Combination of anti-TROP-2 antibody-drug conjugates with other therapeutic agents

Abstract

The present invention relates to a combination of an anti-TROP-2 antibody-drug conjugate with an anti-PD-L1 antibody, or with other chemotherapeutic agents (such as carboplatin or cisplatin), and the use of said combination in the manufacture of a medicament for the prevention and / or treatment of a neoplastic disease, wherein the anti-TROP-2 antibody may be sacituzumab.

Description

[Technical field]

[0001] This application claims priority from Chinese Application No. 202210036236.5, filed on January 13, 2022. The contents disclosed in said Chinese application are incorporated herein by reference in their entirety. The present invention belongs to the fields of tumor therapy and molecular immunology, and relates to the combination of an anti-TROP-2 antibody-drug conjugate with another therapeutic agent, for example a combination of a PD-L1 inhibitor with a chemotherapeutic agent, in the manufacture of a medicament for the prevention and / or treatment of a tumor disease. [Background technology]

[0002] In China, malignant tumors have become a common and frequent disease, seriously threatening human life and health. According to a study by the International Agency for Research on Cancer (IARC), China accounts for approximately 21.8% and 27% of the world's new cases and deaths from malignant tumors, respectively. Chemotherapy remains the main treatment for advanced malignant tumors, but chemotherapy agents can not only kill tumor cells, but also indiscriminately attack normal human cells, causing severe side effects.

[0003] In recent years, with the application of immune checkpoint inhibitors (ICIs), medicine has entered the era of large-scale immunotherapy drugs, and ICIs have changed the clinical practice of tumor treatment. At present, ICIs have evolved from being initially used as second-line therapy in most tumor types to being used as first-line therapy in some tumor types, and even as adjuvant therapy for a few tumor types, and have moved from monotherapy to combination therapy. Clinically, ICIs are often combined with chemotherapy to enhance efficacy and promote ICIs to induce effective antitumor responses in a broader patient population, and their synergistic effects have been demonstrated in clinical trials.

[0004] It has been reported that camptothecin can activate the immune system and act synergistically with ICIs. Camptothecin (CPT), camptothecin sodium (CPT-Na), irinotecan hydrochloride (CPT-11), and topotecan hydrochloride (TPT) can effectively activate dendritic cells via the nuclear factor-κB (NF-κB)-related pathway and upregulate the surface expression of major histocompatibility complex class II (MHC-II), CD40, and CD80 (Mizumoto et al., 2005). In a mouse breast cancer model, it was further observed that the combination of CPT-11 and anti-PD-L1 effectively promoted the increase of infiltrating proliferative CD8+ T cells (Ki67+CD8+ T cells) in draining lymph nodes and tumors, and the antitumor effect was significantly superior to that of monotherapy (Iwai et al., 2018). In another study, CPT-11 liposomes effectively activated tumor-killing T cell-mediated immune responses by stimulating human melanoma cells and regulating the expression of genes involved in the TP53 pathway, and when combined with anti-PD-1 or anti-PD-L1 antibodies, they could effectively extend the survival time of colon cancer-bearing mice (McKenzie et al. 2018). In addition, CPT-11 and its active metabolite SN38 were shown to have the ability to further induce immunogenic cell death (ICD), and showed synergistic antitumor effects in combination with anti-PD-1 and anti-PD-L1 monoclonal antibodies in mouse pancreatic cancer and melanoma models, respectively (Liu et al. 2021, Gong et al. 2020).

[0005] The trend in cancer treatment to selectively kill tumor cells and minimize damage to normal cells has been around for a long time. In recent years, it has been found that therapeutic antibodies can be conjugated with bioactive molecules to form antibody-drug conjugates (ADCs). ADC drugs are conjugates formed when individual antibodies are bound to small molecule cytotoxic drugs via linkers. When ADC drugs enter the blood, the antibody components specifically bind to tumor cell surface antigens, enter the cells via endocytosis, and release cytotoxic drugs to kill tumor cells. ADC drugs directly target tumor cells, greatly reducing the toxicity and side effects of chemotherapy drugs on other normal cells and reducing the occurrence of systemic adverse events. The combination of ICIs and chemotherapy drugs that activate the immune system can synergistically enhance anti-tumor immune responses and kill tumors, so the combination of ADCs with immunomodulatory effects and ICIs may not only achieve the goal of synergy, but also further overcome the limitations of ICIs and chemotherapy drugs. For example, when ICIs are combined with chemotherapy, it is possible to avoid bone marrow suppression produced by toxic molecules, peripheral immune tolerance and autoimmune complications due to the activation of the immune system by toxic molecules (Bauzon et al. 2019). Summary of the Invention [Problem to be solved by the invention]

[0006] The present invention provides methods, pharmaceutical compositions, uses, and kits for the treatment of cancer with combinations of therapeutic agents, such as combinations of antibody drug conjugates with other therapeutic agents. [Means for solving the problem]

[0007] One aspect of the invention provides the use of anti-TROP-2 antibody-drug conjugates and other therapeutic agents in the manufacture of a medicament for treating cancer in a subject.

[0008] In some embodiments, the other therapeutic agent is one or more selected from the group consisting of an anti-PD-L1 antibody, or antigen-binding fragment thereof, and a chemotherapeutic agent.

[0009] In some embodiments, the use comprises administering to a subject an anti-TROP-2 antibody-drug conjugate and an anti-PD-L1 antibody, or antigen-binding fragment thereof.

[0010] In some embodiments, the anti-TROP-2 antibody-drug conjugate comprises a camptothecin and an anti-TROP-2 antibody or antigen-binding fragment thereof comprising a heavy chain variable region and a light chain variable region, the heavy chain variable region comprising an HCDR1 set forth in SEQ ID NO:1, an HCDR2 set forth in SEQ ID NO:2, and an HCDR3 set forth in SEQ ID NO:3, and the light chain variable region comprising an LCDR1 set forth in SEQ ID NO:4, an LCDR2 set forth in SEQ ID NO:5, and an LCDR3 set forth in SEQ ID NO:6.

[0011] In some embodiments, the anti-PD-L1 antibody or antigen-binding fragment thereof is one or more selected from the group consisting of durvalumab, atezolizumab, and embafolimab.

[0012] In some embodiments, the anti-PD-L1 antibody or antigen-binding fragment thereof comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises HCDR1 set forth in SEQ ID NO:7, HCDR2 set forth in SEQ ID NO:8, and HCDR3 set forth in SEQ ID NO:9, and the light chain variable region comprises LCDR1 set forth in SEQ ID NO:10, LCDL2 set forth in SEQ ID NO:11, and LCDL3 set forth in SEQ ID NO:12.

[0013] In some embodiments, the use further comprises administering to the subject a chemotherapeutic agent.

[0014] In some embodiments, the chemotherapeutic agent is selected from a platinum agent.

[0015] In some embodiments, the platinum agent is selected from the group consisting of cisplatin, carboplatin, sulfatodiaminocyclohexane platinum, nedaplatin, oxaliplatin, lobaplatin, satraplatin, miboplatin, enloplatin, iproplatin, or dicycloplatin.

[0016] In some embodiments, the anti-TROP-2 antibody comprises a heavy chain set forth in SEQ ID NO:13 and a light chain set forth in SEQ ID NO:14.

[0017] In some embodiments, the anti-PD-L1 antibody or antigen-binding fragment thereof comprises a heavy chain variable region set forth in SEQ ID NO:15, and a light chain variable region set forth in SEQ ID NO:16.

[0018] In some embodiments, the anti-PD-L1 antibody or antigen-binding fragment thereof comprises a mutation in the amino acid sequence of an anti-PD-L1 antibody of the invention. The amino acid sequence of the variant is identical to the reference sequence except that it has one, two, three, four, or five amino acid substitutions, deletions, and / or additions.

[0019] In some embodiments, substitutions, deletions, and / or additions are made to the CDRs, hi some embodiments, substitutions, deletions, and / or additions are made to the framework regions.

[0020] In some embodiments, one, two, three, four or five amino acid substitutions are conservative substitutions.

[0021] In some embodiments, the anti-PD-L1 antibody or antigen-binding fragment thereof comprises the V L V that shares at least 95%, 90%, 85%, 80%, 75%, or 50% sequence identity with one of the domains L It has a PD-L1 domain and exhibits specific binding to PD-L1.

[0022] In some embodiments, the anti-PD-L1 antibody or antigen-binding fragment thereof comprises the V H V that shares at least 95%, 90%, 85%, 80%, 75%, or 50% sequence identity with one of the domains H It has a PD-L1 domain and exhibits specific binding to PD-L1.

[0023] In some embodiments, the anti-PD-L1 antibody or antigen-binding fragment thereof comprises the V L V with up to 1, 2, 3, 4, 5 or more amino acid substitutions, deletions, and / or additions compared to one of the domains L It has a PD-L1 domain and exhibits specific binding to PD-L1.

[0024] In some embodiments, the anti-PD-L1 monoclonal antibody or antigen-binding fragment thereof comprises the V H V with up to 1, 2, 3, 4, 5 or more amino acid substitutions, deletions, and / or additions compared to one of the domains H It has a PD-L1 domain and exhibits specific binding to PD-L1.

[0025] In some embodiments, the anti-PD-L1 antibody or antigen-binding fragment thereof comprises the V L a VL domain that has up to one, two, three, four, five or more amino acid substitutions, deletions, and / or additions compared to one of the VH domains of the anti-PD-L1 antibodies of the invention; and a VH domain that has up to one, two, three, four, five or more amino acid substitutions, deletions, and / or additions compared to one of the VH domains of the anti-PD-L1 antibodies of the invention. H It has a PD-L1 domain and exhibits specific binding to PD-L1.

[0026] Generally, variants of the anti-PD-L1 monoclonal antibodies and antigen-binding fragments disclosed in the present invention may be derived from the amino acid sequence (e.g., heavy chain, light chain, V chain, H , V Lor humanized sequence), and more preferably at least 80%, more preferably at least 85%, more preferably at least 90%, and most preferably at least 95%, 98% or 99%. In the present invention, the term "identity" or "homology" is defined as the percentage of amino acid residues in a candidate sequence that are identical to a reference sequence, after aligning sequences if necessary and introducing vacancies to achieve maximum sequence identity, without considering conservative substitutions as part of the sequence identity. Any N-terminal, C-terminal, or internal extensions, deletions, or insertions of the antibody sequence shall not be construed as affecting sequence identity or homology.

