Combination therapy for treating trop-2 expressing cancers

Abstract

The present disclosure relates to methods of treating, ameliorating, preventing, or delaying recurrence or metastasis of a Trop-2 expressing cancer (e.g., metastatic castration-resistant prostate cancer, non-small cell lung cancer) in a subject by administering to the subject an effective amount of: (a) an anti-Trop-2 antibody drug conjugate (ADC) (e.g., gosatuzumab); and (b) an adenosine pathway inhibitor (e.g., etradiam, quiniklurostat). The present disclosure also relates to methods of treating, ameliorating, preventing, or delaying the recurrence or metastasis of a cancer expressing a tumor antigen (TA) in a subject by administering an effective amount of: a) a tumor antigen targeting antibody-drug conjugate (ADC) comprising a topoisomerase I inhibitor (TopI ADC); and b) an adenosine pathway inhibitor.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of U.S. Provisional Application No. 63 / 330,700 filed on April 13, 2022, U.S. Provisional Application No. 63 / 370,228 filed on August 2, 2022, and U.S. Provisional Application No. 63 / 377,918 filed on September 30, 2022 under 35 U.S.C. §119(e), each of which is hereby incorporated by reference in its entirety. Technical Field

[0003] The present disclosure relates to a method for treating, alleviating, preventing or delaying the recurrence or metastasis of a cancer expressing Trop-2 (e.g., metastatic castration-resistant prostate cancer, non-small cell lung cancer) in a subject by administering to the subject an effective amount of the following substances: (a) an anti-Trop-2 antibody drug conjugate (ADC) (e.g., sacituzumab govitecan); and (b) an adenosine pathway inhibitor (e.g., etrumadenant, quemliclustat). The present disclosure also relates to a method for treating, alleviating, preventing or delaying the recurrence or metastasis of a cancer expressing a tumor antigen (TA) in a subject by administering an effective amount of the following substances: a) a tumor antigen-targeted antibody-drug conjugate (ADC) (TopI ADC) comprising a topoisomerase I inhibitor; and b) an adenosine pathway inhibitor. Background Art

[0004] Anti-Trop-2 antibody drug conjugates, such as gosartuzumab and datopotamab deruxtecan, are undergoing clinical studies for the treatment of a variety of cancers that express Trop-2. Although evidence of clinical efficacy has been obtained in the monotherapy setting, further therapeutic benefit to patients is still needed.

[0005] It has been reported that Trop-2 is expressed in a variety of epithelial cancers, including breast cancer, bladder cancer, lung cancer, colorectal cancer, and prostate cancer. Prostate cancer is the most commonly diagnosed cancer in men in the United States (US) and the second most common cause of cancer-related mortality. In 2019, an estimated 174,650 new cases were diagnosed, with 31,620 related deaths (National Cancer Institute. SEER Cancer Stat Facts: Prostate Cancer. Accessed on February 25, 2020, at seer.cancer.gov / statfacts / html / prost.html.). Adenocarcinoma accounts for 95% of prostate cancer (LieAK. Histology of prostate cancer. Oncolex Oncology Encyclopedia. Accessed on February 25, 2020, at oncolex.org / Prostate-cancer / Background / Histology.). Most cases (90%) are diagnosed at a local or regional stage, and treatment options include active surveillance, surgery, or radiation therapy. The 5-year relative survival rate is 98% for all stages, but is 30% for late-stage disease.

[0006] The treatment algorithm for metastatic or advanced prostate cancer is more complex. Patients with locally advanced disease initially receive androgen ablation with radiation therapy or prostatectomy, while the first-line therapy for metastatic disease is androgen ablation plus systemic therapy (e.g., second-generation hormone therapy or chemotherapy based on docetaxel). Disease progression under androgen deprivation is called castration-resistant prostate cancer (CRPC). Specifically, the Prostate Cancer Working Group 2 (PCWG2) defines CRPC as a persistent increase in serum prostate-specific antigen (PSA) levels, progression of pre-existing local or metastatic disease, and / or the appearance of new metastases against the background of castration-level serum testosterone (<50ng / dL; Scher HI et al., J Clin Oncol. (2008) 26 (7): 1148-1159).

[0007] The prognosis of CRPC is associated with several factors, including performance status, the presence or absence of bone pain symptoms, the extent of disease on bone scan, and serum alkaline phosphatase (ALP) levels. Bone metastases occur in approximately 80% of men with CRPC and can produce significant morbidity, including pain, pathological fractures, spinal cord compression, and bone marrow failure. Paraneoplastic effects are also common and include anemia, weight loss, fatigue, hypercoagulability, and increased susceptibility to infection (Saad F and Hotte S. Can Urol Assoc J. (2010) 4(6):380-384).

[0008] In the past decade, the U.S. Food and Drug Administration (FDA) has approved six new agents for the treatment of metastatic CRPC (mCRPC), resulting in significant improvements in overall survival (OS; Fay AP and Antonarakis ES. Ann Transl Med. (2019) 7(Suppl 1): S7.). However, the clinical benefit of each agent alone is rarely durable, with a median overall survival (OS) of approximately 2 to 3 years. Due to the complexity of the disease and the challenges of successful treatment, mCRPC remains an area of ​​high unmet medical need in which new therapeutic developments are being actively explored.

[0009] Lung cancer is the leading cause of cancer-related mortality worldwide. It is estimated that in 2020, there will be more than 2 million new cases of lung cancer and about 1.8 million deaths worldwide. In the United States (US), it is estimated that there will be more than 235,000 new cases of lung cancer and more than 131,000 deaths in 2021. About 80% to 85% of all lung cancers are non-small cell lung cancers (NSCLC) (Ettinger et al., J Natl Compr Canc Netw (2019); 17(12): 1464-72), of which more than half are discovered at an advanced stage (Siegel et al., CA Cancer J Clin (2019); 69(1): 7-34).

[0010] Several genomic alterations that have an impact on therapy selection have been identified in NSCLC, and molecular testing is part of the standard of care for NSCLC. Of these, epidermal growth factor receptor (EGFR) gene mutations (10% to 50% of NSCLC mutations) and anaplastic lymphoma kinase (ALK) gene rearrangements (5%) are the most common and are associated with response to EGFR and ALK tyrosine kinase inhibitors, which have been widely approved and used clinically as first-line agents for these subtypes. Other genomic alterations, such as ROS proto-oncogene 1 (ROS1) gene rearrangements, proto-oncogene B-raf (BRAF) point mutations, MET exon 14 skipping, RET alterations, and neurotrophic tyrosine receptor kinase (NTRK) mutations occur less frequently, but therapies targeting such alterations have been approved. Unfortunately, only a minority of new NSCLC cases have actionable genomic alterations, although the list of actionable genomic alterations identified is growing.

[0011] Recent advances in immune checkpoint inhibitor (CPI) therapy have significantly improved the prognosis of advanced lung cancer, and these immuno-CPI therapies, as monotherapy (programmed cell death ligand 1 [PD-L1] tumor proportion score [TPS] ≥1%) or in combination with platinum doublet chemotherapy (regardless of PD-L1 expression), are primarily used in the first-line metastatic setting based on the results of KEYNOTE-024, KEYNOTE-042, KEYNOTE-189, and KEYNOTE-407, as well as in similar studies for participants without actionable genomic alterations. For patients with nonsquamous NSCLC, chemotherapy / immunotherapy regimens such as pembrolizumab / (carboplatin or cisplatin) / pemetrexed are recommended regardless of PD-L1 expression. For patients with metastatic squamous cell NSCLC, chemotherapy / immunotherapy regimens such as pembrolizumab / carboplatin / (paclitaxel or nab-paclitaxel) are recommended (Ettinger et al., J Natl Compr Canc Netw (2019); 17(12): 1464-72).

[0012] After failure of immune checkpoint inhibitor therapy and platinum-based chemotherapy, most patients have limited treatment options. According to the National Comprehensive Cancer Network Guidelines, after failure of platinum-based therapy and / or immune checkpoint therapy, regardless of the presence of genomic alterations and PD-L1 status, the use of single-agent chemotherapy (including taxanes) is the standard treatment for patients with recurrent or metastatic NSCLC (Ettinger et al., J Natl Compr Canc Netw (2019); 17(12): 1464-72). In this context, the main options for single-agent chemotherapy generally include docetaxel (with or without ramucirumab) and pemetrexed (for non-squamous tumors, if not previously used). In a study of docetaxel versus best supportive care for recurrent NSCLC, the median progression-free survival (PFS) was about 3 months and the median overall survival (OS) was about 6 to 8 months (Shepherd et al., J Clin Oncol (2000); 18(10): 2095-103). These numbers have been confirmed in more contemporary studies using docetaxel after failure of platinum-based regimens for NSCLC (Horn et al., J Clin Oncol (2017); 35(35):3924-33; Mazieres et al., Journal of Thoracic Oncology (2021); 16(1):140-50). Although docetaxel is considered the standard of care for patients who have failed platinum-based regimens and checkpoint inhibitors, novel agents remain a significant unmet medical need in the follow-up treatment of advanced or metastatic NSCLC.

[0013] Immune checkpoint inhibitors have rekindled interest in the clinical development of anticancer immunotherapy. The latter relies on therapeutic modulation of the tumor microenvironment or other aspects of the immune system to overcome the immunosuppressive mechanisms caused by tumors on the host immune system. Although the approval of nivolumab, pembrolizumab, atezolizumab, and ipilimumab has demonstrated their proven benefits in a variety of tumor types, checkpoint inhibition has not been shown to be effective in the treatment of metastatic prostate cancer, with a response rate of less than 5% for monotherapy (Antonarakis ES et al., J Clin Oncol. (2020) 38 (5): 395-405.).

[0014] Antibody-drug conjugates (ADCs) are a rapidly growing class of drugs in oncology, with several different ADCs currently approved for cancer treatment and many more in preclinical and clinical development (e.g., Drago, JZ et al., Nat Rev Clin Oncol (2021) 18, 327–344). ADCs are typically composed of a monoclonal antibody linked to a cytotoxic drug (payload). ADCs are designed to specifically limit the delivery of cytotoxic drugs to cells expressing the target antigen of the corresponding antibody (e.g., Trop-2, Her-2, Nectin-4) and adjacent tumor tissue (bystander effect). Due to the tumor-targeted delivery of cytotoxic agents, ADCs typically have a greatly improved therapeutic window compared to systemically administered cytotoxic agents. Examples of ADCs that have received marketing approval from the United States Food and Drug Administration (US FDA) include gemtuzumab, vebutinib, trastuzumab enrofloxacin (T-DM1), oepatuzumab, trastuzumab delutec (T-DXd), vepotuzumab, sacituzumab delutec, enrofloxacin, and belantamab mofortin.

[0015] The adenosine pathway mediates immunosuppression in the tumor microenvironment (e.g., Allard, B. et al., Nat Rev Clin Oncol (2020) 17, 611–629). Adenosine pathway inhibitors (including various CD39 inhibitors, CD73 inhibitors, and adenosine receptor antagonists) are under clinical investigation as promising agents for stimulating anticancer immune responses.

[0016] Despite advances in cancer treatment, many patients remain refractory to currently available therapies or relapse after responding to available therapies, leading to the need to develop novel agents and combinations of agents for the treatment of multiple types of cancer, including mCRPC. Summary of the invention

[0017] In one aspect, provided herein is a method for treating, alleviating, reducing, preventing or delaying the recurrence or metastasis of Trop-2 positive cancer, comprising co-administering to a subject an effective amount of: a) an anti-Trop-2 antibody-drug conjugate (ADC); and b) an adenosine pathway inhibitor.

[0018] In some embodiments, the methods provided herein are for treating a Trop-2 positive cancer, comprising co-administering to a subject effective amounts of: a) an anti-Trop-2 antibody-drug conjugate (ADC); and b) an adenosine pathway inhibitor.

