antibody-drug conjugate (ADC) treatment, and / or immunotherapy, and the chemotherapy is preferably platinum-containing treatment.

4. The use according to any one of claims 1 to 3, wherein The urinary system tumor is urothelial carcinoma or bladder cancer.

5. The use according to claim 4, wherein The urothelial carcinoma is advanced urothelial carcinoma; preferably locally advanced or metastatic urothelial carcinoma.

6. The use according to any one of claims 1 to 5, wherein 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, SEQ ID NO: 2, and SEQ ID NO: 3, respectively; and the light chain variable region comprises LCDR1, LCDR2, and LCDR3 as shown 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) and a light chain variable region (VL), wherein the heavy chain variable region comprises an amino acid sequence as shown in SEQ ID NO: 7 or at least 80% or 90% identical thereto, and the light chain variable region comprises an amino acid sequence as shown in SEQ ID NO: 8 or at least 80% or 90% identical thereto; More preferably, the anti-nectin-4 antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises an amino acid sequence as shown in SEQ ID NO: 9 or at least 80%, 90% identical thereto, and the light chain comprises an amino acid sequence as shown in SEQ ID NO: 10 or at least 80%, 90% identical thereto.

7. The use according to any one of claims 1 to 6, wherein The anti-nectin-4 antibody drug conjugate is administered at a dosage 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 antibody drug conjugate is administered 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; preferably, once every 3 weeks, or twice every 3 weeks; Preferably, the dosage 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 administration frequency is once every 3 weeks; or, the dosage 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, and the administration frequency is twice every 3 weeks.

8. Use of an anti-nectin-4 antibody-drug conjugate in combination with an immunotherapeutic agent in the preparation of a medicament for treating tumors; the anti-nectin-4 antibody-drug conjugate comprises the following structure: in: 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; Preferably, the immunotherapeutic agent is an anti-PD-L1 antibody and / or an anti-CTLA-4 antibody; Preferably, the anti-nectin-4 antibody is as defined in claim 6 , and the dosage and frequency of administration of the anti-nectin-4 antibody-drug conjugate are as defined in claim 7 .

9. The use according to claim 8, wherein 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 shown in SEQ ID NO: 11, SEQ ID NO: 12, and SEQ ID NO: 13, respectively, and the light chain variable region comprises LCDR1, LCDR2, and LCDR3 as shown in SEQ ID NO: 14, SEQ ID NO: 15, and SEQ ID NO: 16, respectively; Preferably, the heavy chain variable region comprises an amino acid sequence as shown in SEQ ID NO: 17, or at least 80%, 90% identical thereto, and the light chain variable region comprises an amino acid sequence as shown in SEQ ID NO: 18, or at least 80%, 90% identical thereto; More preferably, the anti-PD-L1 antibody comprises a heavy chain and a light chain, the heavy chain comprising an amino acid sequence as shown in SEQ ID NO: 19 or at least 80%, 90% identical thereto, and the light chain comprising an amino acid sequence as shown in SEQ ID NO: 20 or at least 80%, 90% identical thereto.

10. The use according to claim 8 or 9, wherein The dosage of the anti-PD-L1 antibody is 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 frequency of administration of the anti-PD-L1 antibody is 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 dosage 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; the frequency of administration of the anti-PD-L1 antibody is once every 3 weeks; More preferably, the dosage of the anti-PD-L1 antibody is about 1200 mg, and the administration frequency is once every 3 weeks.

11. The use according to claim 8, wherein 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 NO:21, SEQ ID NO:22, and SEQ ID NO:23, respectively, and the light chain variable region comprises LCDR1, LCDR2, and LCDR3 as shown 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 as shown in SEQ ID NO: 27, or at least 90% identical thereto, and the light chain variable region comprises an amino acid sequence as shown in SEQ ID NO: 28, or at least 90% identical thereto; More preferably, the anti-CTLA-4 antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises an amino acid sequence as shown in SEQ ID NO: 29 or at least 80%, 90% identical thereto, and the light chain comprises an amino acid sequence as shown in SEQ ID NO: 30 or at least 80%, 90% identical thereto.

12. The use according to claim 8 or 11, wherein The anti-CTLA-4 antibody is administered in a dosage 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 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 once a single administration, preferably once every 6 weeks or once a single administration; Preferably, the dosage 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; the frequency of administration of the anti-CTLA-4 antibody is once every 6 weeks or a single administration; More preferably, the anti-CTLA-4 antibody is administered once in week 1 at a dosage of about 280 mg or 210 mg, is not administered in weeks 2-12, and starting from week 13, is administered at a dosage of about 70 mg, with a dosing frequency of once every 6 weeks.

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

14. The use according to any one of claims 8 to 13, wherein The tumor is urothelial carcinoma or bladder cancer; Preferably, the urothelial carcinoma is advanced urothelial carcinoma; more preferably, it is locally advanced or metastatic urothelial carcinoma.

15. The use according to claim 14, wherein The bladder cancer is muscle-invasive bladder cancer, preferably non-metastatic muscle-invasive bladder cancer.

16. The use according to any one of claims 8 to 15, wherein The subject with the tumor has not been treated before, or has received anti-tumor treatment before; Preferably, the subject has previously failed or is intolerant to anti-tumor therapy; Preferably, the subject with the tumor has previously received platinum-containing chemotherapy, immunotherapy, and / or antibody-drug conjugate (ADC) treatment.

17. A kit or article of manufacture comprising an anti-nectin-4 antibody drug conjugate as defined in any one of claims 1, 6-7 and 13, and / or an immunotherapeutic agent as defined in any one of claims 8-13; Preferably, the kit or article 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 and an anti-CTLA-4 antibody; or an anti-nectin-4 antibody drug conjugate and an anti-PD-L1 antibody and an anti-CTLA-4 antibody.

18. A pharmaceutical composition comprising an anti-nectin-4 antibody drug conjugate as defined in any one of claims 1, 6 to 7, and 13, and an immunotherapeutic agent as defined in any one of claims 8 to 13; 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 and an anti-CTLA-4 antibody; or an anti-nectin-4 antibody-drug conjugate and an anti-PD-L1 antibody and an anti-CTLA-4 antibody.

19. Use of the pharmaceutical kit or product according to claim 17, or the pharmaceutical composition according to claim 18, in the preparation of a medicament for treating tumors; Preferably, the tumor is as defined in any one of claims 2-53 and 15.

20. A method for preventing or treating tumors, comprising administering to a subject in need thereof: 1) an anti-nectin-4 antibody-drug conjugate, or 2) an anti-nectin-4 antibody-drug conjugate and an immunotherapeutic agent; wherein 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 following structure: in: 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; Preferably, the anti-nectin-4 antibody drug conjugate is combined as defined in any one of claims 1, 6-7 and 13, and the immunotherapeutic agent is defined in any one of claims 8-13; The tumor is as defined in any one of claims 2-5 and 15.

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