[0027] In some embodiments, the anti-PD-L1 monoclonal antibody is a human antibody. In other embodiments, the anti-PD-L1 monoclonal antibody is a humanized antibody.

[0028] In some embodiments, the antibody drug conjugate has the following chemical structure: [ka] γ represents the average number of drug-linker units attached per antibody molecule in the antibody-drug conjugate, the average number being in the range of 6 to 10. In some embodiments, the average number of γ is 6 to 9. In some embodiments, the average number of γ is 6 to 8, e.g., about 6.1, 6.2, 6.3, 6.4, 6.5, 6.6.6, 6.7, 6.8, 6.9, 7, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7.8, or 7.9.

[0029] In some embodiments, the cancer is a solid tumor or a non-solid tumor, e.g., selected from the group consisting of esophageal cancer (such as esophageal adenocarcinoma and esophageal squamous cell carcinoma), brain tumor, lung cancer (e.g., small cell lung cancer and non-small cell lung cancer), squamous cell carcinoma, bladder cancer, gastric cancer, ovarian cancer, peritoneal cancer, pancreatic cancer, breast cancer, head and neck cancer, cervical cancer, endometrial cancer, colorectal cancer, liver cancer, renal cancer, non-Hodgkin's lymphoma, central nervous system tumors (such as glioblastoma multiforme, glioma, or sarcoma), prostate cancer, and thyroid cancer.

[0030] In some embodiments, the cancer is selected from the group consisting of lung cancer, breast cancer, and ovarian epithelial cancer.

[0031] In some embodiments, the cancer is non-small cell lung cancer (NSCLC) or triple-negative breast cancer (TNBC).

[0032] In some embodiments, the non-small cell lung cancer is selected from EGFR wild-type or mutated non-small cell lung cancer.

[0033] In some embodiments, the non-small cell lung cancer is advanced / metastatic non-small cell lung cancer.

[0034] In some embodiments, the non-small cell lung cancer is advanced non-small cell lung cancer that has not received systemic therapy or has received at most first-line chemotherapy.

[0035] In some embodiments, the non-small cell lung cancer is ALK rearrangement-negative non-small cell lung cancer.

[0036] In some embodiments, the EGFR mutation is a single mutation or a compound mutation.

[0037] In some embodiments, the breast cancer is selected from the group consisting of triple negative breast cancer, HR+ / HER2- breast cancer, HR- / HER2+ breast cancer, HR+ / HER2+ breast cancer, and BRCA+ breast cancer.

[0038] In some embodiments, the breast cancer is triple-negative breast cancer.

[0039] In some embodiments, the ovarian cancer is ovarian epithelial cancer.

[0040] In some embodiments, the anti-TROP-2 antibody-drug conjugate and the other therapeutic agent are present in a unit dosage form.

[0041] In some embodiments, the anti-TROP-2 antibody-drug conjugate and the other therapeutic agent are present in the same formulation unit.

[0042] In some embodiments, the anti-TROP-2 antibody-drug conjugate and the other therapeutic agent are present in different formulation units.

[0043] In some embodiments, the anti-TROP-2 antibody-drug conjugate and another therapeutic agent are administered in combination.

[0044] In some embodiments, the anti-TROP-2 antibody-drug conjugate and the other therapeutic agent are administered separately.

[0045] In some embodiments, the anti-TROP-2 antibody-drug conjugate and the other therapeutic agent are administered sequentially.

[0046] In some embodiments, the anti-TROP-2 antibody-drug conjugate is administered first, followed by the other therapeutic agent.

[0047] In some embodiments, the administration cycle of the antibody-drug conjugate is 14 to 42 days. In some embodiments, the administration cycle of the antibody-drug conjugate is 14 days, 21 days, 28 days, or 42 days. In some embodiments, the administration cycle of the antibody-drug conjugate is 14 days. In some embodiments, the administration cycle of the antibody-drug conjugate is 21 days.

[0048] In some embodiments, the administration cycle of the other therapeutic agent is 14 to 42 days, for example, 14 days, 21 days, 28 days, or 42 days.

[0049] In some embodiments, the administration cycle of the anti-PD-L1 antibody or antigen-binding fragment thereof is 14 to 42 days. In some embodiments, the administration cycle of the anti-PD-L1 antibody or antigen-binding fragment thereof is 14 days, 21 days, 28 days, or 42 days.

[0050] In some embodiments, the administration cycle of the anti-PD-L1 antibody or antigen-binding fragment thereof is 14 days.In some embodiments, the administration cycle of the anti-PD-L1 antibody or antigen-binding fragment thereof is 21 days.

[0051] In some embodiments, the administration cycle of the platinum agent (e.g., carboplatin or cisplatin) is 21 to 42 days. In some embodiments, the administration cycle of the platinum agent (e.g., carboplatin or cisplatin) is 21 days, 28 days, or 42 days. In some embodiments, the administration cycle of the platinum agent (e.g., carboplatin or cisplatin) is 21 days. In some embodiments, the administration cycle of the platinum agent (e.g., carboplatin or cisplatin) is 28 days. In some embodiments, the administration cycle of the platinum agent (e.g., carboplatin or cisplatin) is 42 days.

[0052] In some embodiments, the antibody-drug conjugate is administered at a dose of 1 to 10 mg / kg, preferably selected from the group consisting of 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg / kg, or 10 mg / kg. In some embodiments, the antibody-drug conjugate is administered at a dose of 4 mg / kg or 5 mg / kg.

[0053] In some embodiments, the anti-PD-L1 antibody or antigen-binding fragment thereof is administered at a dose of 900 to 1500 mg, preferably selected from the group consisting of 900 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, and 1500 mg.

[0054] In some embodiments, the anti-PD-L1 antibody or antigen-binding fragment thereof is administered at a single dose of 900 mg or 1200 mg.

[0055] In some embodiments, the non-small cell lung cancer is advanced non-small cell lung cancer that has not received systemic therapy or has received at most first-line chemotherapy, and the anti-PD-L1 antibody or antigen-binding fragment thereof is administered at a dose of 900 mg or 1200 mg per dose.

[0056] In some embodiments, the antibody drug conjugate is administered at a dose of 4 mg / kg or 5 mg / kg per administration, the non-small cell lung cancer is advanced non-small cell lung cancer that has not received systemic therapy or has received at most first-line chemotherapy, and the anti-PD-L1 antibody or antigen-binding fragment thereof is administered at a dose of 900 mg or 1200 mg per administration.

[0057] In some embodiments, the breast cancer is triple-negative breast cancer and the anti-PD-L1 antibody or antigen-binding fragment thereof is administered at a dose of 900 mg or 1200 mg per dose.

[0058] In some embodiments, the antibody drug conjugate is administered at a dose of 4 mg / kg or 5 mg / kg per administration, the breast cancer is triple-negative breast cancer, and the anti-PD-L1 antibody or antigen-binding fragment thereof is administered at a dose of 900 mg or 1200 mg per administration.

[0059] In some embodiments, the anti-TROP-2 antibody drug conjugate and other therapeutic agent comprises an anti-PD-L1 antibody or antigen-binding fragment thereof and one or more chemotherapeutic agents selected from the group consisting of carboplatin or cisplatin in the manufacture of a medicament for non-small cell lung cancer, triple negative breast cancer, and ovarian cancer.

[0060] In some embodiments, carboplatin is administered at a dose of 1 to 10 mg / ml / min, preferably 1 mg / ml / min, 2 mg / ml / min, 2.5 mg / ml / min, 3 mg / ml / min, 3.75 mg / ml / min, 4 mg / ml / min, 5 mg / ml / min, 6 mg / ml / min, 7 mg / ml / min, and 8 mg / ml / min, calculated as area under the curve (AUC). In some embodiments, carboplatin is administered at a dose of 5 mg / ml / min or 3.75 mg / ml / min or 2.5 mg / ml / min.

[0061] In some embodiments, cisplatin is administered at a dose of 50 to 150 mg / m 2 , preferably 50 mg / m 2 , 75 mg / m 2 , 100 mg / m 2 , 120 mg / m 2 , 150 mg / m 2 is administered at a dose of

[0062] In some embodiments, the antibody drug conjugate and the anti-PD-L1 antibody or antigen-binding fragment thereof are administered in a single dose, as described above.

[0063] In some embodiments, the subject is a non-small cell lung cancer patient who has not previously received checkpoint inhibitor therapy and has not received a first-line systemic chemotherapy regimen or has received at most a first-line systemic chemotherapy regimen.

[0064] In some embodiments, the subject is a non-small cell lung cancer patient who has previously received adjuvant, neoadjuvant, or definitive chemoradiotherapy and whose cancer has progressed during or within 6 months of completing treatment.

[0065] In some embodiments, the subject is a non-small cell lung cancer patient who has been treated with an EGFR kinase inhibitor and has failed the treatment.

[0066] In some embodiments, the subject has previously failed treatment with a first or second generation EGFR tyrosine kinase inhibitor (TKI) and is negative for the T790M mutation in exon 20 of EGFR.

[0067] In some embodiments, the subject has previously failed treatment with a third generation EGFR tyrosine kinase inhibitor (TKI).

[0068] In some embodiments, the subject has not been previously treated with systemic anti-tumor therapy for locally advanced or metastatic non-small cell lung cancer and has not been treated with an immune checkpoint inhibitor.

[0069] In some embodiments, the subject is a patient with unresectable locally advanced, recurrent, or metastatic triple-negative breast cancer who has not received prior systemic therapy.

[0070] Another aspect of the invention is also a method of treating cancer in a subject, comprising administering to the subject a therapeutically effective amount of an anti-TROP-2 antibody-drug conjugate and other therapeutic agent, as described above.

[0071] In some embodiments, the other therapeutic agent is one or more selected from the group consisting of an anti-PD-L1 antibody, or antigen-binding fragment thereof, and a chemotherapeutic agent, as described above.