[0019] In some embodiments, the anti-Trop-2 ADC comprises a topoisomerase I inhibitor.

[0020] In some embodiments, the topoisomerase I inhibitor is camptothecin (CPT).

[0021] In some embodiments, the topoisomerase I inhibitor is topotecan, irinotecan, belotecan, or exatecan.

[0022] In some embodiments, the topoisomerase I inhibitor is SN38 or Dxd.

[0023] In some embodiments, the topoisomerase I inhibitor is selected from the group consisting of irinotecan, topotecan, and SN-38.

[0024] In some embodiments, the topoisomerase I inhibitor is SN38.

[0025] In some embodiments, the anti-Trop-2 ADC has the structural formula mAb-CL2A-SN-38, the structure of which is represented by the following formula:

[0026]

[0027] (Described, for example, in U.S. Pat. No. 7,999,083).

[0028] In some embodiments, the anti-Trop-2 ADC comprises sacizumab (hRS7; described, e.g., in Figures 3 and 4 of WO2003074566).

[0029] In some embodiments, the anti-Trop-2 ADC is selected from the group consisting of gosartuzumab, dexamethasone delutec (DS-1062), ESG-401, SKB-264, DAC-02, and BAT-8003.

[0030] In some embodiments, the anti-Trop-2 ADC is gosartuzumab.

[0031] In some embodiments, the adenosine pathway inhibitor is a CD39 inhibitor, a CD73 inhibitor, or an adenosine receptor antagonist.

[0032] In some embodiments, the adenosine pathway inhibitor is a plurality of adenosine pathway inhibitors. In some embodiments, the plurality of adenosine pathway inhibitors include a CD73 inhibitor and an adenosine receptor antagonist. In some embodiments, the CD73 inhibitor is quetiapine and the adenosine receptor antagonist is edradinam.

[0033] In some embodiments, the adenosine pathway inhibitor is an adenosine receptor antagonist.

[0034] In some embodiments, the adenosine pathway inhibitor is imadinam, NIR178, ID11902, IN-A003, NTI-55, TT-10, TT-228, PBF-1129 (Palobiofarma), TT-702, edradinan, INCB106385, M1069, HM87277, RVU-330, or TT-53.

[0035] In some embodiments, the adenosine pathway inhibitor is a dual antagonist of the adenosine A2A receptor (A2AR; ADORA2A) and A2B receptor (A2BR; ADORA2B).

[0036] In some embodiments, the adenosine pathway inhibitor is edradinan (AB928; GS-0928), taminadenant, TT-10, TT-4, or M1069.

[0037] In some embodiments, the adenosine pathway inhibitor is edradinam.

[0038] In some embodiments, the adenosine pathway inhibitor is a CD73 inhibitor.

[0039] In some embodiments, the CD73 inhibitor is olerumab, BMS-986179, ulelimab, AK119, quetiapine, mopalimumab, HLX23, INCA00186, IBI325, NZV930, ORIC-533, Sym024, IPH5301, IOA-237, JAB-BX100, PT199, TRB010, CD73 ASO, ABSK-051, AK131, BR101, BP1200, CB708, GB7002, or ATG-037.

[0040] In some embodiments, the CD73 inhibitor is quelicustat (AB680, GS-0680), ulelimab, mopalimumab, ORIC-533, ATG-037, PT-199, AK131, NZV930, BMS-986179, or olelumab.

[0041] In some embodiments, the CD73 inhibitor is quetiapine.

[0042] In some embodiments, the method further comprises co-administering an additional therapeutic agent or treatment modality.

[0043] In some embodiments, the additional therapeutic agents or treatment modalities include one, two, three, or four additional therapeutic agents and / or treatment modalities.

[0044] In some embodiments, the additional therapeutic agent comprises an anti-PD-(L)1 antibody.

[0045] In some embodiments, the anti-PD-(L)1 antibody is pembrolizumab, nivolumab, cemiprilimab, pidilizumab, spartalizumab, atezolizumab, avelumab, durvalumab, cocilimab, sazanlimab, tislelizumab, rivolimab, batilizumab, toripalimab, sitrilimab, genoluzumab, palolizumab, lodalizumab, carrelizumab, budigalimab, avelumab, dotalimumab, envolimab, sintilimab, or sepalizumab.

[0046] In some embodiments, the anti-PD-(L)1 antibody is sepalizumab.

[0047] In some embodiments, the additional therapeutic agent comprises an anti-TIGIT antibody.

[0048] In some embodiments, the anti-TIGIT antibody is tisleliumab, vembryomab, dunalimab, AB308, AK127, BMS-986207, rapasumab, or ietinib.

[0049] In some embodiments, the anti-TIGIT antibody is dunalimab. In some embodiments, the anti-TIGIT antibody is rapasumab.

[0050] In some embodiments, the additional therapeutic agents include an anti-PD-(L1) antibody and an anti-TIGIT antibody.

[0051] In some embodiments, the additional therapeutic agent includes a) sepalizumab and dunalimab, b) sepalizumab and AB308, c) atezolizumab and tirilimab, d) pembrolizumab and vembrolizumab, e) pembrolizumab and dunalimab, f) pembrolizumab and AB308, g) MK-7684A (pembrolizumab / vembrolizumab co-formulation), h) durvalumab and dunalimab, i) sepalizumab and rapasumab, or j) pembrolizumab and rapasumab.

[0052] In some embodiments, the additional therapeutic agents include sepalimumab and dunalimab.

[0053] In some embodiments, the Trop-2-positive cancer is a solid epithelial cancer.

[0054] In some embodiments, the solid epithelial cancer is selected from breast cancer (e.g., triple-negative breast cancer (TNBC), HR + / Her2 - Breast cancer, HR + / Her2低 In some embodiments, breast cancer is triple negative breast cancer (TNBC), HR + / Her2 - Breast cancer, or HR + / Her2 低 Breast cancer.

[0055] In some embodiments, the prostate cancer is castration-resistant prostate cancer (CRPC).

[0056] In some embodiments, the lung cancer is non-small cell lung cancer (NSCLC).

[0057] In some embodiments, the lung cancer is (i) squamous NSCLC or (ii) non-squamous NSCLC.

[0058] In some embodiments, the lung cancer is free of EGFR, ALK, and other actionable genomic alterations.

[0059] In some embodiments, the Trop-2-positive cancer is (i) an unresectable locally advanced cancer, or (ii) a metastatic cancer.

[0060] In some embodiments, the cancer has progressed following at least one prior anti-cancer therapy.

[0061] In some embodiments, the cancer has progressed following previous treatment with a novel hormonal agent (NHA; first or second generation nonsteroidal antiandrogen, abiraterone).

[0062] In some embodiments, the cancer has progressed or recurred following platinum-based chemotherapy.

[0063] In some embodiments, the cancer has progressed or recurred following checkpoint inhibitor therapy (CPI).

[0064] In some embodiments, the cancer has progressed or relapsed following treatment with platinum-based chemotherapy and anti-PD-(L)1 antibody therapy, either in combination or sequentially in any order.

[0065] In some embodiments, the cancer has progressed or recurred following tyrosine kinase inhibitor therapy.

[0066] In some embodiments, the subject is treatment naive.

[0067] In some embodiments, the subject has not received prior therapy selected from the group consisting of: taxane therapy (taxane naive), checkpoint inhibitor therapy (CPI naive), and topoisomerase I inhibitor therapy.

[0068] In some embodiments, the subject has not received prior taxane therapy (taxane naive), checkpoint inhibitor therapy (CPI naive), or topoisomerase I inhibitor therapy.

[0069] In some embodiments, taxane therapy includes paclitaxel, nab-paclitaxel Docetaxel or cabazitaxel.

[0070] In some embodiments, the checkpoint inhibitor therapy comprises an anti-CTLA4 antibody or an anti-PD(L)1 antibody.

[0071] In some embodiments, topoisomerase I inhibitor therapy includes topotecan, irinotecan, belotecan, or exatecan.

[0072] In some embodiments, the anti-Trop-2 ADC and the adenosine pathway inhibitor are co-administered simultaneously.

[0073] In some embodiments, the anti-Trop-2 ADC and the adenosine pathway inhibitor are co-administered sequentially.

[0074] In some embodiments, the subject is a human.

[0075] In some embodiments, the anti-Trop-2 ADC is administered in one or more doses ranging from 8 mg / kg to 10 mg / kg.

[0076] In some embodiments, the anti-Trop2 ADC is administered in one or more doses of 8 mg / kg or 10 mg / kg.

[0077] In some embodiments, the anti-Trop2 ADC is administered in one or more doses of 10 mg / kg.

[0078] In some embodiments, the anti-Trop-2 ADC is administered intravenously.

[0079] In some embodiments, the anti-Trop-2 ADC is administered on days 1 and 8 of a 21 day cycle.

[0080] In some embodiments, the adenosine pathway inhibitor is administered in one or more doses of 75 mg or 150 mg.

[0081] In some embodiments, the adenosine pathway inhibitor is administered in one or more doses of 150 mg.

[0082] In some embodiments, the adenosine pathway inhibitor is administered orally (PO).

[0083] In some embodiments, the adenosine pathway inhibitor is administered once daily (QD).

[0084] In some embodiments, the anti-PD(L)1 antibody is administered in one or more doses of 360 mg.

[0085] In some embodiments, the anti-PD(L)1 antibody is administered intravenously (IV).

[0086] In some embodiments, the anti-PD(L)1 antibody is administered once every three weeks (Q3W).

[0087] In some embodiments, gosatuzumab is administered intravenously (IV) at a dose of 10 mg / kg on days 1 and 8 of a 21-day treatment cycle, edrinam is administered orally (PO) at a dose of 150 mg once a day (QD) on each day of the 21-day treatment cycle, and optionally, sepalizumab is administered intravenously (IV) on day 1 of a 21-day treatment cycle (Q3W).

[0088] In some embodiments, the anti-cancer effect is observed as determined by the following indicators: objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), duration of response (DOR), overall survival (OS), complete response (CR), partial response (PR), PSA response rate, radiographic response rate, change from baseline in blood and tumor tissue microenvironment pharmacodynamic (PD) biomarkers, or a combination of these indicators. In some embodiments, tumor response or progression is determined according to RECIST version 1.1.

[0089] In some embodiments, provided herein is a method for treating, alleviating, reducing, preventing or delaying the recurrence or metastasis of castration-resistant prostate cancer (CRPC), comprising co-administering an effective amount of the following substances to a human patient: a) gosartuzumab; and b) eltrodinam. In some embodiments, provided herein is a method for treating metastatic castration-resistant prostate cancer (mCRPC), comprising co-administering an effective amount of the following substances to a human patient: a) gosartuzumab; and b) eltrodinam. In some embodiments, the method further comprises co-administering an anti-PD-(L)1 antibody to a human patient. In some embodiments, the anti-PD-(L)1 antibody is selected from the group consisting of: pembrolizumab, nivolumab, cemiprilimab, pidilizumab, spartalizumab, atezolizumab, avelumab, durvalumab, coxilimab, sazanlizumab, tislelizumab, rivulimab, batilizumab, toripalimab, cetrilimab, genolumab, palolizumab, lodalimab, carrelizumab, budigalimab, avelumab, dotalimumab, envolimab, sintilimab and sepalimab. In some embodiments, the method further comprises co-administering sepalimab to the human patient. In some embodiments, the human mCRPC patient has previously progressed while undergoing ADT. In some embodiments, the human mCRPC patient has previously progressed while using ADT. In some embodiments, the human mCRPC patient has not received CPI and taxane.In some embodiments, the human mCRPC patient has measurable or non-measurable disease by RECIST 1.1.

[0090] In some embodiments, the CRPC is metastatic CRPC (mCRPC).