[0072] In some embodiments, the anti-TROP-2 antibody-drug conjugate comprises a camptothecin and an anti-TROP-2 antibody or antigen-binding fragment thereof comprising a heavy chain variable region and a light chain variable region, the heavy chain variable region comprising an HCDR1 set forth in SEQ ID NO:1, an HCDR2 set forth in SEQ ID NO:2, and an HCDR3 set forth in SEQ ID NO:3, and the light chain variable region comprising an LCDR1 set forth in SEQ ID NO:4, an LCDR2 set forth in SEQ ID NO:5, and an LCDR3 set forth in SEQ ID NO:6.

[0073] In some embodiments, the anti-PD-L1 antibody or antigen-binding fragment thereof is one or more selected from the group consisting of durvalumab, atezolizumab, and embafolimab.

[0074] In some embodiments, the anti-PD-L1 antibody or antigen-binding fragment thereof comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises an HCDR1 set forth in SEQ ID NO:7, an HCDR2 set forth in SEQ ID NO:8, and an HCDR3 set forth in SEQ ID NO:9, and the light chain variable region comprises an LCDR1 set forth in SEQ ID NO:10, an LCDR2 set forth in SEQ ID NO:11, and an LCDR3 set forth in SEQ ID NO:12.

[0075] In some embodiments, the chemotherapeutic agent is selected from a platinum agent.

[0076] In some embodiments, the platinum agent is selected from the group consisting of cisplatin, carboplatin, sulfatodiaminocyclohexaneplatin, nedaplatin, oxaliplatin, lobaplatin, satraplatin, miboplatin, enloplatin, iproplatin, or dicycloplatin.

[0077] In some embodiments, the anti-TROP-2 antibody comprises a heavy chain set forth in SEQ ID NO:13 and a light chain set forth in SEQ ID NO:14.

[0078] In some embodiments, the anti-PD-L1 antibody or antigen-binding fragment thereof comprises a heavy chain variable region set forth in SEQ ID NO:15, and a light chain variable region set forth in SEQ ID NO:16.

[0079] In some embodiments, the anti-PD-L1 antibody or antigen-binding fragment thereof comprises a mutation in the amino acid sequence of an anti-PD-L1 antibody of the invention. The amino acid sequence of the variant is identical to the reference sequence except that it has one, two, three, four, or five amino acid substitutions, deletions, and / or additions.

[0080] In some embodiments, substitutions, deletions, and / or additions are made to the CDRs, hi some embodiments, substitutions, deletions, and / or additions are made to the framework regions.

[0081] In some embodiments, one, two, three, four or five amino acid substitutions are conservative substitutions.

[0082] In some embodiments, the anti-PD-L1 antibody or antigen-binding fragment thereof comprises the V L V that shares at least 95%, 90%, 85%, 80%, 75%, or 50% sequence identity with one of the domains L It has a PD-L1 domain and exhibits specific binding to PD-L1.

[0083] In some embodiments, the anti-PD-L1 antibody or antigen-binding fragment thereof comprises the V H V that shares at least 95%, 90%, 85%, 80%, 75%, or 50% sequence identity with one of the domains H It has a PD-L1 domain and exhibits specific binding to PD-L1.

[0084] In some embodiments, the anti-PD-L1 antibody or antigen-binding fragment thereof may comprise the V L V with up to 1, 2, 3, 4, 5 or more amino acid substitutions, deletions, and / or additions compared to one of the domains L It has a PD-L1 domain and exhibits specific binding to PD-L1.

[0085] In some embodiments, the anti-PD-L1 monoclonal antibody or antigen-binding fragment thereof comprises the V H V with up to 1, 2, 3, 4, 5 or more amino acid substitutions, deletions, and / or additions compared to one of the domains H It has a PD-L1 domain and exhibits specific binding to PD-L1.

[0086] In some embodiments, the anti-PD-L1 antibody or antigen-binding fragment thereof comprises the V L V with up to 1, 2, 3, 4, 5 or more amino acid substitutions, deletions, and / or additions compared to one of the domains L domain and have up to one, two, three, four, five or more amino acid substitutions, deletions, and / or additions compared to one of the VH domains of the anti-PD-L1 antibodies of the invention, and exhibit specific binding to PD-L1.

[0087] In general, variants of the anti-PD-L1 monoclonal antibodies and antigen-binding fragments thereof disclosed in the present invention have an amino acid sequence that has at least 75% amino acid sequence identity, more preferably at least 80%, more preferably at least 85%, more preferably at least 90%, and most preferably at least 95%, 98% or 99% identity, compared to the amino acid sequence of a reference antibody or antigen-binding fragment (e.g., heavy chain, light chain, VH, VL or humanized sequence). In the present invention, the term "identity" or "homology" is defined as the percentage of amino acid residues in a candidate sequence that are identical to a reference sequence, after aligning the sequence if necessary and introducing vacancies to achieve maximum sequence identity, without considering conservative substitutions as part of the sequence identity. Any N-terminal, C-terminal, or internal extensions, deletions, or insertions of the antibody sequence shall not be construed as affecting sequence identity or homology.

[0088] In some embodiments, the anti-PD-L1 monoclonal antibody is a human antibody. In other embodiments, the anti-PD-L1 monoclonal antibody is a humanized antibody.

[0089] In some embodiments, the antibody drug conjugate has the following chemical structure: [ka] γ represents the average number of drug-linker units attached per antibody molecule in the antibody-drug conjugate, the average number being in the range of 6 to 10. In some embodiments, the average number of γ is 6 to 9. In some embodiments, the average number of γ is 6 to 8, e.g., about 6.1, 6.2, 6.3, 6.4, 6.5, 6.6.6, 6.7, 6.8, 6.9, 7, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7.8, or 7.9.

[0090] In some embodiments, the cancer is a solid tumor or a non-solid tumor, e.g., selected from the group consisting of esophageal cancer (such as esophageal adenocarcinoma and esophageal squamous cell carcinoma), brain tumor, lung cancer (e.g., small cell lung cancer and non-small cell lung cancer), squamous cell carcinoma, bladder cancer, gastric cancer, ovarian cancer, peritoneal cancer, pancreatic cancer, breast cancer, head and neck cancer, cervical cancer, endometrial cancer, colorectal cancer, liver cancer, renal cancer, non-Hodgkin's lymphoma, central nervous system tumors (such as glioblastoma multiforme, glioma, or sarcoma), prostate cancer, and thyroid cancer.

[0091] In some embodiments, the cancer is selected from the group consisting of lung cancer, breast cancer, and ovarian epithelial cancer.

[0092] In some embodiments, the cancer is non-small cell lung cancer (NSCLC) or triple-negative breast cancer (TNBC).

[0093] In some embodiments, the non-small cell lung cancer is selected from EGFR wild-type or mutated non-small cell lung cancer.

[0094] In some embodiments, the non-small cell lung cancer is advanced / metastatic non-small cell lung cancer.

[0095] In some embodiments, the non-small cell lung cancer is advanced non-small cell lung cancer that has not received systemic therapy or has received at most first-line chemotherapy.

[0096] In some embodiments, the non-small cell lung cancer is ALK rearrangement-negative non-small cell lung cancer.

[0097] In some embodiments, the EGFR mutation is a single mutation or a compound mutation.

[0098] In some embodiments, the breast cancer is selected from the group consisting of triple negative breast cancer, HR+ / HER2- breast cancer, HR- / HER2+ breast cancer, HR+ / HER2+ breast cancer, and BRCA+ breast cancer.

[0099] In some embodiments, the breast cancer is triple-negative breast cancer.

[0100] In some embodiments, the ovarian cancer is ovarian epithelial cancer.

[0101] In some embodiments, the cancer is non-small cell lung cancer as described above.

[0102] In some embodiments, the aforementioned anti-TROP-2 antibody drug conjugates for the treatment of non-small cell lung cancer are administered in combination with an anti-PD-L1 antibody or antigen-binding fragment thereof and / or a chemotherapeutic agent once every two weeks or once every three weeks.

[0103] In some embodiments, the cancer is a breast cancer as described above, preferably triple-negative breast cancer.

[0104] In some embodiments, the aforementioned anti-TROP-2 antibody drug conjugates for the treatment of breast cancer are administered in combination with an anti-PD-L1 antibody or antigen-binding fragment thereof, and / or a chemotherapeutic agent once every two weeks or once every three weeks.

[0105] In some embodiments, the administration cycle of the antibody-drug conjugate is 14 to 42 days. In some embodiments, the administration cycle of the antibody-drug conjugate is 14 days, 21 days, 28 days, or 42 days. In some embodiments, the administration cycle of the antibody-drug conjugate is 14 days. In some embodiments, the administration cycle of the antibody-drug conjugate is 21 days.

[0106] In some embodiments, the administration cycle of the other therapeutic agent is 14 to 42 days, for example, 14 days, 21 days, 28 days, or 42 days.

[0107] In some embodiments, the administration cycle of the anti-PD-L1 antibody or antigen-binding fragment thereof is 14-42 days. In some embodiments, the administration cycle of the anti-PD-L1 antibody or antigen-binding fragment thereof is 14 days, 21 days, 28 days, or 42 days. In some embodiments, the administration cycle of the anti-PD-L1 antibody or antigen-binding fragment thereof is 14 days. In some embodiments, the administration cycle of the anti-PD-L1 antibody or antigen-binding fragment thereof is 21 days.

[0108] In some embodiments, the administration cycle of the platinum agent (e.g., carboplatin or cisplatin) is 21 to 42 days. In some embodiments, the administration cycle of the platinum agent (e.g., carboplatin or cisplatin) is 21 days, 28 days, or 42 days. In some embodiments, the administration cycle of the platinum agent (e.g., carboplatin or cisplatin) is 21 days. In some embodiments, the administration cycle of the platinum agent (e.g., carboplatin or cisplatin) is 28 days. In some embodiments, the administration cycle of the platinum agent (e.g., carboplatin or cisplatin) is 42 days.

[0109] In some embodiments, the anti-TROP-2 antibody-drug conjugate and another therapeutic agent are administered in combination.

[0110] In some embodiments, the anti-TROP-2 antibody-drug conjugate and the other therapeutic agent are administered separately.

[0111] In some embodiments, the anti-TROP-2 antibody-drug conjugate and the other therapeutic agent are administered sequentially.

[0112] In some embodiments, the anti-TROP-2 antibody-drug conjugate is administered first, followed by the other therapeutic agent.

[0113] In some embodiments, the antibody-drug conjugate is administered at a dose of 1 to 10 mg / kg, preferably 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg / kg, or 10 mg / kg per administration. In some embodiments, the antibody-drug conjugate is administered at a dose of 4 mg / kg or 5 mg / kg per administration.

[0114] In some embodiments, the anti-PD-L1 antibody or antigen-binding fragment thereof is administered at a dose of 900 to 1500 mg, preferably selected from the group consisting of 900 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, and 1500 mg.

[0115] In some embodiments, the anti-PD-L1 antibody or antigen-binding fragment thereof is administered at a single dose of 900 mg or 1200 mg.

[0116] In some embodiments, the non-small cell lung cancer is advanced non-small cell lung cancer that has not received systemic therapy or has received at most first-line chemotherapy, and the anti-PD-L1 antibody or antigen-binding fragment thereof is administered at a dose of 900 mg or 1200 mg per dose.

[0117] In some embodiments, the antibody drug conjugate is administered at a dose of 4 mg / kg or 5 mg / kg per administration, the non-small cell lung cancer is advanced non-small cell lung cancer that has not received systemic therapy or has received at most first-line chemotherapy, and the anti-PD-L1 antibody or antigen-binding fragment thereof is administered at a dose of 900 mg or 1200 mg per administration.

[0118] In some embodiments, the breast cancer is triple-negative breast cancer and the anti-PD-L1 antibody or antigen-binding fragment thereof is administered at a dose of 900 mg or 1200 mg per dose.

[0119] In some embodiments, the antibody drug conjugate is administered at a dose of 4 mg / kg or 5 mg / kg per administration, the breast cancer is triple-negative breast cancer, and the anti-PD-L1 antibody or antigen-binding fragment thereof is administered at a dose of 900 mg or 1200 mg per administration.

[0120] In some embodiments, the method of the invention is a method for the treatment of non-small cell lung cancer, triple-negative breast cancer, and ovarian cancer, comprising administering to a subject a therapeutically effective amount of an anti-TROP-2 antibody-drug conjugate and another therapeutic agent, wherein the other therapeutic agent comprises an anti-PD-L1 antibody or antigen-binding fragment thereof, and a chemotherapeutic agent, the chemotherapeutic agent being one or more selected from the group consisting of carboplatin or cisplatin.

[0121] In some embodiments, carboplatin is administered at a dose of 1 to 10 mg / ml / min, preferably 1 mg / ml / min, 2 mg / ml / min, 2.5 mg / ml / min, 3 mg / ml / min, 3.75 mg / ml / min, 4 mg / ml / min, 5 mg / ml / min, 6 mg / ml / min, 7 mg / ml / min, 8 mg / ml / min, calculated as area under the curve (AUC). In some embodiments, carboplatin is administered at a dose of 5 mg / ml / min, 3.75 mg / ml / min, or 2.5 mg / ml / min.

[0122] In some embodiments, cisplatin is administered at a dose of 50 to 150 mg / m2, preferably 50 mg / m2, 75 mg / m2, 100 mg / m2, 120 mg / m2, or 150 mg / m2 per dose.

[0123] In some embodiments, the antibody drug conjugate and the anti-PD-L1 antibody or antigen-binding fragment thereof are administered in a single dose, as described above.

[0124] In some embodiments, the subject is a non-small cell lung cancer patient who has not previously received checkpoint inhibitor therapy and has not received a systemic chemotherapy regimen or has received at most a first-line systemic chemotherapy regimen.

[0125] In some embodiments, the subject is a non-small cell lung cancer patient who has previously received adjuvant, neoadjuvant, or definitive chemoradiotherapy and whose cancer has progressed during or within 6 months of completing treatment.

[0126] In some embodiments, the subject is a non-small cell lung cancer patient who has been treated with an EGFR kinase inhibitor and has failed the treatment.

[0127] In some embodiments, the subject has previously failed treatment with a first or second generation EGFR tyrosine kinase inhibitor (TKI) and is negative for the T790M mutation in exon 20 of EGFR.

[0128] In some embodiments, the subject has previously failed treatment with a third generation EGFR tyrosine kinase inhibitor (TKI).

[0129] In some embodiments, the subject has not been treated with systemic anti-tumor therapy for locally advanced or metastatic non-small cell lung cancer and has not been treated with an immune checkpoint inhibitor.

[0130] In some embodiments, the subject is a patient with unresectable locally advanced, recurrent, or metastatic triple-negative breast cancer who has not received prior systemic therapy.

[0131] Another aspect of the invention also provides the aforementioned anti-TROP-2 antibody drug conjugate and another therapeutic agent for treating cancer in a subject, wherein the other therapeutic agent comprises one or more selected from the group consisting of an anti-PD-L1 antibody, or antigen-binding fragment thereof, and a chemotherapeutic agent.

[0132] Another aspect of the invention also provides one or more kits comprising the above-described combination of anti-TROP-2 antibody-drug conjugates and other therapeutic agents.

[0133] In some embodiments, the kit is used for pre-treatment and / or intra-treatment testing.

[0134] In some embodiments, the kit comprises the anti-TROP-2 antibody drug conjugate in one compartment, the anti-PD-L1 antibody or antigen-binding fragment thereof in another compartment, and carboplatin in yet another compartment.

[0135] In some embodiments, the kit comprises the anti-TROP-2 antibody drug conjugate in one compartment, the anti-PD-L1 antibody or antigen-binding fragment thereof in another compartment, and cisplatin in another compartment.

[0136] In some embodiments, the kit further comprises instructions for administering the anti-TROP-2 antibody drug conjugate, the anti-PD-L1 antibody or antigen-binding fragment thereof, carboplatin or cisplatin.

[0137] In some embodiments, the kit is used to treat cancer as described above.

[0138] Another aspect of the invention also provides a pharmaceutical composition comprising the anti-TROP-2 antibody-drug conjugate as described above, comprising an anti-PD-L1 antibody or antigen-binding fragment thereof as described above, and one or more chemotherapeutic agents.

[0139] In some embodiments, the pharmaceutical composition further comprises one or more pharma- ceutically acceptable excipients, diluents, or carriers.

[0140] Another aspect of the invention also provides the use of one or more of the above-mentioned TROP-2 antibody drug conjugates, and the above-mentioned anti-PD-L1 antibody or antigen-binding fragment thereof, and a chemotherapeutic agent in the manufacture of a medicament for treating a tumor.

[0141] Another aspect of the invention provides the use of an anti-TROP-2 antibody-drug conjugate in combination with an anti-PD-L1 antibody or antigen-binding fragment thereof as described above in the manufacture of a medicament for treating a tumor.

[0142] Another aspect of the invention also provides the use of a combination of an anti-TROP-2 antibody-drug conjugate, an anti-PD-L1 antibody, or an antigen-binding fragment thereof, and carboplatin / cisplatin as described above in the manufacture of a medicament for treating a tumor. Effect of the Invention

[0143] The present invention provides methods of treating the aforementioned cancers using a combination of the aforementioned anti-TROP-2 antibody drug conjugates with other therapeutic agents (e.g., an anti-PD-L1 antibody or antigen-binding fragment thereof, and a chemotherapeutic agent).

[0144] The invention provides the use of a therapeutic combination for the treatment of cancer as described above, the therapeutic combination comprising an anti-TROP-2 antibody drug conjugate and another therapeutic agent (e.g. a PD-L1 antibody or antigen-binding fragment thereof and a chemotherapeutic agent).

[0145] The present invention also provides a therapeutic combination for the treatment of cancer as described above, comprising administering to a subject in need of treatment: (a) the anti-TROP-2 antibody-drug conjugate described above; (b) other therapeutic agents as described above (e.g., anti-PD-L1 antibodies or antigen-binding fragments thereof, chemotherapeutic agents, etc.).

[0146] In some embodiments, the method reduces the size of the tumor by at least about 10%, eg, about 10%, 20%, 30% or more.

[0147] In some embodiments, the method reduces tumor size by about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%.

[0148] In some embodiments, the method reduces the proliferative capacity of the tumor and stabilizes the disease. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0149] Definition of Terms Certain technical and scientific terms are specifically defined below. All other technical and scientific terms used herein are generally understood by their ordinary artisanal meaning in the art to which this disclosure pertains, unless specifically defined elsewhere herein.

[0150] "Antibody" refers to an immunoglobulin molecule that recognizes and specifically binds to a target, such as a protein, polypeptide, peptide, carbohydrate compound, polynucleotide, lipid, or combinations thereof, by at least one antigen recognition site within the variable region of the immunoglobulin molecule. As used herein, "antibody" encompasses intact polyclonal antibodies, intact monoclonal antibodies, chimeric antibodies, humanized antibodies, human antibodies, antibody-containing fusion proteins, and other modified immunoglobulin molecules, so long as the antibody exhibits the desired biological activity. Antibodies can belong to one of five major classes, IgA, IgD, IgE, IgG, IgM, or any of their subclasses (isotypes), (IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2), based on the properties of the heavy chain constant domains, called α, δ, ε, γ, and μ, respectively. The different classes of immunoglobulins have well-known subunit structures and three-dimensional structures. Antibodies can be naked antibodies or can be conjugated to other molecules, such as toxins or radioisotopes.

[0151] "Antibody fragment" refers to a portion of an intact antibody. "Antigen-binding fragment" refers to a portion of an intact antibody that binds to an antigen. An antigen-binding fragment may contain the antigen-determining variable regions of the intact antibody. Examples of antibody fragments include, but are not limited to, Fab, Fab', F(ab')2 and Fv fragments, linear antibodies, and single chain antibodies.

[0152] An "anti-TROP-2 antibody" or an "antibody targeting TROP-2" refers to an antibody that can bind to TROP-2 with sufficient affinity such that it can be used as a diagnostic and / or therapeutic agent targeting TROP-2 (e.g., the RS7 antibody).