[0091] In some embodiments, CRPC is resistant or refractory to one or more anti-cancer therapies.

[0092] In some embodiments, CRPC has progressed after prior NHA therapy (first- or second-generation nonsteroidal antiandrogens, abiraterone).

[0093] In some embodiments, the human patient has not received prior therapy selected from the group consisting of: taxane therapy (taxane naive), checkpoint inhibitor therapy (CPI naive), and topoisomerase I inhibitor therapy.

[0094] In some embodiments, the human patient has not received prior taxane therapy (taxane naive), checkpoint inhibitor therapy (CPI naive), or topoisomerase I inhibitor therapy.

[0095] In some embodiments, taxane therapy includes paclitaxel, nab-paclitaxel Docetaxel or cabazitaxel.

[0096] In some embodiments, the checkpoint inhibitor therapy comprises an anti-CTLA4 antibody or an anti-PD(L)1 antibody.

[0097] In some embodiments, topoisomerase I inhibitor therapy includes topotecan, irinotecan, belotecan, or exatecan.

[0098] In some embodiments, provided herein is a method for treating, alleviating, reducing, preventing or delaying the recurrence or metastasis of non-small cell lung cancer (NSCLC), comprising co-administering to a human patient an effective amount of the following substances: a) gosartuzumab; b) edrinam; and c) an anti-PD-(L)1 antibody. In some embodiments, the anti-PD-(L)1 antibody is selected from the group consisting of pembrolizumab, nivolumab, cemiprilimab, pidilizumab, spartalizumab, atezolizumab, avelumab, durvalumab, cocilimab, sazanlimab, tislelizumab, rivulimab, batilizumab, toripalimab, sitrilimab, genoluzumab, palomundumab, lodalizumab, carrelizumab, budigalimab, avelumab, dotalimumab, envolimab, sintilimab and sepalizumab. In some embodiments, the anti-PD-(L)1 antibody is sepali monoclonal antibody. In some embodiments, the NSCLC has progressed or relapsed after platinum-based chemotherapy. In some embodiments, the NSCLC has progressed or relapsed after checkpoint inhibitor therapy (CPI). In some embodiments, the NSCLC has progressed or relapsed after receiving platinum-based chemotherapy and anti-PD-(L)1 antibody therapy in combination or in any order. In some embodiments, the NSCLC has progressed or relapsed after tyrosine kinase inhibitor therapy. In some embodiments, the NSCLC is (i) unresectable locally advanced cancer, or (ii) metastatic cancer.

[0099] In some embodiments, gosatuzumab is administered intravenously (IV) at a dose of 8 mg / kg or 10 mg / kg on days 1 and 8 of a 21-day treatment cycle and edrinam is administered orally (PO) once daily (QD) at a dose of 75 mg or 150 mg on each day of the 21-day treatment cycle.

[0100] In some embodiments, gosatuzumab is administered intravenously (IV) at a dose of 10 mg / kg on days 1 and 8 of a 21-day treatment cycle and edrinam is administered orally (PO) at a dose of 150 mg once daily (QD) on each day of the 21-day treatment cycle.

[0101] In some embodiments, sepalimumab is administered intravenously (IV) on day 1 of a 21-day treatment cycle (Q3W).

[0102] In some embodiments, an anti-cancer effect is observed as determined by the following indicators: objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), duration of response (DOR), overall survival (OS), complete response (CR), partial response (PR), PSA response rate, radiographic response rate, change from baseline in blood and tumor tissue microenvironment pharmacodynamic (PD) biomarkers, or a combination of these indicators. In some embodiments, an anti-cancer effect is observed as determined by the following indicators: objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), complete response (CR), partial response (PR), PSA response rate, radiographic response rate, or change from baseline in blood and tumor tissue microenvironment pharmacodynamic (PD) biomarkers.

[0103] In some embodiments of the methods provided herein, an anti-CD47 antibody (eg, mololimab) is not co-administered to the subject or human patient.

[0104] In some embodiments of the methods provided herein, an MCL1 inhibitor (eg, GS-9716) is not co-administered to the subject or human patient.

[0105] In some embodiments of the methods provided herein, a FLT3 agonist (eg, GS-3583, CDX-301) is not administered to the subject or human patient.

[0106] In another aspect, the present invention provides a method for treating, alleviating, reducing, preventing or delaying tumor antigen positive (TA + ) a method for preventing the recurrence or metastasis of cancer, comprising co-administering to a subject an effective amount of the following substances: a) a tumor antigen (TA) targeting ADC (TopI ADC) comprising a topoisomerase I inhibitor; b) an adenosine pathway inhibitor; and c) optionally, an anti-PD(L)1 antibody.

[0107] In another aspect, provided herein is an anti-Trop-2 ADC for use in combination with an adenosine pathway inhibitor and optionally an anti-PD(L)1 antibody in a method for treating, alleviating, reducing, preventing or delaying recurrence or metastasis of a Trop-2 positive cancer, wherein the method comprises administering to a subject an anti-Trop-2 ADC, an adenosine pathway inhibitor and optionally an additional anti-PD(L)1 antibody.

[0108] In another aspect, TopI ADC is provided herein for use in combination with an adenosine pathway inhibitor and optionally an anti-PD(L)1 antibody for treating, alleviating, reducing, preventing or delaying tumor antigen positive (TA + ) cancer recurrence or metastasis, wherein the method comprises administering to a subject a TopI ADC, an adenosine pathway inhibitor, and optionally an anti-PD(L)1 antibody. DETAILED DESCRIPTION

[0109] Provided herein are methods for treating, alleviating, reducing, preventing or delaying Trop-2 positive (Trop-2 ADC) by co-administering to a subject an effective amount of a) an anti-Trop-2 antibody-drug conjugate (anti-Trop-2 ADC) and b) an adenosine pathway inhibitor. + ) cancer recurrence or metastasis. Also provided herein is a method for treating, alleviating, reducing, preventing or delaying tumor antigen positive (TA) by co-administering to a subject an effective amount of a) a tumor antigen (TA) targeting ADC (TopI ADC) comprising a topoisomerase I inhibitor and b) an effective amount of an adenosine pathway inhibitor. + ) Combination therapy for the recurrence or metastasis of cancer. In some embodiments, the combination therapy provided herein also includes the co-administration of an additional therapeutic agent, such as a checkpoint inhibitor, or an additional treatment modality (e.g., surgery, radiation). In some embodiments, the anti-Trop-2 ADC is gosatuzumab. In some embodiments, TopI ADC is trastuzumab-derunotecan (T-DXd). In some embodiments, an adenosine pathway inhibitor is a CD39 inhibitor (e.g., TTX-030, IPH5201, SRF617), a CD73 inhibitor (e.g., queliclostra, oreluzumab), or an adenosine receptor antagonist (e.g., eitridinam, imatinam, NIR178). In some embodiments, a checkpoint inhibitor is an anti-PD(L)1 antibody (e.g., sepalizumab, pembrolizumab, nivolumab, atezolizumab, durvalumab). In some embodiments, the Trop-2 positive cancer is castration-resistant prostate cancer (CRPC) or non-small cell lung cancer (NSCLC).

[0110] In another aspect, provided herein is an anti-Trop-2 ADC (e.g., gosatuzumab) for use in combination with an adenosine pathway inhibitor (e.g., edredinam) and an optional additional therapeutic agent (such as a checkpoint inhibitor (e.g., an anti-PD(L)1 antibody)) or an additional treatment modality (e.g., surgery, radiation) for use in a method for treating, alleviating, reducing, preventing, or delaying the recurrence or metastasis of a Trop-2 positive cancer, wherein the method comprises administering an anti-Trop-2 ADC, an adenosine pathway inhibitor, and an optional additional therapeutic agent or additional treatment modality to a subject (e.g., a human cancer patient). In some embodiments, the anti-Trop-2 ADC is gosatuzumab. In some embodiments, the adenosine pathway inhibitor is a CD39 inhibitor (e.g., TTX-030, IPH5201, SRF617), a CD73 inhibitor (e.g., quilibrumab, olerulumab), or an adenosine receptor antagonist (e.g., edredinam, imadinam, NIR178). In some embodiments, the checkpoint inhibitor is an anti-PD(L)1 antibody (e.g., sepalizumab, pembrolizumab, nivolumab, atezolizumab, durvalumab). In some embodiments, the Trop-2 positive cancer is castration-resistant prostate cancer (CRPC) or non-small cell lung cancer (NSCLC).

[0111] In another aspect, TopI ADCs are provided herein for use in a method for treating, alleviating, reducing, preventing or delaying the recurrence or metastasis of TA-positive cancers in combination with an adenosine pathway inhibitor (e.g., a CD39 inhibitor, a CD73 inhibitor, an adenosine receptor antagonist) and an optional additional therapeutic agent (such as a checkpoint inhibitor (e.g., an anti-PD(L)1 antibody)) or an additional treatment modality (e.g., surgery, radiation), wherein the method comprises administering TopI ADC, an adenosine pathway inhibitor and an optional additional therapeutic agent or additional treatment modality to a subject (e.g., a human cancer patient). In some embodiments, the TopI ADC is trastuzumab-derunotecan (T-DXd). In some embodiments, the adenosine pathway inhibitor is a CD39 inhibitor (e.g., TTX-030, IPH5201, SRF617), a CD73 inhibitor (e.g., quilibrumab, oleruumab), or an adenosine receptor antagonist (e.g., edredinam, imadinam, NIR178). In some embodiments, the checkpoint inhibitor is an anti-PD(L)1 antibody (e.g., sepalizumab, pembrolizumab, nivolumab, atezolizumab, durvalumab). In some embodiments, the Trop-2 positive cancer is castration-resistant prostate cancer (CRPC) or non-small cell lung cancer (NSCLC).

[0112] The present disclosure is based at least in part on the recognition that, compared with a single agent therapy using one of the combination agents a) and b), a combination therapy comprising co-administering a) anti-Trop2 ADC or TopI ADC and b) an adenosine pathway inhibitor may have an improved anti-cancer effect. The improved anti-cancer effect may include, for example, an improved overall response rate (ORR), an improved partial response rate (PR), an improved complete response rate (CR), an improved duration of remission (DOR), an improved overall survival (OS), an improved progression-free survival (PFS), an improved quality of life (QoL) indicator, and the like. The combination therapy described herein generally has a tolerable safety profile, for example, as determined by the incidence and / or severity of observed adverse events (AEs) or serious adverse events (SAEs). In some embodiments, the combination therapy described herein has an improved safety profile, for example, compared with a monotherapy involving a co-administered agent, or relative to the standard treatment for a given indication (e.g., a chemotherapy regimen selected by a physician).