[0153] An "anti-PD-L1 antibody" or an "antibody targeting PD-L1" refers to an antibody that can specifically bind PD-L1 and has sufficient affinity to be used as a PD-L1 targeted therapeutic. For example, an anti-PD-L1 antibody binds to an unrelated non-PD-L1 protein with less than about 10% of the extent to which it binds to PD-1, as measured by radioimmunoassay (RIA). In certain embodiments, the dissociation constant (Kd) of an antibody that binds to PD-L1 is 1 μM or less, 100 nM or less, 10 nM or less, 1 nM or less, or 0.1 nM or less. In certain embodiments, an antibody or antigen-binding fragment thereof that binds to PD-1 comprises the three heavy chain CDR-1, CDR-2, and CDR-3 sequences set forth in SEQ ID NO:7, SEQ ID NO:8, and SEQ ID NO:9, respectively, and the three light chain CDR-1, CDR-2, and CDR-3 sequences set forth in SEQ ID NO:10, SEQ ID NO:11, and SEQ ID NO:12, respectively. In certain embodiments, the antibody or antigen-binding fragment thereof that binds to PD-1 further comprises a heavy chain variable region sequence set forth in SEQ ID NO:18 and a light chain variable region sequence set forth in SEQ ID NO:19.

[0154] "Particular selective therapy" or "particular selective therapy" refers to a therapeutic regimen including, but not limited to, surgery, radiation therapy, chemotherapy, differentiation therapy, biotherapy, immunotherapy, or administration of one or more anti-cancer agents (e.g., cytotoxic agents, anti-proliferative compounds, and / or anti-angiogenic agents).

[0155] The terms "first-line treatment," "first line therapy," and "front line therapy" refer to the preferred standard initial treatment for a particular condition (e.g., cancer of a particular type and duration) and are distinct from "second-line" therapies that are tried when first-line therapy does not work properly. "Third-line" therapies are tried when first- and second-line therapies do not work properly.

[0156] For example, the combination of an anti-TROP-2 antibody drug conjugate provided herein and an anti-PD-L1 antibody or antigen-binding fragment thereof can be administered as a first line therapy, a second line therapy, or a third line therapy.

[0157] The combination of an anti-TROP-2 antibody drug conjugate and an anti-PD-L1 antibody or antigen-binding fragment thereof provided herein may be administered as a first line treatment to patients who have previously received 0, 1, 2, 3, 4, 5, 6 or more lines of therapy, provided that the patient has not previously received treatment with a combination of an anti-TROP-2 antibody drug conjugate and an anti-PD-L1 antibody or antigen-binding fragment thereof provided herein.

[0158] The combination of an anti-TROP-2 antibody drug conjugate provided herein and an anti-PD-L1 antibody or antigen-binding fragment thereof may be administered as a first line treatment to patients who have received at least a first line, at least a second line, or at least a third line treatment, provided that they have not previously been treated with a combination of an anti-TROP-2 antibody drug conjugate provided herein and an anti-PD-L1 antibody or antigen-binding fragment thereof.

[0159] In some embodiments, the combination of an anti-TROP-2 antibody drug conjugate and an anti-PD-L1 antibody or antigen-binding fragment thereof provided herein can be administered as first-line therapy to patients who have received no more than the first-line, no more than the second-line, no more than the third-line, no more than the fourth-line, no more than the fifth-line, or no more than the sixth-line of therapy.

[0160] In certain embodiments, the combination of the anti-TROP-2 antibody drug conjugate and anti-PD-L1 antibody or antigen-binding fragment thereof provided herein may be administered as adjuvant, neoadjuvant, or maintenance therapy.

[0161] "Adjuvant therapy" refers to systemic therapy given after surgery. Broadly defined, adjuvant therapy is any treatment given in addition to primary treatment to kill cancer cells that may have spread, even if no metastases have been detected by radiation or laboratory tests.

[0162] "Neoadjuvant therapy" refers to systemic therapy administered before surgery.

[0163] "Maintenance therapy" refers to treatment that helps prevent cancer from coming back after it has disappeared with initial treatment.

[0164] The term "RS7 antibody" refers to the commercially available antibody sacituzumab targeting TROP-2, which is an anti-TROP-2 antibody comprising three heavy chain CDR-1, CDR-2, and CDR-3 sequences shown in SEQ ID NO:1, SEQ ID NO:2, and SEQ ID NO:3, respectively, and three light chain CDR-1, CDR-2, and CDR-3 sequences shown in SEQ ID NO:4, SEQ ID NO:5, and SEQ ID NO:6, respectively (see US Patent 7,517,964). The anti-TROP-2 antibody RS7 that can be used in the present disclosure can be obtained by the method of designing and constructing vectors for displaying antibodies and constructing antibody libraries disclosed in Chinese Patent Publication No. 103476941, or by screening and obtaining the G-MAB® library of Sollent Therapeutics.

[0165] A "linker" is any chemical moiety that can stably and covalently link a compound (typically a drug such as camptothecin and its derivatives) to a cellular binding agent (e.g., an anti-TROP-2 antibody or fragment thereof). The linker is often or substantially resistant, for example, to disulfide bond cleavage under conditions under which the compound or antibody remains active.

[0166] "Cancer" and "cancerous" refer to or describe a disease state in which a mammalian cell population is characterized by unregulated cell growth. Examples of cancer include ovarian cancer, fallopian tube cancer, and peritoneal cancer. Another example of cancer is endometrial cancer. The cancer may be a cancer that expresses TROP-2 (a "TROP-2-expressing cancer").

[0167] "Cancer cells," "tumor cells," and grammatical equivalents refer to the total population of cells derived from a tumor or precancerous lesion, including non-tumorigenic cells, which comprise the majority of tumor cells, and tumorigenic stem cells (cancer stem cells). The term "tumor cells" herein is modified with the term "non-tumorigenic" to distinguish between tumor cells and cancer stem cells only when the term refers to tumor cells that lack the capacity for renewal or differentiation.

[0168] An "advanced" cancer is one that has spread beyond the initial site or organ by local invasion or metastasis. The term progressive cancer includes both locally advanced and metastatic disease.

[0169] "Metastatic" cancer refers to cancer that spreads from one part of the body to another.

[0170] "Refractory" cancer refers to cancer that progresses even when a cancer patient is treated with antitumor therapy (e.g. chemotherapy).

[0171] A "recurrent" cancer is one that has responded to initial treatment and then regrows at the initial site or a distant site.

[0172] "Subject" refers to an animal (e.g., a mammal) undergoing a particular treatment, including, but not limited to, non-human primates, rodents, and the like. In general, the terms "subject" and "patient" are used interchangeably herein when referring to a human individual. The mammal may be one or more species selected from the group consisting of Hominidae, Bovine (e.g., cows), Porcine (e.g., pigs), Ovine (e.g., sheep), Caprine (e.g., goats), Equine (e.g., horses), Canine (e.g., dogs), Feline (e.g., domestic cats), Leporidae (e.g., rabbits), Rodent (e.g., rats, mice), and the like. In a specific embodiment, the subject is a human.

[0173] A "recurrent" patient is one who develops signs or symptoms of cancer after remission. Optionally, the patient relapses after adjuvant or neoadjuvant therapy.

[0174] Administration "in combination with one or more other therapeutic agents" includes simultaneous (concurrent) or consecutive administration in any order.

[0175] Combination therapy can result in "synergism," where the combined effect of the active ingredients exceeds the sum of the effects of the individual compounds. Synergism can be achieved (1) when the active ingredients are formulated together and administered or delivered simultaneously in a combined single dose formulation; (2) when each active ingredient is delivered in separate formulations in a sequential, alternating, or parallel manner; or (3) when each active ingredient is administered by other regimens. When delivered as an alternative therapy, synergism can be achieved when the compounds are administered or delivered sequentially, such as by separate injections in different syringes. This synergistic combination produces an effect that exceeds the additive effect of the individual components of the combination.

[0176] The therapeutic agents and compositions provided in the present disclosure can be administered by any suitable enteral or parenteral route of administration. "Enteral" administration refers to administration via any site of the digestive tract. Examples of enteral routes include oral, mucosal, buccal, rectal, or intragastric. "Parenteral" administration refers to administration via a route other than parenteral. Examples of parenteral administration include intravenous, intramuscular, intradermal, intraperitoneal, intratumoral, intravesical, intraarterial, intrathecal, intraarticular, orbital, intracardiac, intratracheal, intraarticular, intraarticular, intrathecal, intrathecal, intrathecal, epidural, epidural, intrasternal, subcutaneous, and topical administration. The therapeutic agents and compositions of the present disclosure can be administered using any suitable method, such as injection, infusion, implantable infusion pump, or osmotic pump. The appropriate route and method of administration may vary depending on many factors, such as the particular therapeutic agent used, the desired absorption rate, the particular formulation or dosage form used, the type or severity of the disease being treated, the particular site of action, the condition of the patient, etc., and can be readily selected by one of ordinary skill in the art.

[0177] An "effective amount" of an antibody, antibody-drug conjugate, or other therapeutic agent disclosed herein refers to an amount sufficient to achieve a specifically described purpose. An "effective amount" can be determined empirically and in a conventional manner for the described purpose.

[0178] A "therapeutically effective amount" refers to an amount of an antibody, immunoconjugate or other agent effective to "treat" a disease or condition in an individual or mammal. In the case of cancer, a therapeutically effective amount of an agent may reduce the number of cancer cells; may reduce the size or burden of the tumor; may inhibit (i.e., slow to some extent, and in one embodiment, stop) cancer cell invasion into surrounding organs; may inhibit (i.e., slow to some extent, and in one embodiment, stop) tumor metastasis; may inhibit to some extent tumor growth; may alleviate to some extent one or more cancer-related symptoms; and / or result in a favorable response, such as an increase in progression-free survival (PFS), disease-free survival (DFS), overall survival (OS), complete response (CR), partial response (PR), or in some cases stable disease (SD), delayed disease progression (PD), increased time to progression (TTP), or a combination thereof. See the definition of "treatment" herein. The drugs may be cytostatic and / or cytotoxic in terms of preventing the growth of cancer cells and / or killing existing cancer cells.

[0179] PFS, DFS, and OS can be measured according to the standards set by the National Cancer Institute and the U.S. Food and Drug Administration for new drug approval. See Johnson et al., J. Clin. Oncol. 21(7):1404-1411 (2003).

[0180] "Progression-free survival" (PFS) refers to the time from registration to disease progression or death. PFS is commonly measured using the Kaplan-Meier method and Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria. Progression-free survival is generally defined as the time when a patient is alive and their cancer has not gotten worse.

[0181] "Time to progression" (TTP) is defined as the time from enrollment to disease progression. TTP is commonly measured using RECIST 1.1 criteria.

[0182] "Complete response" or "CR" indicates the disappearance of all tumor or cancer lesions in response to treatment. It does not necessarily mean that the cancer has been cured.

[0183] "Partial response" or "PR" means a reduction in the size or volume of one or more tumors or lesions, or the extent of cancer in the body, in response to treatment.

[0184] "Stable disease" refers to disease that has not progressed or recurred. Stable disease means that the tumor has not shrunk enough to qualify for a partial response, nor has the tumor grown enough to qualify for progressive disease.

[0185] "Disease progression" means the appearance of one or more new lesions or tumors and / or overt progression of existing non-target lesions.Disease progression may also be defined as a 20% or greater increase in tumor mass or tumor spread since the start of treatment.

[0186] "Disease-free survival" (DFS) refers to the length of time a patient remains disease-free during and after treatment.

[0187] "Overall survival" (OS) refers to the time from patient enrollment to the date of death or last known survival date. OS includes an increase in life expectancy compared to untreated individuals or patients. Overall survival is defined as a patient surviving a given period of time, e.g., 1 year, 5 years, etc., from the time of diagnosis or treatment. In patient populations, overall survival is measured as median overall survival (mOS).

[0188] "Extended survival" or "increased chance of survival" means an increase in PFS and / or OS for treated patients compared to untreated patients or compared to a control regimen (e.g., a regimen used as standard of care for the type of cancer).

[0189] "Treatment" or "palliative" refers to a therapeutic measure that cures, slows progression, relieves symptoms, and / or halts progression of a diagnosed condition or pathology. Thus, patients in need of treatment include those diagnosed with or suspected of having the disease. In one embodiment, the methods of the present invention successfully "treat" a patient's cancer if the patient exhibits one or more of the following characteristics: a reduction in the number or complete absence of cancer cells; a reduction in tumor burden; inhibition or elimination of cancer cell invasion into surrounding organs, such as the spread of cancer to soft tissue and bone; suppression or elimination of tumor metastasis; inhibition or elimination of tumor growth; amelioration of one or more symptoms associated with a particular cancer; a reduction in morbidity and mortality; an improvement in quality of life; a reduction in tumor formation, tumor frequency, or tumorigenicity; a reduction in the number or frequency of cancer stem cells within a tumor; differentiation of tumor-forming cells to a non-tumorigenic state; an increase in progression-free survival (PFS), disease-free survival (DFS), overall survival (OS), duration of response (DOR), disease control rate (DCR), complete response (CR), partial response (PR), stable disease (SD), delayed disease progression (PD), prolonged time to progression (TTP), or any combination thereof.

[0190] Prevention or prophylactic measures refer to measures to prevent and / or delay the onset of the targeted disease state or condition. Thus, those in need of prevention or prophylactic measures include those prone to having the disease and those who should be prevented.

[0191] In this specification, where an embodiment is described using the term "comprising," it is understood that similar embodiments described using the terms "consisting of" and / or "consisting essentially of" are also provided.

[0192] All ranges mentioned in the present invention are inclusive unless expressly stated otherwise; that is, the range includes the upper and lower values ​​of the range and all values ​​therebetween. For example, a numerical value or "about" provided by the present invention can include variations of ±1%, ±2%, ±3%, ±4%, ±5%, ±10%, ±15%, ±20% and their numerical equivalents. Also, all ranges are intended to include all subranges included, but not necessarily explicitly stated. For example, a range of 14-21 days includes 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, and 21 days. Also, as used in the present invention, the term "or" refers to alternatives that can be combined where appropriate; that is, "or" includes each option listed individually and combinations thereof.

[0193] All technical and scientific terms used herein have the same meaning as commonly understood by ordinary artisans in the art to which this disclosure pertains, unless otherwise defined. In case of conflict, the explanations herein (including definitions) shall prevail. Throughout the specification and claims, "comprises" (and variations such as "comprises" or "comprising") shall be understood to mean the inclusion of an integer or group of integers, but not the exclusion of other integers or groups of integers. Unless the context otherwise requires, singular terms shall include the plural, and plural terms shall include the singular. Examples following, for example, "for example" or "such as," are not intended to be exhaustive or limiting.

[0194] Specific methods and materials are described herein, although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure. The materials, methods, and examples are illustrative and not limiting.

[0195] Sequence information The sequence information of the present invention is provided as follows: [Table 1] EXAMPLES

[0196] Examples The examples and embodiments described herein are for illustrative purposes only, and it is appreciated that those skilled in the art may suggest various modifications or changes to these embodiments, and that these modifications are within the spirit and scope of the present application.

[0197] Example 1: Treatment of patients with EGFR wild-type and ALK rearrangement-negative locally advanced or metastatic non-small cell lung cancer who have not been treated with immune checkpoint inhibitors and who have not received a systemic chemotherapy regimen or who have received at most a first-line systemic chemotherapy regimen, with a combination of an anti-TROP-2 antibody-drug conjugate and an anti-PD-L1 antibody

[0198] 1. Study drug combination: (1) Anti-TROP-2 antibody-drug conjugate: The anti-TROP-2 antibody-drug conjugate used in the examples was BT001021, which was prepared according to the method described in Example 32 of WO2019114666. (2) Anti-PD-L1 antibody: the PD-L1 antibody used in the examples was 5C10H2L2-IgG1mt, which was prepared according to the methods described in Examples 1 to 4 and 15 of WO2017148424.

[0199] Of these, the heavy chain variable region sequence of 5C10H2L2-IgG1mt is SEQ ID NO: 15, the light chain variable region is SEQ ID NO: 16, the light chain constant region is Ig kappa chain C region, ACCESSION: P01834, the heavy chain constant region is Ig gamma-1 chain C region, ACCESSION: P01857, amino acid residues 234, 235, and 237 (EU numbering system) were mutated as follows: L234A, L235A, and G237A.

[0200] 2. Method of administration Anti-TROP-2 antibody-drug conjugate: TROP-2 antibody-drug conjugate was administered by intravenous infusion at a dose of 4 mg / kg or 5 mg / kg on day 1 of each cycle in cycles of 2-week or 3-week dosing cycles; Anti-PD-L1 antibodies: Anti-PD-L1 antibodies were administered intravenously at a dose of 900 mg or 1200 mg on day 1 of each cycle in cycles of 2-week or 3-week treatment cycles; On day 1 of each cycle, the anti-TROP-2 antibody-drug conjugate and anti-PD-L1 antibody were administered sequentially according to the administration method described above.

[0201] 3.Efficacy evaluation Primary endpoints: incidence and severity of adverse events (AEs), objective response rate (ORR) Secondary endpoints: progression-free survival (PFS), duration of response (DOR), disease control rate (DCR), overall survival (OS), pharmacokinetic properties and immunogenicity.

[0202] 4.Results A 69-year-old man was diagnosed with EGFR wild-type, ALK rearrangement-negative non-small cell lung cancer, with multiple metastases in the mediastinum, peritoneal cavity, retroperitoneal lymph nodes, liver, bone, etc. The patient had not received previous systemic therapy. The anti-TROP-2 antibody-drug conjugate of the present invention is administered in combination with an anti-PD-L1 antibody at a dose of 1200 mg once every 3 weeks. A partial response to the disease was observed after 6 weeks of treatment, and the response was sustained. After multiple response evaluations, the total volume reduction rate of the target lesions reached 61.3%.

[0203] Example 2: Treatment of patients with EGFR wild-type and ALK rearrangement-negative locally advanced or metastatic non-small cell lung cancer who have not been previously treated with an immune checkpoint inhibitor and who have not received a systemic chemotherapy regimen or who have received at most a first-line systemic chemotherapy regimen, with a combination of an anti-TROP-2 antibody-drug conjugate and an anti-PD-L1 antibody and cisplatin / carboplatin.

[0204] 1. Combination of test drugs: The anti-TROP-2 antibody-drug conjugate and anti-PD-L1 antibody used in the examples were the same as those in Example 1. Cisplatin and carboplatin were both commercially available drugs.

[0205] 2. Method of administration Anti-TROP-2 antibody-drug conjugate: Anti-TROP-2 antibody-drug conjugate was administered by intravenous infusion at a dose of 4 mg / kg or 5 mg / kg on day 1 of each cycle in a dosing cycle of every 3 weeks; Anti-PD-L1 antibody: Anti-PD-L1 antibody was administered by intravenous infusion at a dose of 1200 mg on day 1 of each cycle in a 3-week dosing cycle; Carboplatin: Carboplatin was administered intravenously at an AUC of 5 mg / ml / min on day 1 of each cycle in cycles of 3 weeks; Cisplatin: Cisplatin was administered at 75 mg / m on day 1 of each 3-week cycle. 2 The drug was administered intravenously at a dose of

[0206] On day 1 of each cycle, the anti-TROP-2 antibody-drug conjugate, anti-PD-L1 antibody, and carboplatin will be administered sequentially, or the anti-TROP-2 antibody-drug conjugate, anti-PD-L1 antibody, and cisplatin will be administered sequentially, according to the administration method described above.

[0207] 3.Efficacy evaluation Primary endpoints: incidence and severity of adverse events (AEs), objective response rate (ORR) Secondary endpoints: progression-free survival (PFS), duration of response (DOR), disease control rate (DCR), overall survival (OS), pharmacokinetic properties and immunogenicity.

[0208] 4.Results A 34-year-old man was diagnosed with EGFR wild-type, ALK rearrangement-negative non-small cell lung cancer with multiple metastases to the bilateral supraclavicular fossae, mediastinum, hepatic hilum, retroperitoneal lymph nodes, adrenal glands, bone, and brain. The patient had not received any previous systemic therapy. A combination of the anti-TROP-2 antibody-drug conjugate of the present invention at a dose of 5 mg / kg, an anti-PD-L1 antibody at a dose of 1200 mg, and carboplatin at a dose of AUC 5 mg / ml / min was administered every 3 weeks. Six weeks after administration, stable disease was observed, with a reduction in total target lesion volume of up to 16.4%.