[0113] definition

[0114] As used herein, the term "antibody" refers to a polypeptide comprising a canonical immunoglobulin sequence element sufficient to confer specific binding to a specific target antigen (e.g., a heavy chain variable domain, a light chain variable domain, and / or one or more CDRs sufficient to confer specific binding to a specific target antigen). Therefore, the term "antibody" includes, for example, but not limited to, human antibodies, non-human antibodies, antibody fragments, and antigen-binding agents including antibody fragments, including their synthetic forms, engineered forms, and modified forms. For example, the term "antibody" includes both naturally occurring antibodies and non-naturally occurring antibodies. In general, an antibody may include at least two heavy (H) chains and two light (L) chains interconnected by disulfide bonds, or an antigen-binding molecule thereof. Each H chain includes a heavy chain variable region (abbreviated herein as VH) and a heavy chain constant region. The heavy chain constant region includes three constant domains CH1, CH2, and CH3. Each light chain includes a light chain variable region (abbreviated herein as VL) and a light chain constant region. The light chain constant region includes one constant domain CL. The VH and VL regions can be further subdivided into hypervariable regions, called complementarity determining regions (CDRs), interspersed with more conserved regions, called framework regions (FRs). Each VH and VL contains three CDRs and four FRs, which are arranged from the amino terminus to the carboxyl terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4. The variable regions of the heavy and light chains contain binding domains that interact with antigens. The constant region of an antibody (Ab) can mediate the binding of immunoglobulins to host tissues or factors, including various cells of the immune system (e.g., effector cells) and the first component (C1q) of the classical complement system. Naturally produced antibodies are glycosylated, usually on the CH2 domain. Examples of antibodies include monoclonal antibodies, monospecific antibodies, polyclonal antibodies, multispecific antibodies (including bispecific antibodies), engineered antibodies, recombinantly produced antibodies, fully synthetic antibodies, humanized antibodies, chimeric antibodies, immunoglobulins, tetrameric antibodies comprising two heavy chain molecules and two light chain molecules, antibody light chain monomers, antibody heavy chain monomers, antibody light chain dimers, antibody heavy chain dimers, antibody light chain-antibody heavy chain pairs, intrabodies, antibody fusions (sometimes referred to herein as "antibody conjugates"), heteroconjugate antibodies, single domain antibodies, monovalent antibodies, single chain antibodies or single-chain Fv (scFv), camelized antibodies, affibodies, Fab fragments, Fab' fragments, F(ab')2 fragments, Fd' fragments, Fd fragments, isolated CDRs, single-chain Fv, polypeptide-Fc fusions, single domain antibodies (e.g., shark single domain antibodies (such as IgNAR) or fragments thereof); camelid antibodies; disulfide-linked Fv (sdFv), anti-idiotypic (anti-Id) antibodies (including, e.g., anti-anti-Id antibodies), minibodies, domain antibodies, synthetic antibodies (sometimes referred to herein as "antibody mimetics"), single chain or tandem diabodies Microantibodies, Ankyrin repeat protein or DART, TCR-like antibodies, MicroProteins And antigen-binding fragments of any of the above.

[0115] As used herein, the term "antibody-drug conjugate" generally refers to a compound comprising an antibody targeting a tumor antigen, optionally connected by a linker, and an anticancer agent payload. In some embodiments, the tumor antigen is tumor-associated calcium signal transducer 2 (Trop-2; NCBI Gene ID: 4070). In some embodiments, the tumor antigen targeting antibody is an anti-Trop-2 antibody (e.g., saccharomyces cerevisiae or dedabotulinumab). In some embodiments, the payload is a topoisomerase I inhibitor (e.g., SN38 or Dxd). Many ADC linker chemicals are known to those skilled in the art and are cited herein (e.g., CL2A).

[0116] As used herein, the term "topoisomerase I inhibitor" refers to a small molecule compound that can inhibit the activity of DNA topoisomerase type I enzyme. Type I topoisomerase can catalyze changes in DNA topology via transient single-strand breaks in DNA. Type I topoisomerase can be further classified into type 1A and type 1B subtypes. Descriptions of type I topoisomerase can be found in, for example, Baker et al., (2009) Nucleic Acids Res 37 (3), 693-701. Topoisomerase inhibitors that can be used as payloads in ADCs described herein include inhibitors based on camptothecin (CPT) and non-camptothecins. Available camptothecins include, for example, topotecan, irinotecan, belotecan, exatecan, and their derivatives. Useful non-camptothecins include, for example, indenoquinolines (e.g., indeno[1,2-c]isoquinoline, NSC314622, indolecan (LMP-400), innotecan (LMP-776), phenanthridines (e.g., Topovale (ARC-111)), and indolecarbazoles (e.g., BE-13793C). In some embodiments, the topoisomerase I inhibitor is a camptothecin (e.g., irinotecan, topotecan, belotecan, or an exatecan derivative, such as SN38 or Dxd). In some embodiments, the topoisomerase I inhibitor is SN38. In some embodiments, the topoisomerase I inhibitor is Dxd.

[0117] As used herein, the term "anti-PD(L)1 antibody" refers to: a) an antibody that binds to programmed cell death protein 1 (PD-1, CD279; NCBI Gene ID: 5133) or programmed death ligand 1 (PD-L1, CD274; NCBI Gene ID: 29126); and b) an antibody that inhibits the PD-1 / PD-L1 interaction and the PD-1 / PD-L1 pathway. The PD-1 / PD-L1 pathway and its role in cancer immunotherapy are described, for example, in Salmaninejad et al., J. Cell Physiol (2019) 234(10): 16824-16837. Anti-PD(L)1 antibodies that can be used in the methods provided herein include, for example, pembrolizumab, nivolumab, cemiprilimab, pidilizumab, spartalizumab, atezolizumab, avelumab, durvalumab, cocilimab, sazanlimab, tislelizumab, rivulimab, batilizumab, toripalimab, cetrilimab, genoluzumab, palolizumab, lodalizumab, carrelizumab, budigalimab, avelumab, dotalimumab, envolimab, sintilimab and sepalizumab. In some embodiments, the anti-PD(L)1 antibody is sepalizumab.

[0118] As used herein, the term "effective amount" or "therapeutically effective amount" refers to the following amount of a therapeutic agent (e.g., ADC, adenosine pathway inhibitor, checkpoint inhibitor) administered in the methods provided herein: when administered alone or in combination with another therapeutic agent to a cell, tissue or subject, the amount is sufficient to achieve treatment or beneficial results in the subject. The therapeutically effective amount can vary according to the subject, the disease or condition being treated, the subject's weight and age, the severity of the disease or condition, and the mode of administration, which can be easily determined by a person of ordinary skill in the art. The effective amount also refers to the amount of the therapeutic agent sufficient to treat, prevent, alleviate, improve or alleviate the disease condition, or delay or slow the progression of the disease when used in the context of the combination therapy provided herein, and the amount of the rate increase sufficient to achieve the treatment, cure, prevention or improvement of such conditions. When applied to a separate therapeutic agent administered independently, the effective amount refers to a separate active ingredient. When applied to a combination, a therapeutically effective amount refers to the combined amount of active ingredients that produce a therapeutic effect, whether administered in combination, continuously or simultaneously. In some embodiments, as described herein, an effective amount or therapeutically effective amount of a therapeutic agent (e.g., ADC, adenosine pathway inhibitor, checkpoint inhibitor) administered to a subject in the methods provided herein together with one or more additional therapeutic agents can (i) reduce the number of diseased cells; (ii) reduce tumor size; (iii) inhibit, block, slow down, and preferably prevent diseased cells from infiltrating peripheral organs to a certain extent; (iv) inhibit (e.g., slow down and preferably prevent) tumor metastasis to a certain extent; (v) inhibit tumor growth; (vi) prevent or delay tumor occurrence and / or recurrence; and / or (vii) alleviate one or more symptoms associated with cancer to a certain extent. In various embodiments, the amount is sufficient to improve, alleviate, reduce, and / or delay one or more of the symptoms of cancer.

[0119] As used herein, the term "treatment" refers to reversing, alleviating a disease or disorder as described herein or one or more symptoms thereof, delaying its onset or inhibiting its progress. In some embodiments, treatment may be administered after one or more symptoms occur. In other embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to susceptible individuals before the onset of symptoms (e.g., according to a history of symptoms and / or according to genetic factors or other susceptibility factors). Treatment may also be continued after symptoms have subsided, for example, to prevent or delay its recurrence. In some embodiments, the methods provided herein refer to treating subjects (e.g., human cancer patients) with cancer. In some embodiments, treating subjects (e.g., human cancer patients) with cancer includes suppressing cancer or cancer cell proliferation in treated subjects. In some embodiments, human cancer patients are treated using the methods provided herein so that anti-tumor effects or anti-cancer effects are observed in treated patients.

[0120] As used herein, the terms "inhibit cancer" and "inhibit cancer cell proliferation" refer to inhibiting the growth, division, maturation or vitality of cancer cells, and / or causing the death of cancer cells alone or in aggregate with other cancer cells through cytotoxicity, nutrient depletion or apoptosis induction.

[0121] As used herein, the term "anti-tumor effect", "anti-cancer effect" or "anti-cancer efficacy" refers to a biological effect that can be manifested as a reduction in tumor volume, a reduction in the number of tumor cells, a reduction in tumor cell proliferation, a reduction in the number of metastases, an extension of overall survival or progression-free survival, an extension of life expectancy, or an improvement in various physiological symptoms associated with a tumor. In some embodiments, the anti-cancer effect is measured using one or more endpoint criteria (e.g., primary endpoint, secondary endpoint, or exploratory endpoint) used in the clinical studies described herein. Exemplary clinical endpoint criteria that can be used to measure the anti-cancer effect associated with the methods provided herein include objective response rate (ORR), complete response (CR) rate, partial response (PR) rate, disease control rate (DCR), progression-free survival (PFS), duration of remission (DOR), overall survival (OS), (e.g., intratumoral immune activation or induction of cancer cell death) based on biomarker (e.g., based on tumor tissue or blood biomarker) signal, patient quality of life (QoL) indicators (e.g., based on patient surveys), and others. In some embodiments, the anti-tumor effect (e.g., tumor remission or progression) is determined according to RECIST version 1.1 (Eisenhauer et al., Eur J Cancer (2009); 45(2): 228-47). The anti-cancer effect can be observed using any diagnostic method known to the skilled person, such as computed tomography (CT), magnetic resonance imaging (MRI), radiography, and the like.

[0122] As used herein, an "increase" or "enhancement" amount is generally a "statistically significant" amount (e.g., with respect to tumor size, cancer cell proliferation or growth), and can include an increase of 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 9, 10, 15, 20, 30, 40, or 50 times or more (e.g., 100, 500, 1000 times) (including all integers and decimal points between these multiples and greater than 1, such as 2.1, 2.2, 2.3, 2.4, etc.) the amounts or levels described herein. It may also include an increase of at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 100%, at least 150%, at least 200%, at least 500%, or at least 1000% of the amounts or levels described herein.

[0123] As used herein, "lower" or "decrease" or a "smaller" amount (e.g., with respect to tumor size, cancer cell proliferation or growth) refers to a decrease of about 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 9, 10, 15, 20, 30, 40, or 50 times or more (e.g., 100, 500, 1000 times) (including all integers and decimal points between these multiples and greater than 1, e.g., 1.5, 1.6, 1.7, 1.8, etc.) the amount or level described herein. It may also include a decrease of at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90%, at least 100%, at least 150%, at least 200%, at least 500%, or at least 1000% of the amounts or levels described herein.

[0124] As used herein, the term "adverse event" (AE) refers to any undesirable medical event that occurs in a clinical study participant to which a study drug is administered and that is not necessarily causally related to treatment. Therefore, an AE can be any unfavorable and / or unexpected sign (including clinically significant abnormal laboratory test results), symptom or disease that is temporarily associated with the use of a study drug, regardless of whether the AE is considered to be related to the study drug. Adverse events may also include pre- or post-treatment complications that occur due to protocol-specified procedures or special circumstances. In some embodiments, pre-existing events that increase in severity or change in nature after the start of the study drug or during participation in a clinical study or due to participation in a clinical study are also considered AEs.

[0125] As used herein, the term "serious adverse event" (SAE) means a) death; b) life-threatening condition; c) hospitalization of a participant, or prolongation of an existing hospitalization; d) persistent or severe disability or incapacitation; e) congenital anomaly or birth defect; or f) a medically significant event or reaction as determined by the attending physician. Examples of medically significant events include intensive treatment of allergic bronchospasm in the emergency room or at home; blood dyscrasias or seizures that did not result in hospitalization; and progression of drug dependence or drug abuse.

[0126] As used herein, the terms "cancer expressing a tumor antigen" or "tumor antigen-positive cancer" are used interchangeably and refer to a cancer with a detectable level of expression of a tumor antigen (TA). In some embodiments, the tumor antigen is Trop-2. Tumor antigen expression in cancerous tissue or cancer cells can be detected in a sample from a subject with cancer (e.g., a human cancer patient) by any method known to a technician, for example, as protein, mRNA, or cell surface expression levels. For example, tumor antigen expression can be determined by methods such as immunohistochemistry (IHC), Western blot, fluorescence in situ hybridization (FISH), polymerase chain reaction (PCR), next-generation exome sequencing, or fluorescence-associated cell sorting (FACS). As used herein, in order to be considered TA-positive (e.g., Trop-2-positive), it is not required that every cell in a tumor or tumor sample has a detectable level of tumor antigen expression. In some embodiments, in "TA-expressing cancer" or "TA-positive cancer", less than 99%, less than 95%, less than 90%, less than 80%, less than 70%, less than 60%, less than 50%, less than 40%, less than 30%, less than 20%, or less than 10% of the cells in the tumor or tumor sample have detectable tumor antigen expression levels. In some embodiments, in "TA-expressing cancer" or "TA-positive cancer", more than 99%, more than 95%, more than 90%, more than 80%, more than 70%, more than 60%, more than 50%, more than 40%, more than 30%, more than 20%, or more than 10% of the cells in the tumor or tumor sample have detectable tumor antigen expression levels. In some embodiments, "TA-expressing cancer" or "TA-positive cancer" (e.g., Trop-2-positive cancer) refers to a cancer for which treatment with a certain anti-Trop-2 ADC or TopI ADC is indicated as a single agent therapy or a combination therapy. For example, the TA-positive cancer indications of anti-Trop-2 ADCs or TopI ADCs that have received marketing authorization from health regulatory agencies (e.g., FDA, EMA) are listed on the agency-approved drug label. In some embodiments, a TA-positive (e.g., Trop-2 + ) cancer is a cancer in which an anti-Trop-2 ADC or TopI ADC has demonstrated an anti-cancer effect attributable to the anti-Trop-2 ADC or TopI ADC. Such anti-cancer effects can be demonstrated in preclinical models (e.g., mouse xenograft or syngeneic cancer models) or in clinical trials conducted on human cancer patients. In some embodiments, a TA-expressing cancer or TA-positive cancer does not express detectable levels of Trop-2, for example, as determined by IHC and / or FISH analysis.

[0127] As used herein, the term "tumor antigen targeting antibody-drug conjugate (ADC)" generally refers to an ADC comprising a tumor antigen binding antibody. Such TA binding antibodies can generally direct ADC to cancer cells expressing TA in tumor tissue. In some embodiments, the TA binding antibody is a neutralizing antibody or a blocking antibody (competing with another binding partner for binding to TA). In some embodiments, the TA binding antibody can modulate TA-related molecular or cell signaling events. In some embodiments, the TA binding antibody has antagonistic or agonistic activity relative to TA. TA-targeted ADCs that can be used in the methods provided herein include, but are not limited to, gemtuzumab, vebutuximab, emmetuzumab (T-DM1), otuzumab, trastuzumab derunotecan (T-DXd), dabotuzumab derunotecan (DATO-DXD), vepotuzumab, gosatuzumab, labetuzumab govinotecan, ennozumab, and belantamab mofortin. In some embodiments, the TA-targeted ADC does not bind to Trop-2.

[0128] List of abbreviations and acronyms

[0129]

[0130]

[0131] Antibody-drug conjugates (ADCs)

[0132] The treatment methods provided herein include co-administering an antibody-drug conjugate (ADC) to a subject, such as a human cancer patient. In some embodiments, the ADC includes an anti-Trop-2 antibody, an anticancer agent payload, and an optional linker (anti-Trop-2 ADC) connecting the anti-Trop-2 antibody to the payload. In some embodiments, the anticancer agent payload in the anti-Trop-2 ADC is a topoisomerase I inhibitor (e.g., SN38, Dxd). In some embodiments, the anticancer agent payload in the anti-Trop-2 ADC does not include a topoisomerase I inhibitor. In some embodiments, the ADC includes a tumor antigen (TA) targeting antibody, a topoisomerase I inhibitor payload, and an optional linker (TopI ADC) connecting the TA targeting antibody to the payload. In some embodiments, the TA targeting antibody in the TopI ADC is an anti-Trop-2 antibody. In some embodiments, the TA targeting antibody in the TropI ADC does not include an anti-Trop-2 antibody.

[0133] The ADCs that can be used in the methods provided herein may include any form of antibodies or antigen-binding fragments thereof. For example, ADCs may include, but are not limited to, any form of monospecific or multispecific (e.g., bispecific, trispecific) antibodies or antigen-binding fragments thereof, such as BiKE, TriKE, In some embodiments, the ADC includes a non-immunoglobulin antibody mimetic (e.g., including adnectin, affimer, affilin, affimer, affitin, alphabody, anticalin, peptide aptamer, armadillo repeat protein (ARM), atrimer, avimer, designed ankyrin repeat protein, fynomer, knottin, Kunitz domain peptide, monomer, and nanoCLAMP).

[0134] In some embodiments, the ADC antibody is a blocking antibody. In some embodiments, the ADC antibody is a neutralizing antibody. In some embodiments, the ADC antibody is an agonist or activating antibody. In some embodiments, the ADC antibody is an antagonist or inhibitory antibody.

[0135] In some embodiments, ADC includes IgG antibody or its antigen binding fragment. IgG antibody or its antigen binding fragment can be various isotypes, such as IgG1, IgG2, IgG3 or IgG4. In some embodiments, ADC antibody comprises human IgG1 hinge sequence and constant region sequence. ADC antibody can be chimeric human-mouse, chimeric human-primate, humanized (human framework region and mouse hypervariable (CDR) region) or fully human antibody, and their variants. In some embodiments, ADC antibody is half IgG4 antibody (referred to as "single antibody"), as described in, for example, van der Neut Kolfschoten et al. (Science 2007; 317: 1554-1557). In some embodiments, ADC antibody or its antigen binding fragment is designed or selected to include a human constant region sequence belonging to a specific allotype, and when the antibody or ADC is administered to a human subject, immunogenicity can be reduced. In some embodiments, the ADC antibody or antigen-binding fragment thereof is a non-Glml allotype (nGlml), such as Glm3, Glm3,1, Glm3,2 or Glm3,1,2. In some embodiments, the allotype is selected from the group consisting of: nGlml, Glm3, nGlml,2 and Km3 allotypes.

[0136] Anti-TROP-2 ADC

[0137] In some embodiments, the ADC that can be used in the methods provided herein includes an anti-Trop-2 antibody, an anticancer agent payload, and optionally a linker connecting the anti-Trop-2 antibody to the payload (anti-Trop-2 ADC). In some embodiments, the payload is a topoisomerase I inhibitor. In some embodiments, the payload does not include a topoisomerase I inhibitor.

[0138] Examples of anti-Trop-2 antibodies that can be used in anti-Trop-2 ADCs to perform the methods provided herein include, but are not limited to, those described in the following patents: WO2020016662 (Abmart), WO2020249063 (Bio-Thera Solutions), US20190048095 (Bio-Thera Solutions), WO2013077458 (LivTech / Chiome), EP20110783675 (Chiome), WO2015098099 (Daiichi Sankyo), WO2017002776 (Daiichi Sankyo), WO2020130125 (Daiichi Sankyo), WO2020240467 (Daiichi Sankyo), US2021093730 (Daiichi Sankyo), US9850312 (Daiichi Sankyo),Sankyo), CN112321715 (Biosion), US2006193865 (Immunomedics / Gilead), WO2011068845 (Immunomedics / Gilead), US2016296633 (Immunomedics / Gilead), US2017021017 (Immunomedics / Gilead), US2017209594 (Immunomedics / Gilead), US2017274093 (Immunomedics / Gilead), US2018110772 (Immunomedics / Gilead), US2018185351 (Immunomedics / Gilead), US2018271992 (Immunomedics / Gilead), WO2018217227 (Immunomedics / Gilead), US2019248917 (Immunomedics / Gilead), CN111534585 (Immunomedics / Gilead), US2021093730 (Immunomedics / Gilead), US2021069343 (Immunomedics / Gilead), US8435539 (Immunomedics / Gilead), US8435529 (Immunomedics / Gilead), US9492566 (Immunomedics / Gilead), WO2003074566 (Gilead), WO2020257648 (Gilead), US2013039861 (Gilead), WO2014163684 (Gilead), US9427464 (LivTech / Chiome), US10501555 (AbruzzoTheranostic / Oncoxx), WO2018036428 (Sichuan Kelun Pharma), WO2013068946 (Pfizer), WO2007095749 (Roche) and WO2020094670 (SynAffix).

[0139] In some embodiments of the methods provided herein, the anti-Trop-2 ADC comprises an antibody selected from saccharotuzumab (hRS7), dedaburumab (hTINA H1L1), and a Trop-2 binding fragment thereof. In some embodiments, the anti-Trop-2 ADC is saccharotuzumab (hRS7). In some embodiments, the anti-Trop-2 antibody is dedaburumab (hTINA H1L1).

[0140] In some embodiments of the methods provided herein, the anti-Trop-2 ADC comprises a VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2, and VL-CDR3 selected from one of Tables 1 to 4. In some embodiments, the anti-Trop-2 ADC comprises the following VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2, and VL-CDR3 amino acid sequences (according to Kabat), respectively:

[0141] SEQ ID NO: 1, 2, 3, 4, 5 and 6, or

[0142] · SEQ ID NO: 7, 8, 9, 10, 11 and 12.

[0143] In some embodiments of the methods provided herein, the anti-Trop-2 ADC comprises a variable domain (VH and VL) selected from Table 5. In some embodiments, the anti-Trop-2 ADC comprises the following VH amino acid sequence and VL amino acid sequence, respectively:

[0144] SEQ ID NO: 49 and 50, or

[0145] ·SEQ ID NO:51 and 52.

[0146]

[0147]

[0148] In some embodiments of the methods provided herein, the anti-Trop-2 ADC comprises an anti-Trop-2 antibody, an anticancer agent payload, and an optional linker connecting the antibody to the payload. In some embodiments, the linker is non-cleavable (e.g., a maleimidocaproyl or maleimidomethylcyclohexane-1-carboxylate linker). In some embodiments, the linker is cleavable. In some embodiments, the linker is acid cleavable (e.g., a hydrazone linker). In some embodiments, the cleavable linker is reducible (e.g., a disulfide linker). In some embodiments, the linker is protease cleavable (e.g., a dipeptide or tetrapeptide linker). In some embodiments, the linker is selected from the linkers disclosed in USPN 7,999,083 (e.g., CL2A, CL6, CL7, CLX or CLY). In some embodiments, the linker is CL2A. Additional linker chemistries useful for anti-Trop-2 ADCs are described, for example, in the following patents: WO21225892 (Shanghai Escugen Biotechnology; ESG-401, STI-3258), WO22010797 (BiOneCure Therapeutics; BIO-106), CN112237634 (Shanghai Fudan-Zhangjiang Biopharmaceutical; FDA018-ADC), WO19114666 (Sichuan Kelun Pharmaceutical; KLA264), WO22078524 (Hangzhou DAC Biotech; DAC-002), WO15098099 (Daiichi Sankyo; dedastatin), WO21147993 (Jiangsu Hengrui Medicine; SHR-A1921), and WO21052402 (Sichuan Baili Pharmaceutical; BL-M02D1).