[0209] Example 3: Treatment of patients with EGFR-mutated, ALK-rearrangement-negative non-small cell lung cancer who had previously been treated with an EGFR tyrosine kinase inhibitor (TKI) without success with a TROP-2 antibody-drug conjugate in combination with an anti-PD-L1 antibody and cisplatin / carboplatin.

[0210] 1. Combination of test drugs: The anti-TROP-2 antibody-drug conjugate and anti-PD-L1 antibody used in the example are the same as those in Example 1. Cisplatin and carboplatin are both commercially available drugs.

[0211] 2. Method of administration Anti-TROP-2 antibody-drug conjugate: Anti-TROP-2 antibody-drug conjugate was administered by intravenous infusion at a dose of 4 mg / kg or 5 mg / kg on day 1 of each cycle in a dosing cycle of every 3 weeks; Anti-PD-L1 antibody: Anti-PD-L1 antibody was administered by intravenous infusion at a dose of 1200 mg on day 1 of each cycle in a 3-week dosing cycle; Carboplatin: Carboplatin was administered intravenously at an AUC of 5 mg / ml / min on day 1 of each cycle in cycles of 3 weeks; Cisplatin: Cisplatin was administered at 75 mg / m on day 1 of each 3-week cycle. 2 The drug was administered intravenously at a dose of

[0212] On day 1 of each cycle, the anti-TROP-2 antibody-drug conjugate, anti-PD-L1 antibody, and carboplatin were administered sequentially, or the anti-TROP-2 antibody conjugate, anti-PD-L1 antibody, and cisplatin were administered sequentially, according to the administration method described above.

[0213] 3.Efficacy evaluation Primary efficacy variables: incidence and severity of adverse events (AEs), objective response rate (ORR) Secondary efficacy variables: progression-free survival (PFS), duration of response (DOR), disease control rate (DCR), overall survival (OS), pharmacokinetic properties and immunogenicity.

[0214] 4.Results A 40-year-old woman was diagnosed with non-small cell lung cancer with an EGFR mutation. The lung cancer was accompanied by multiple metastases in the mediastinum, hilum, para-aortic, phrenic angle lymph nodes, pleura, liver, and brain. The patient had previously been treated with a combination of gefitinib and anlotinib, and JM101 (EGFR monoclonal antibody) and osimertinib, but without success. The anti-TROP-2 antibody-drug conjugate of the present invention at a dose of 5 mg / kg, anti-PD-L1 antibody at a dose of 1200 mg, and carboplatin at a dose of AUC 5 mg / ml / min were administered every 3 weeks. Six weeks after administration, the disease was stabilized and a reduction in the total target lesion volume of up to 21.7% was observed.

[0215] Example 4: Treatment of patients with unresectable locally advanced, recurrent, or metastatic triple-negative breast cancer who have not received prior systemic therapy with an anti-TROP-2 antibody-drug conjugate with or without an anti-PD-L1 antibody

[0216] 1. Test drugs: The anti-TROP-2 antibody-drug conjugate and anti-PD-L1 antibody used in the examples were the same as those in Example 1.

[0217] 2. Method of administration Anti-TROP-2 antibody-drug conjugate: Anti-TROP-2 antibody-drug conjugate was administered by intravenous infusion at a dose of 4 mg / kg or 5 mg / kg on day 1 of each cycle in cycles of 2-week or 3-week dosing cycles; Anti-PD-L1 antibody: PD-L1 antibody was administered intravenously at a dose of 900 mg or 1200 mg on day 1 of each cycle in a treatment cycle of 2 or 3 weeks.

[0218] On day 1 of each cycle, the anti-TROP-2 antibody-drug conjugate and anti-PD-L1 antibody were administered sequentially according to the administration method described above.

[0219] 3.Efficacy evaluation Primary efficacy variables: incidence and severity of adverse events (AEs), objective response rate (ORR) Secondary efficacy variables: progression-free survival (PFS), duration of response (DOR), disease control rate (DCR), overall survival (OS), pharmacokinetic properties and immunogenicity.

[0220] 4.Results A 43-year-old woman was diagnosed with triple-negative breast cancer with lung metastases. The patient had previously received adjuvant chemotherapy with epirubicin and cyclophosphamide, but had progressed more than 12 months after the last chemotherapy. The anti-TROP-2 antibody-drug conjugate of the present invention at a dose of 5 mg / kg and the anti-PD-L1 antibody at a dose of 900 mg were administered every 2 weeks. A partial response was observed 6 weeks after treatment, with a reduction in total target lesion volume of up to 34.4%.

[0221] The above are only preferred embodiments of the present invention, and are not intended to limit the present invention. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principle of the present invention should be included in the scope of protection of the present invention. Further technical solutions between various embodiments may be integrated with each other, but should be based on the practice of ordinary skills of those skilled in the art. If the combination of technical solutions is deemed to be contradictory or unachievable, such combination of technical solutions should be considered as not existing and not within the scope of protection claimed by the present invention.

Claims

1. 1. Use of an anti-TROP-2 antibody-drug conjugate and another therapeutic agent in the manufacture of a medicament for treating cancer in a subject, comprising: the other therapeutic agent is one or more selected from the group consisting of an anti-PD-L1 antibody or an antigen-binding fragment thereof, and a chemotherapeutic agent; The anti-TROP-2 antibody-drug conjugate comprises a camptothecin and an anti-TROP-2 antibody or an antigen-binding fragment thereof, the anti-TROP-2 antibody or the antigen-binding fragment thereof comprising a heavy chain variable region and a light chain variable region; The heavy chain variable region is an HCDR1 having a sequence as set forth in SEQ ID NO:1 or a mutant thereof, an HCDR2 having a sequence as set forth in SEQ ID NO:2 or a mutant thereof, and an HCDR3 having a sequence as set forth in SEQ ID NO:3 or a mutant thereof; and the light chain variable region is an LCDR1 having a sequence as set forth in SEQ ID NO:4 or a mutant thereof, an LCDR2 having a sequence as set forth in SEQ ID NO:5 or a mutant thereof, and an LCDR3 having a sequence as set forth in SEQ ID NO:6 or a mutant thereof; The variant has one or more amino acid substitutions, deletions or additions (e.g., one, two or three amino acid substitutions, deletions or additions) compared to the sequence from which it is derived.

2. 2. The use of claim 1, wherein the anti-PD-L1 antibody or antigen-binding fragment thereof comprises a heavy chain variable region and a light chain variable region, the heavy chain variable region comprises an HCDR1 having the sequence set forth in SEQ ID NO:7 or a variant thereof, an HCDR2 having the sequence set forth in SEQ ID NO:8 or a variant thereof, and an HCDR3 having the sequence set forth in SEQ ID NO:9 or a variant thereof, and the light chain variable region comprises an LCDR1 having the sequence set forth in SEQ ID NO:10 or a variant thereof, an LCDR2 having the sequence set forth in SEQ ID NO:11 or a variant thereof, and an LCDR3 having the sequence set forth in SEQ ID NO:12 or a variant thereof.

3. The use according to claim 1 or 2, wherein the substitution is a conservative substitution.

4. The use according to any one of claims 1 to 3, wherein the antibody or antigen-binding fragment further comprises a framework region derived from a human or mouse immunoglobulin.

5. 5. The use according to any one of claims 1 to 4, wherein the chemotherapeutic agent is selected from platinum agents.

6. 6. The use according to claim 5, wherein the platinum agent is selected from the group consisting of cisplatin, carboplatin, sulfatodiaminocyclohexane platinum, nedaplatin, oxaliplatin, lobaplatin, satraplatin, miboplatin, enloplatin, iproplatin or dicycloplatin.

7. The use according to any one of claims 1 to 6, wherein the antibody-drug conjugate has the following chemical structure: 【Chemistry 1】 (wherein γ represents the average number of drug-linker units attached per antibody molecule in the antibody-drug conjugate, the average number being in the range of 6 to 10.)

8. The use according to any one of claims 1 to 7, wherein the average number of γ is between 6 and 9.

9. The use according to claim 8, wherein the average number of γ is between 6 and 8.

10. 10. The use according to claim 9, wherein the average number of γ is about 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, or 7.

9.

11. The use according to any one of claims 1 to 10, wherein the cancer is a solid or non-solid tumor.

12. 12. The use according to any one of claims 1 to 11, wherein the cancer is selected from the group consisting of esophageal cancer, brain cancer, lung cancer, squamous cell carcinoma, bladder cancer, gastric cancer, ovarian cancer, peritoneal cancer, pancreatic cancer, breast cancer, head and neck cancer, cervical cancer, endometrial cancer, colorectal cancer, liver cancer, renal cancer, non-Hodgkin's lymphoma, central nervous system tumors, prostate cancer, and thyroid cancer.

13. The use according to any one of claims 1 to 12, wherein the cancer is selected from the group consisting of lung cancer, breast cancer, and ovarian epithelial cancer.

14. 14. The use of claim 13, wherein the cancer is selected from the group consisting of non-small cell lung cancer (NSCLC), triple-negative breast cancer (TNBC), and ovarian epithelial cancer.

15. 14. The use according to claim 13, wherein the breast cancer is selected from the group consisting of triple negative breast cancer, HR+ / HER2- breast cancer, HR- / HER2+ breast cancer, HR+ / HER2+ breast cancer, BRCA+ breast cancer.

16. 15. The use according to claim 14, wherein the non-small cell lung cancer is selected from EGFR wild-type or EGFR mutant non-small cell lung cancer.

17. The use according to claim 14, wherein the non-small cell lung cancer is advanced / metastatic non-small cell lung.

18. The use of claim 14, wherein the non-small cell lung cancer is an ALK rearrangement-negative non-small cell lung cancer.

19. The use according to claim 16, wherein the EGFR mutated non-small cell lung cancer is advanced / metastatic and the EGFR mutation is a single mutation or a compound mutation.

20. The use according to any one of claims 1 to 19, wherein the administration cycle of the antibody drug conjugate, the anti-PD-L1 antibody or antigen-binding fragment thereof, and carboplatin or cisplatin is 14 to 42 days, such as 21 to 42 days.

21. 21. The use of claim 20, wherein the administration cycle is 21 days, 28 days or 42 days.

22. The use according to any one of claims 1 to 21, wherein the antibody-drug conjugate is administered at a dose of 1 to 10 mg / kg per administration.