[0149] Exemplary anticancer agent payloads that can be used in the anti-Trop-2 ADCs in the methods provided herein include, for example, microtubule inhibitors, DNA cleaving agents, and topoisomerase I inhibitors. In some embodiments, the microtubule inhibitor is an auristatin (e.g., monomethyl auristatin E (MMAE) or monomethyl auristatin F (MMAF), a taxane, a vinca alkaloid, an epothilone) or a maytansine alkaloid (e.g., maytansine (DM1) or raftansine (DM4)). In some embodiments, the DNA cleaving agent is a calicheamicin (e.g., ozogamicin). In some embodiments, the topoisomerase I inhibitor is a camptothecin (e.g., irinotecan, topotecan, belotecan, or an exatecan derivative, such as SN38 or Dxd). In some embodiments, the topoisomerase I inhibitor is SN38. In some embodiments, the topoisomerase I inhibitor is Dxd. In some embodiments, the topoisomerase I inhibitor is not a camptothecin (i.e., a non-camptothecin topoisomerase I inhibitor). In some embodiments, the non-camptothecin topoisomerase I inhibitor is selected from indenoquinolines (e.g., indeno[1,2-c]isoquinoline, NSC314622, indolecan (LMP-400), indolinecan (LMP-776)), phenanthridines (e.g., Topovale (ARC-111)), and indolocarbazoles (e.g., BE-13793C).

[0150] Additional illustrative anticancer agent payloads that can be conjugated to the anti-Trop-2 ADC include, but are not limited to, anthracyclines (e.g., doxorubicin, daunorubicin, epirubicin, idarubicin), pyrrolobenzodiazepines, (PBD) or its dimer, DNA cross-linker SC-DR002 (D6.5), duocarmycin, duocarmycins (A, B1, B2, C1, C2, D, SA, CC-1065), microtubule lysin B and its analogs (e.g., Tub196), and other anticancer agents described herein.

[0151] Exemplary anti-Trop-2 ADCs that can be used in the methods provided herein are described in the following patents: WO21225892 (Shanghai Escugen Biotechnology; ESG-401, STI-3258), WO22010797 (BiOneCure Therapeutics; BIO-106), CN112237634 (Shanghai Fudan-Zhangjiang Biopharmaceutical; FDA018-ADC), WO19114666 (Sichuan Kelun Pharmaceutical; KLA264), WO22078524 (Hangzhou DAC Biotech; DAC-002), WO15098099 (Daiichi Sankyo; dedastatin), WO21147993 (Jiangsu Hengrui Medicine; SHR-A1921), and WO21052402 (Sichuan Baili Pharmaceutical; BL-M02D1).

[0152] In some embodiments of the methods provided herein, the anti-Trop-2 ADC is selected from gosartuzumab (Immunomedics / Gilead), dedabotulinumab derutec (DS-1062, Dato-Dxd; Daiichi Snakyo / AstraZeneca), SKB-264 (KL-A264; Klus Pharma, Sichuan Kelun Pharma), ESG-401 (Shanghai Escugen Biotechnology / Levena Biopharma), JS-108 (DAC-002; Junshi Bio / Hangzhou DAC), FDA018-ADC (Shanghai Fudan Zhangjiang Bio Pharma), STI-3258 (Sorrento), OXG-64 (Oncoxx), BDI-4702 (OBIPharma), BL-M02D1 (Systimmune), anti-Trop-2 Ab (Mediterrania Theranostic / Legochem), KD-065 (Nanjing KAEDI Biotech), anti-Trop2sdAb (Kisoli Biotech), anti-Trop-2ADC (Shandong Fontacea), LIV-2008 (LivTech / YakultHonsha), TROP2-TRACTr (BiTE;Janux), TROP-2-IR700 (Chiome, photosensitizer), TROP2-XPAT (Amunix), BAT-8003 (Bio-Thera Solutions), GQ-1003 (Genequantum Healthcare, Samsung BioLogics), DAC-002 (Hangzhou DAC Biotech, Shanghai Junshi Biosciences), E1-3s (Immunomedics / Gilead, IBC Pharmaceuticals, s BioTech), humanized anti-Trop2-SN38 antibody conjugate (Shanghai Escugen Biotechnology, TOT Biopharma), anti-Trop2 antibody-CLB-SN-38 conjugate (Shanghai Fudan-Zhangjiang Bio-Pharmaceutical), TROP2-Ab8 (Abmart), Trop2-IgG (Nanjing Medical University (NMU)), 90Y-DTPA-AF650 (Peking University FirstHospital) and hRS7-CM (SynAffix), 89Zr-DFO-AF650 (University of Wisconsin-Madison). In some embodiments, the anti-Trop-2 ADC is gosartuzumab (Immunomedics / Gilead). In some embodiments, the anti-Trop-2 ADC is selected from gosartuzumab, dedabotuzumab derutec (DS-1062), ESG-401, SKB-264, DAC-02, and BAT-8003. In some embodiments, the anti-Trop-2 ADC is gosartuzumab. In some embodiments, the anti-Trop-2 ADC is dedabotuzumab derutec (DS-1062, Dato-Dxd; Daiichi Snakyo / AstraZeneca). Additional examples of useful anti-Trop-2 therapeutic agents include, but are not limited to, those described in WO2016201300 (Gilead) and CN108440674 (Hangzhou Lonzyme Biological Technology). ;

[0153] Exemplary anti-Trop-2 ADCs that can be used in the methods provided herein are described, for example, in USPN 7,999,083 and USPN 9,028,833, which are hereby incorporated by reference in their entirety. In some embodiments, the anti-Trop-2 ADC comprises a topoisomerase I inhibitor. In some embodiments, the topoisomerase I inhibitor is selected from irinotecan, topotecan, and SN-38. In some embodiments, the anti-Trop-2 ADC has the structural formula mAb-CL2A-SN-38, the structure of which is represented by the following formula:

[0154]

[0155] (described, e.g., in USPN 7,999,083). In some embodiments, the drug-antibody ratio (DAR) of CL2A-SN38 to anti-Trop-2 antibody in the anti-Trop2 ADC is ≥7.0 (e.g., DAR=7.6). In some embodiments, the drug-antibody ratio (DAR) of CL2A-SN38 to anti-Trop-2 antibody in the anti-Trop2 ADC is between 7.0 and 8.0 (e.g., DAR=7.6). In some embodiments, the anti-Trop-2 ADC comprises saccharituzumab (hRS7; described, e.g., in Figures 3 and 4 of WO2003074566). In some embodiments, the anti-Trop-2 ADC is gosartuzumab (IMMU-132). Gosartuzumab (SG) is an antibody-drug conjugate (ADC) composed of the following 3 components:

[0156] Humanized monoclonal antibody hRS7 IgG1κ, which binds to trophoblast cell surface antigen 2 (Trop-2; TACSTD2; EGP-1; NCBI Gene ID: 4070), a transmembrane calcium signal transducer overexpressed in many epithelial cancers including triple-negative breast cancer (TNBC).

[0157] The camptothecin-derived agent SN-38 is a topoisomerase I inhibitor.

[0158] A hydrolyzable linker (CL2A) that connects the humanized monoclonal antibody to SN-38.

[0159] Additional exemplary anti-Trop-2 ADCs that can be used in the methods provided herein are described in WO21225892 (Shanghai Escugen Biotechnology). In some embodiments, the anti-Trop-2 ADC includes a linker-payload conjugate having a structure represented by the following formula:

[0160]

[0161] Attached to an anti-Trop-2 antibody (e.g., hRS7). In some embodiments, the anti-Trop-2 ADC has a DAR between 1 and 8. In some embodiments, the anti-Trop-2 ADC has a DAR between 7.0 and 8.0. In some embodiments, the anti-Trop-2 ADC is ESG-401 (STI-3258).

[0162] Additional exemplary anti-Trop-2 ADCs that can be used in the methods provided herein are described in US20210101906 (Sichuan Kelun Pharmaceutical). In some embodiments, the anti-Trop-2 ADC includes a linker-payload conjugate (TL035) having a structure represented by the following formula:

[0163]

[0164] Attached to an anti-Trop-2 antibody (e.g., hRS7). In some embodiments, the anti-Trop-2 ADC has a DAR between 1 and 8. In some embodiments, the anti-Trop-2 ADC has a DAR between 7.0 and 8.0. In some embodiments, the anti-Trop-2 ADC has a DAR of about 7.0. In some embodiments, the anti-Trop-2 ADC is KL-A264.

[0165] Additional exemplary anti-Trop-2 ADCs that can be used in the methods provided herein are described in US2016297890 (Daiichi Sankyo). In some embodiments, the anti-Trop-2 ADC includes a linker-payload conjugate having a structure represented by the following formula:

[0166]

[0167] Attached to an anti-Trop-2 antibody (e.g., hTINA1-H1L1). In some embodiments, the anti-Trop-2 ADC has a DAR between 1 and 8. In some embodiments, the anti-Trop-2 ADC has a DAR <7.0. In some embodiments, the anti-Trop-2 ADC has a DAR of about 4. In some embodiments, the anti-Trop-2 ADC is dexamethasone.

[0168] TopI ADC

[0169] In some embodiments, the ADC that can be co-administered in the methods provided herein includes a tumor antigen (TA) targeting antibody, a topoisomerase I inhibitor payload, and optionally a linker connecting the TA targeting antibody to the payload (TopI ADC). In some embodiments, the TA targeting antibody in the TopI ADC is an anti-Trop-2 antibody. In some embodiments, the TA targeting antibody in the TopI ADC does not include an anti-Trop-2 antibody.

[0170] In some embodiments, a TopI ADC that can be co-administered in the methods provided herein comprises an antibody that binds a tumor antigen selected from the group consisting of carbonic anhydrase IX, B7, CCCL19, CCCL21, CSAp, HER-2 / neu, BrE3, CD1, CD1a, CD2, CD3, CD4, CD5, CD8, CD11A, CD14, CD15, CD16, CD18, CD19, CD20, CD21, CD22, CD23, CD25, CD29, CD30, CD32b, CD33, CD37, CD38, CD40, CD40L, CD44, CD46, CD47, CD48, CD49, CD50, CD51, CD52, CD53, CD54, CD55, CD56, CD57, CD58, CD59, CD50, CD51, CD52, CD53, CD54, CD55, CD56, CD57, CD58, CD59, CD5 5. CD46, CD52, CD54, CD55, CD59, CD64, CD67, CD70, CD74, CD79a, CD80, CD83, CD95, CD126, CD133, CD138, CD147, CD154, CEACAM5, CEACAM-6, alpha-fetoprotein (AFP), VEGF, ED-B fibronectin, EGP-1, EGP-2, EGF receptor (ErbB1), ErbB2, ErbB3, factor H, FHL-1, Flt-3, folate receptor, Ga 733, GROB, HMGB-1, hypoxia-inducible factor (HIF), HM1.24, insulin-like growth factor (ILGF), IFN-a, IFN-b, IL-g, IL-2R, IL-4R, IL-6R, IL-13R, IL-15R, IL-17R, IL-18R, IL-2, IL-6, IL-8, IL-12, IL-15, IL-17, IL-18, IL-25, IP-10, IGF-1R, Ia, HM1.24, gangliosides, HCG, HLA-DR, HLA-G, CD66a-d, MAGE, mCRP, MCP-1, MIP-1A, MIP-1B, macrophage migration inhibitory factor ( MIF), MUC1, MUC2, MUC3, MUC4, MUC5, placental growth factor (P1GF), PSA (prostate-specific antigen), PSMA, PSMA dimer, PAM4 antigen, NCA-95, NCA-90, A3, A33, Ep-CAM, KS-1, Le(y), mesothelin, S100, tenascin, TAC, Tn antigen, Thomas-Friedenreich antigen, tumor necrosis antigen, tumor angiogenesis antigen, TNF-a, TRAIL receptor (R1 and R2), VEGFR, RANTES, T101, cancer stem cell antigen, complement factors C3, C3a, C3b, C5a, C5, and oncogene products.

[0171] In some embodiments, the TopI ADC that can be co-administered in the methods provided herein comprises an antibody that binds a tumor antigen selected from the group consisting of: CEACAM5 (NCBI Gene ID: 1048), CEACAM6 (NCBI Gene ID: 4680), CD74 (NCBI Gene ID: 972), CD19 (NCBI Gene ID: 930), CD20 (NCBI Gene ID: 931), CD22 (NCBI Gene ID: 933), CSAp (NCBI Gene ID: 126731), HLA-DR, HLA-G, MUC5ac (NCBI Gene ID: 4586), and AFP (NCBI Gene ID: 174).

[0172] In some embodiments, the TopI ADC that can be used to perform the methods provided herein comprises an antibody selected from the group consisting of gemtuzumab, brentuximab, berantuzumab, canalizumab, trastuzumab, inotuzumab, gebatumumab, anetuzumab, milvituximab, dituximab, vadatuximab, labetuzumab, ladituzumab, lantuximab, pertrastuzumab, rifatuzumab, indutumab, polotuzumab, pinatuzumab, cotuximab, eupifituzumab, indatuximab, miratumumab, lovatuzumab, enroku, tesotumomab, tetuzumab, dicituzumab, terituzumab, and antigen-binding fragments thereof.

[0173] In some embodiments, the TopI ADCs that can be used in the methods provided herein include an antibody selected from the group consisting of: hLL1 (anti-CD74; USPN 7,312,318), hLL2 (anti-CD22; USPN 7,074,403), hRFB4 (anti-CD22), hPAM4 (anti-MUC5ac; USPN 7,282,567), hMN-3 (anti-NOTCH3; USPN 7,541,440), hMN-14 (labetuzumab; anti-CEACAM5; USPN 6,676,924); hMN15 (anti-CEACAM6; USPN 7,541,440); hA19 (anti-CD19; USPN 7,109,304), hA20 (anti-CD22; USPN 7,251,164), hMu-9 (anti-CSAp; USPN 7,251,164); 7,387,773), hL243 (anti-HLA-DR; USPN 7,612,180), and hIMMU-31 (anti-AFP; USPN 7,300,655), which antibodies are also described in, for example, USPN 7,999,083.

[0174] In some embodiments of the methods provided herein, TopI ADC comprises a linker connecting a topoisomerase I inhibitor payload to a tumor antigen targeting antibody. In some embodiments, the linker is non-cleavable (e.g., maleimidocaproyl or maleimidomethylcyclohexane-1-carboxylate linker). In some embodiments, the linker is cleavable. In some embodiments, the linker is acid cleavable (e.g., hydrazone linker). In some embodiments, the cleavable linker is reducible (e.g., disulfide linker). In some embodiments, the linker is protease cleavable (e.g., dipeptide or tetrapeptide linker). In some embodiments, the linker is selected from the linkers disclosed in USPN 7,999,083 (e.g., CL2A, CL6, CL7, CLX or CLY). In some embodiments, the linker is CL2A. Additional linker chemistries useful for anti-TopI ADCs are described, for example, in the following patents: WO21225892 (Shanghai Escugen Biotechnology; ESG-401, STI-3258), WO22010797 (BiOneCure Therapeutics; BIO-106), CN112237634 (Shanghai Fudan-Zhangjiang Biopharmaceutical; FDA018-ADC), WO19114666 (Sichuan Kelun Pharmaceutical; KLA264), WO22078524 (Hangzhou DAC Biotech; DAC-002), WO15098099 (Daiichi Sankyo; dedastatin), WO21147993 (Jiangsu Hengrui Medicine; SHR-A1921), and WO21052402 (Sichuan Baili Pharmaceutical; BL-M02D1).

[0175] In some embodiments of the methods provided herein, the topoisomerase I inhibitor included in the TopI ADC is a camptothecin (e.g., irinotecan, topotecan, belotecan, or exatecan derivatives, such as Dxd or SN38). In some embodiments, the topoisomerase I inhibitor in the TopI ADC is Dxd. In some embodiments, the topoisomerase I inhibitor in the TopI ADC is SN38. In some embodiments, the topoisomerase I inhibitor in the TopI ADC is not camptothecin. In some embodiments, the non-camptothecin topoisomerase I inhibitor is selected from indenoquinoline (e.g., indeno[1,2-c]isoquinoline, NSC314622, indonotecan (LMP-400), indonotecan (LMP-776)), phenanthridine (e.g., Topovale (ARC-111)) and indolecarbazole (e.g., BE-13793C).

[0176] In some embodiments, the TopI ADC has the structural formula mAb-CL2A-SN-38, which is represented by the following formula:

[0177]

[0178] (Described, for example, in U.S. Pat. No. 7,999,083).

[0179] In some embodiments, TopI ADCs that can be used in the methods provided herein include antibodies targeting carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5; CD66e; NCBI Gene ID: 1048). In some embodiments, the CEACAM5 antibody is hMN-14 (e.g., as described in WO1996011013). In some embodiments, the anti-CEACAM5 ADC is as described in WO2010093395 (anti-CEACAM5-CL2A-SN38). In some embodiments, the TopI ADC is labetuzumab govenotecan (IMMU-130).

[0180] In some embodiments, the TopI ADC that can be used in the methods provided herein includes antibodies targeting MHC class II cell surface receptors encoded by the human leukocyte antigen complex (HLA-DR). In some embodiments, the HLA-DR antibody is hL243 (e.g., as described in WO2006094192). In some embodiments, the HLA-DR-ADC is as described in WO2010093395 (anti-HLA-DR-CL2A-SN38). In some embodiments, the antibodies and / or fusion proteins provided herein are administered together with the HLA-DR-ADC IMMU-140.

[0181] Additional exemplary TopI ADCs that can be co-administered in the methods provided herein are described in WO21225892 (Shanghai Escugen Biotechnology). In some embodiments, the TopI ADC includes a linker-payload conjugate having a structure represented by the following formula:

[0182]

[0183] Attached with tumor antigen targeting antibodies.

[0184] Additional exemplary TopI ADCs that can be co-administered in the methods provided herein are described in US20210101906 (Sichuan Kelun Pharmaceutical). In some embodiments, the TopI ADC includes a linker-payload conjugate (TL035) having a structure represented by the following formula:

[0185]

[0186] Attached with tumor antigen targeting antibodies.

[0187] Additional exemplary TopI ADCs that can be co-administered in the methods provided herein are described in US2016297890 (Daiichi Sankyo). In some embodiments, the TopI ADC includes a linker-payload conjugate having a structure represented by the following formula:

[0188]

[0189] Attached to a tumor antigen targeting antibody (e.g., trastuzumab). In some embodiments, the DAR of the TopI ADC is about 4. In some embodiments, the TopI ADC is trastuzumab-derutin (T-DXd).

[0190] Adenosine pathway inhibitors

[0191] The adenosine pathway is one of several pathways that can promote tumor immune evasion in the tumor microenvironment. It is believed that the conversion of proinflammatory extracellular ATP to immunosuppressive adenosine (eADO) can promote tumor progression and evade antitumor immunity. The role of the adenosine pathway in immuno-oncology is described in, for example, Allard et al., (2020) Nat Rev Clin Oncol 17, 611-629.

[0192] Adenosine pathway inhibitors that can be co-administered in the methods provided herein can include, for example, CD39 inhibitors (ectonucleoside triphosphate diphosphohydrolase-1; ENTPD1; NCBI Gene ID: 953); CD73 inhibitors (exto-5'-nucleotidase; NT5E; NCBI Gene ID: 4907); or adenosine receptors such as adenosine A 2A Adenosine receptor (ADORA2A; NCBI Gene ID: 135) or 2B Receptor (ADORA2B; NCBI Gene ID: 136). In some embodiments, adenosine pathway inhibitors that can be co-administered in the methods provided herein include CD38 inhibitors (cyclic ADP ribose hydrolase; NCBI Gene ID: 952).

[0193] CD39 inhibitors

[0194] The CD39 inhibitors that can be co-administered in the methods provided herein include small molecule inhibitors and macromolecular inhibitors (e.g., anti-CD39 antibodies) of CD39. Exemplary CD39 inhibitors are described in, for example, WO09095478, WO12085132, WO16073845, WO17157948, WO18049145, WO18065552, WO18065622, WO19027935, WO19178269, WO21056610, WO21037037, WO21055329, WO21088838, and WO22111576. In some embodiments, the CD39 inhibitor is selected from TTX-030 (AbbVie / Trishula), IPH5201 (AstraZeneca / Innate Pharma), SRF617 (Surface Oncology), CD39 ASO (Secarna Pharmaceuticals), JS-019 (ShanghaiJunshi Biosciences), anti-CD39 (Arcus Biosciences), ES002 (Elpiscience Biopharmaceuticals), and CD39xPD1 (Biotheus).

[0195] CD73 inhibitors

[0196] CD73 inhibitors that can be co-administered in the methods provided herein include small molecule inhibitors and macromolecular inhibitors of CD73 (e.g., anti-CD73 antibodies). Exemplary CD73 inhibitors that can be used in the methods provided herein are described in, for example, U.S. Pat. No. 11,001,603, the compounds of which are hereby incorporated by reference herein.Additional illustrative CD73 inhibitors that can be co-administered in the methods provided herein are described, for example, in WO15164573, WO16055609, WO16075099, WO16081746, WO16081748, WO17064043, WO17098421, WO17100670, WO17118613, WO17153952, WO18013611, WO18067424, WO18065627, WO18094148, WO18110555, WO18119284, WO18137598, WO18183635, WO18208980, WO 18208727, WO18215535, WO18237173, WO18237157, WO19053617, WO19090111, WO19129059, WO19168744, WO19166701, WO19173291, WO19173692, WO 19170131, WO19224025, WO19232244, WO19246403, WO20046813, WO20047082, WO20051686, WO20097127, WO20098599, WO20139803, WO20143836, WO2 0143710, WO20151707, WO20205538, WO20202038, WO20210970, WO20210938, WO20216697, WO20221209, WO20244606, WO20253568, WO20257429, WO2 1011689, WO21029450, WO21032173, WO21040356, WO21041319, WO21043229, WO21044005, WO21087136, WO21087463, WO21088901, WO21097223, WO21 105916, WO21113625, WO21138467, WO21205383, WO21213466, WO21213475, WO21216898, WO21222522, WO21227306, WO21241729, WO21257643, WO21259199, WO22007677, WO22052886, WO22068929, WO22083049, WO22083049, WO22090711, WO22095975, WO22095953, WO22096020 and WO22121914.In some embodiments, the CD73 inhibitor is selected from olelumab (AstraZeneca), BMS-986179 (BMS), ulelimab (I-MAB Biopharma), AK119 (Akeso Biopharma), quemliclustat (AB680, Arcus Biosciences), mopalimumab (Corvus Pharmaceuticals), HLX23 (Shanghai Henlius Biotech), INCA00186 (Incyte), IBI325 (Innovent Bio), NZV930 (Novartis / Surface Oncology), ORIC-533 (ORIC Pharma), Sym024 (Servier), IPH5301 (Innate), IOA-237 (iOnctura), JAB-BX100 (Jacobio), PT199 (Phanes Therapeutics), TRB010 (Trican Biotechnology), CD73 ASO (Secarna Pharmaceuticals), 622 (3sBio), ABSK-051 (AbbiskoTherapeutics), AK131 (CD73xPD1, Akeso Biopharma), CD73i (Aurigene), BR101 (BioRay), BP1200 (BrightPath), CB708 (Antengene / Calithera), GB7002 (Genbase Bio), ATG-037 (Antengene), and CD73i (Biotheus). In some embodiments, the CD73 inhibitor is quilibrium (AB680, GS-0680), ulelimab, mopalimumab, ORIC-533, ATG-037, PT-199, AK131, NZV930, BMS-986179, or olerumumab. In some embodiments, the CD73 inhibitor is olerumumab or quilibrium. In some embodiments, the CD73 inhibitor is quilibrium.