23. 23. The use of any one of claims 1 to 22, wherein the antibody-drug conjugate is administered at a dose selected from the group consisting of 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg / kg, and 10 mg / kg per administration.

24. The use according to any one of claims 1 to 23, wherein the anti-PD-L1 antibody or antigen-binding fragment thereof is administered at a dose of 900 to 1500 mg per administration.

25. 25. The use of claim 24, wherein the anti-PD-L1 antibody or antigen-binding fragment thereof is administered at a dose selected from the group consisting of 900 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, and 1500 mg per dose.

26. Carboplatin is administered at a dose of 1 to 10 mg / ml / min per dose, calculated as the area under the curve (AUC), and cisplatin is administered at a dose of 50 to 150 mg / ml per dose. ２ 26. The use according to any one of claims 1 to 25, wherein the dose is

27. Carboplatin is administered at a dose selected from the group consisting of 1 mg / ml / min, 2 mg / ml / min, 2.5 mg / ml / min, 3 mg / ml / min, 3.75 mg / ml / min, 4 mg / ml / min, 5 mg / ml / min, 6 mg / ml / min, 7 mg / ml / min, and 8 mg / ml / min per dose, calculated as area under the curve (AUC); or cisplatin is administered at a dose selected from the group consisting of 50 mg / ml / min per dose. ２ , 75 mg / m ２ , 100 mg / m ２ , 120 mg / m ２ , and 150 mg / m ２ 27. The use according to claim 26, wherein the dose is selected from the group consisting of

28. A method of treating cancer in a subject, comprising administering to the subject a therapeutically effective amount of a combination of an anti-TROP-2 antibody-drug conjugate and another therapeutic agent, wherein the other chemotherapeutic agent is one or more selected from the group consisting of an anti-PD-L1 antibody or an antigen-binding fragment thereof, and a chemotherapeutic agent; The anti-TROP-2 antibody-drug conjugate comprises a camptothecin and an anti-TROP-2 antibody or antigen-binding fragment thereof, comprising a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region is HCDR1 having the sequence shown in SEQ ID NO: 1 or a variant thereof, HCDR2 having the sequence shown in SEQ ID NO: 2 or a variant thereof, and HCDR3 having the sequence shown in SEQ ID NO: 3 or a variant thereof, and the light chain variable region is LCDR1 having the sequence shown in SEQ ID NO: 4 or a variant thereof, LCDR2 having the sequence shown in SEQ ID NO: 5 or a variant thereof, and LCDR3 having the sequence shown in SEQ ID NO: 6 or a variant thereof, and the variants have one or more amino acid substitutions, deletions, or additions (e.g., one, two, or three amino acid substitutions, deletions, or additions) compared to the sequence from which they are derived.

29. 29. The method of claim 28, wherein the anti-PD-L1 antibody or antigen-binding fragment comprises a heavy chain variable region and a light chain variable region, the heavy chain variable region comprises an HCDR1 having the sequence set forth in SEQ ID NO:7 or a variant thereof, an HCDR2 having the sequence set forth in SEQ ID NO:8 or a variant thereof, and an HCDR3 having the sequence set forth in SEQ ID NO:9 or a variant thereof, and the light chain variable region comprises an LCDR1 having the sequence set forth in SEQ ID NO:10 or a variant thereof, an LCDR2 having the sequence set forth in SEQ ID NO:11 or a variant thereof, and an LCDR3 having the sequence set forth in SEQ ID NO:12 or a variant thereof.

30. 30. The method of any one of claims 28 to 29, wherein the substitution is a conservative substitution.

31. 31. The method of any one of claims 28 to 30, wherein the antibody or antigen-binding fragment further comprises a framework region derived from a human or mouse immunoglobulin.

32. 32. The method of any one of claims 28 to 31, wherein the chemotherapeutic agent is selected from platinum agents.

33. 33. The method of claim 32, wherein the platinum agent is selected from the group consisting of cisplatin, carboplatin, sulfatodiaminocyclohexane platinum, nedaplatin, oxaliplatin, lobaplatin, satraplatin, miboplatin, enloplatin, iproplatin, or dicycloplatin.

34. 34. The method of any one of claims 28 to 33, wherein the antibody-drug conjugate has the following chemical structure: 【Chemistry 2】 (wherein γ represents the average number of drug-linker units attached per antibody molecule in the antibody-drug conjugate, the average number being in the range of 6 to 10.)

35. 35. The method according to any one of claims 28 to 34, wherein the average number of γ is between 6 and 9.

36. 36. The method of claim 35, wherein the average number of γ is between 6 and 8.

37. 36. The method of claim 35, wherein the average number of γ is about 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, or 7.

9.

38. 38. The method of any one of claims 28 to 37, wherein the cancer is a solid tumor or a non-solid tumor.

39. 39. The method of any one of claims 28 to 38, wherein the cancer is selected from the group consisting of esophageal cancer, brain cancer, lung cancer, squamous cell carcinoma, bladder cancer, gastric cancer, ovarian cancer, peritoneal cancer, pancreatic cancer, breast cancer, head and neck cancer, cervical cancer, endometrial cancer, colorectal cancer, liver cancer, renal cancer, non-Hodgkin's lymphoma, central nervous system tumors, prostate cancer, and thyroid cancer.

40. 40. The method of any one of claims 28 to 39, wherein the cancer is selected from the group consisting of lung cancer, breast cancer, and ovarian cancer.

41. 41. The method of claim 40, wherein the cancer is selected from the group consisting of non-small cell lung cancer (NSCLC) or triple negative breast cancer (TNBC) or ovarian epithelial cancer.

42. 41. The method of claim 40, wherein the breast cancer is selected from the group consisting of triple negative breast cancer, HR+ / HER2- breast cancer, HR- / HER2+ breast cancer, HR+ / HER2+ breast cancer, and BRCA+ breast cancer.

43. 42. The method of claim 41, wherein the non-small cell lung cancer is selected from EGFR wild-type or EGFR mutant non-small cell lung cancer.

44. 42. The method of claim 41, wherein the non-small cell lung cancer is selected from advanced / metastatic non-small cell lung cancer.

45. 42. The method of claim 41, wherein the non-small cell lung cancer is an ALK rearrangement-negative non-small cell lung cancer.

46. 44. The method of claim 43, wherein the EGFR mutated non-small cell lung cancer is advanced / metastatic and the EGFR mutation is a single mutation or a compound mutation.

47. 47. The method of any one of claims 28 to 46, wherein the administration cycle of the antibody drug conjugate, the anti-PD-L1 antibody or antigen-binding fragment thereof, and carboplatin or cisplatin is 14 to 42 days, such as 21 to 42 days.

48. 48. The method of claim 47, wherein the administration cycle is 21 days, 28 days, or 42 days.

49. The method of any one of claims 28 to 48, wherein the antibody-drug conjugate is administered at a dose selected from the group consisting of 1 to 10 mg / kg per administration.

50. 50. The method of any one of claims 28 to 49, wherein the antibody-drug conjugate is administered at a dose selected from the group consisting of 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg / kg, and 10 mg / kg per administration.

51. The method of any one of claims 28 to 50, wherein the anti-PD-L1 antibody or antigen-binding fragment thereof is administered at a dose selected from the group consisting of 900 to 1500 mg per dose.

52. 52. The method of claim 51, wherein the anti-PD-L1 antibody or antigen-binding fragment thereof is administered at a dose selected from the group consisting of 900 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, and 1500 mg per dose.

53. Carboplatin is administered at a dose of 1 to 10 mg / ml / min per dose, calculated as the area under the curve (AUC), or cisplatin is administered at a dose of 50 to 150 mg / ml per dose. ２ 53. The method of any one of claims 28 to 52, wherein the dose is

54. 54. The method of claim 53, wherein carboplatin is administered at a dose of 1 mg / ml / min, 2 mg / ml / min, 2.5 mg / ml / min, 3 mg / ml / min, 3.75 mg / ml / min, 4 mg / ml / min, 5 mg / ml / min, 6 mg / ml / min, 7 mg / ml / min, or 8 mg / ml / min per dose, calculated as area under the line (AUC), or the cisplatin is administered at a dose of 50 mg / m2, 75 mg / m2, 100 mg / m2, 120 mg / m2, or 150 mg / m2 per dose.

55. Subjects were patients with non-small cell lung cancer who had not previously received checkpoint inhibitor therapy and had not received a first-line systemic chemotherapy regimen or had received at most a first-line systemic chemotherapy regimen; or Subjects were non-small cell lung cancer patients who had previously received adjuvant, neoadjuvant, or definitive chemoradiotherapy and whose disease had progressed during or within 6 months of completing treatment, or Subjects were patients with non-small cell lung cancer who had previously been treated with and failed an EGFR kinase inhibitor, or Subjects were patients with locally advanced or metastatic non-small cell lung cancer who had not previously been treated with systemic anti-tumor therapy and had not previously been treated with immune checkpoint inhibitor therapy, or 55. The method of any one of claims 28 to 54, wherein the subject is a patient with unresectable locally advanced, recurrent, or metastatic triple-negative breast cancer who has not received prior systemic therapy.

56. 56. The method of any one of claims 28 to 55, wherein the tumor size is reduced by at least about 10%.

57. 57. A kit comprising an anti-TROP-2 antibody-drug conjugate and another therapeutic agent, wherein the other therapeutic agent is one or more selected from the group consisting of an anti-PD-L1 antibody or antigen-binding fragment thereof, and a chemotherapeutic agent, wherein the anti-TROP-2 antibody-drug conjugate, the anti-PD-L1 antibody or antigen-binding fragment thereof, and the chemotherapeutic agent are defined in any one of claims 1 to 56.

58. 57. A pharmaceutical composition comprising an anti-TROP-2 antibody-drug conjugate and another therapeutic agent, wherein the other therapeutic agent is one or more selected from the group consisting of an anti-PD-L1 antibody or an antigen-binding fragment thereof, and a chemotherapeutic agent, wherein the anti-TROP-2 antibody-drug conjugate, the anti-PD-L1 antibody or an antigen-binding fragment thereof, and the chemotherapeutic agent are defined in any one of claims 1 to 56.

59. 59. The composition of claim 58, further comprising one or more pharma- ceutically acceptable excipients, diluents or carriers.

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