[0197] Adenosine receptor antagonists

[0198] The adenosine receptor antagonists that can be co-administered in the methods provided herein can be selective antagonists of adenosine A2A receptors (A2AR; ADORA2A) or A2B receptors (A2BR; ADORA2B), or dual A2A / 2BR antagonists. In some embodiments, the adenosine receptor antagonist is a selective A2aR antagonist. In some embodiments, the adenosine receptor antagonist is a selective antagonist of adenosine A2A receptor (A2AR; ADORA2A), selected from imadinam (AstraZeneca), NIR178 (Novartis / Palobiofarma) ID11902 (Ildong), IN-A003 (Inno.n), NTI-55 (A2aR / TLR7, Nammi), TT-10 (Tarus Therapeutics) and TT-228 (Teon Therapeutics). In some embodiments, the adenosine receptor antagonist is a selective A2BR antagonist. In some embodiments, the adenosine receptor antagonist is an adenosine A2B receptor (A2BR; ADORA2B) selective antagonist selected from PBF-1129 (Palobiofarma) and TT-702 (Teon Therapeutics). In some embodiments, the adenosine receptor antagonist is a dual A2A / 2BR antagonist. In some embodiments, the adenosine receptor antagonist is a dual adenosine A2A / A2B receptor antagonist selected from edredinam (AB928, Arcus Biosciences), INCB106385 (Incyte), M1069 (Merck KGaA), A2aR / A2bR (Domain / Merck KgaA), HM87277 (A1 / A2aR / A2bR, Hanmi Pharmaceutical), RVU-330 (Ryvu) and TT-53 (Tarus Therapeutics). In some embodiments, the adenosine receptor antagonist is edredinam. Adenosine receptor antagonists can be small molecule antagonists or macromolecular antagonists.

[0199] Additional illustrative adenosine receptor antagonists that can be co-administered in the methods provided herein are described, for example, in WO07103776, WO07134958, WO08086201, WO09009178, WO09033161, WO09037463, WO09037468, WO09037467, WO09055548, WO09055308, WO10008775, WO11027805, WO11050160, WO11055391, WO12135084, WO141011 20. WO14101113, WO14106861, WO15027431, WO16081290, WO16126570, WO16200717, WO16209787, WO17008205, WO18013951, WO19086074, WO2019118313, WO20053263, WO20106558, WO20103930, WO20103939, WO20106560, WO20112706, WO20112700, WO 20216152, WO20135210, WO20135195, WO20150677, WO20150675, WO20150674, WO20150676, WO20152132, WO20156505, WO201 59905, WO21018172, WO20227156, WO2101873, WO20260196, WO20253867, WO20263058, WO20260857, WO21011670, WO2109370 1. Described in WO21041360, WO21099832, WO21105916, WO21146631, WO21156439, WO21179074, WO21185256, WO21194623, WO21191376, WO21191380, WO21191378, WO21191379, WO21224636, WO22020552, WO22020550, WO22023772, WO22072601 and WO22123272.

[0200] Exemplary adenosine receptor antagonists that can be used in the methods provided herein are described, for example, in U.S. Pat. No. 10,399,962, the compounds of which are hereby incorporated by reference herein. In some embodiments, the adenosine pathway inhibitor is a dual antagonist of adenosine A2A receptor (A2AR; ADORA2A) and A2B receptor (A2BR; ADORA2B). In some embodiments, the adenosine pathway inhibitor is edrodinam (AB928; GS-0928), taminadenant, TT-10, TT-4, or M1069. In some embodiments, the adenosine pathway inhibitor is edrodinam.

[0201] Eltrodinam (AB928) is a small molecule dual antagonist of both A2AR and A2BR that can inhibit adenosine-driven damage to tumor-infiltrating lymphocytes (mainly through A2AR on CD8+ T cells and NK cells) and myeloid cells (through A2BR on dendritic cells and macrophages) in the absence of any agonist activity. Eltrodinam can achieve high penetration into tumor tissue, has strong efficacy in the presence of high concentrations of adenosine, and shows low nonspecific protein binding.

[0202] PD(L)1 inhibitors

[0203] In some embodiments, the combined treatment methods provided herein include co-administering a PD(L)1 inhibitor. The PD(L)1 inhibitors that can be co-administered can include small molecule PD(L)1 inhibitors and macromolecular PD(L)1 inhibitors (e.g., anti-PD(L)-1 antibodies).

[0204] Exemplary small molecule PD(L)1 inhibitors that can be co-administered in the methods provided herein include, for example, CA-170, GS-4224, GS-4416, and lazertinib (GNS-1480; PD-L1 / EGFR). Additional illustrative small molecule PD(L)1 inhibitors are described, for example, in Guzik et al., (2019) Molecules 24(11), 2071.

[0205] Anti-PD(L)1 Antibodies

[0206] Exemplary anti-PD-(L)1 antibodies that can be co-administered in the methods provided herein include, for example, pembrolizumab, nivolumab, cemiprilimab, pidilizumab, spartalizumab, atezolizumab, avelumab, durvalumab, cocilimab, sazanlimab, tislelizumab, rivulimab, batilizumab, toripalimab, cetrilimab, genoluzumab, palolizumab, lodalizumab, carrelizumab, budigalimab, avelumab, dotalimumab, envolimab, sintilimab and sepalizumab. In some embodiments, the anti-PD-(L)1 antibody is sepalizumab.

[0207] Additional illustrative anti-PD-(L)1 antibodies that can be co-administered in the methods provided herein include pembrolizumab, nivolumab, cemiplizumab, pidilizumab, AMP-224, MEDI0680 (AMP-514), spartalizumab, atezolizumab, avelumab, durvalumab, BMS-936559, coxilimab (CK-301), sazanalizumab (PF-06801591), tislelizumab (BGB-A317), GLS-010 (WBP-3055), AK-400 (AK-400), spartalizumab, atezolizumab, avelumab, durvalumab, BMS-936559, CK-301, sazanalizumab (PF-06801591), tislelizumab (BGB-A317), GLS-010 (WBP-3055), AK-400 (AK-400), spartalizumab, atezolizumab, avelumab, durvalumab, BMS-936559, -103 (HX-008), AK-105, CS-1003, HLX-10, Rivulizumab (MGA-012), BI-754091, Batilizumab (AGEN-2034), AMG-404, Teplizumab (JS-001), Cetrilimab (JNJ-63723283), Genolizumab (CBT-501), LZM-009, Paclolimab (BCD-100), Lodalizumab (LY-3300054), SHR-1201, Carrelizumab (SHR -1210), Sym-021, budigalimab (ABBV-181), PD1-PIK, BAT-1306, avelumab (MSB0010718C), CX-072, CBT-502, dotalimumab (TSR-042), MSB-2311, JTX-4014, BGB-A333, SHR-1316, CS-1001 (WBP-3155), envolimab (KN-035), sintilimab (IBI-308), HLX-20, KL-A1 67, STI-A1014, STI-A1015 (IMC-001), BCD-135, FAZ-053, TQB-2450, MDX1105-01, GS-4224, GS-4416, INCB086550, MAX10181, Sepalizumab (AB122), Spartalizumab (PDR-001), and compounds disclosed in WO2018195321, WO2020014643, WO2019160882 or WO2018195321,As well as the multispecific inhibitors FPT-155 (CTLA4 / PD-L1 / CD28), PF-06936308 (PD-1 / CTLA4), MGD-013 (PD-1 / LAG-3), FS-118 (LAG-3 / PD-L1), RO-7247669 (PD-1 / LAG-3), MGD-019 (PD-1 / CTLA4), KN-046 (PD-1 / CTLA4), MEDI-5752 (CTLA4 / PD-1), RO-7121661 (PD-1 / TIM-3), RG7769 (PD-1 / TIM-3), TAK-252 (PD-1 / OX40L), XmAb-20717 (PD-1 / CTLA4), AK-104 (CTLA4 / PD-1), FS-118 (LAG-3 / PD-L1), FPT-155 (CTLA4 / PD-L1 / CD28), GEN-1046 (PD-L1 / 4-1BB), bintrafuspα (M7824; PD-L1 / TGFβ-EC domain), CA-170 (PD-L1 / VISTA), CDX-527 (CD27 / PD-L1), LY-3415244 (TIM3 / PDL1), and INBRX-105 (4-1BB / PDL1).

[0208] Anti-TIGIT antibodies

[0209] Exemplary anti-TIGIT antibodies that can be co-administered in the methods provided herein include, for example, tisleliumab, vebolimumab, dunalimab, AB308, AK127, BMS-986207, rapasumab, and etilizumab. In some embodiments, the anti-TIGIT antibody is dunalimab. In some embodiments, the anti-TIGIT antibody is AB308. In some embodiments, the anti-TIGIT antibody is rapasumab.

[0210] In some embodiments, the anti-TIGIT antibody is an Fc silent antibody. In some embodiments, the anti-TIGIT antibody comprises one or more mutations in the Fc region to reduce, prevent or eliminate binding to Fc receptors. In some embodiments, the anti-TIGIT antibody comprises one or more mutations in the Fc region to reduce, prevent or eliminate binding to FcγR. In some embodiments, any antibody disclosed herein comprises one or more mutations in the Fc region to reduce, prevent or eliminate binding to FcγRIIIA. In some embodiments, any antibody disclosed herein comprises one or more mutations in the Fc region to reduce, prevent or eliminate binding to FcγRIV. In some embodiments, the anti-TIGIT antibody comprises one or more mutations in the Fc region to reduce, prevent or eliminate ADCC, ADCP and / or CDC. In some embodiments, the anti-TIGIT antibody comprises one or more substitutions in the Fc region to reduce, prevent or eliminate binding to an Fc receptor, wherein the one or more substitutions occur at EU index positions 228, 233, 234, 235, 235, 235, 236, 237, 265, 297, 322, 327, 328, 330, 331, and any combination of these positions. In some embodiments, the anti-TIGIT antibody comprises one or more substitutions in the Fc region to reduce, prevent or eliminate binding to an Fc receptor, wherein the one or more substitutions include S228P, E233P, L234A, L235A, L235E, L235F, G236R, G237A, D265A, N297A, K322A, A327G, L328R, A330S, P331S, and any combination of these substitutions. Additional mutations in the Fc region that reduce, prevent or eliminate binding to Fc receptors, and alternative strategies for reducing, preventing or eliminating binding to Fc receptors are described, for example, in Saunders, Front Immunol. (2019) 10: 1296; Tao, J Exp Med. (1993) 178: 661–667; Canfield and Morrison, J Exp Med. (1991) 173(6): 1483-1491; Armour, Eur. J. Immunol. (1999) 29(8): 2613-2624; Shields, J. Biol. Chem. (2001) 276(9): 6591-6604, and U.S. Pat. No. 6,624,821.

[0211] In some embodiments, the anti-TIGIT antibody is an Fc-enabled antibody. In some embodiments, the anti-TIGIT antibody comprises one or more mutations in the Fc region to enable binding to or enhance binding to an Fc receptor. In some embodiments, the anti-TIGIT antibody comprises one or more mutations in the Fc region to enable binding to or enhance binding to FcγR. In some embodiments, any antibody disclosed herein comprises one or more mutations in the Fc region to enable binding to or enhance binding to FcγRIIIA. In some embodiments, any antibody disclosed herein comprises one or more mutations in the Fc region to enable binding to or enhance binding to FcγRIV. In some embodiments, the anti-TIGIT antibody comprises one or more mutations in the Fc region to enable binding to or enhance binding to ADCC, ADCP, and / or CDC. In some embodiments, the anti-PD-(L)1 antibody comprises one or more substitutions in the Fc region to enhance binding to or enable binding to an Fc receptor, wherein the one or more substitutions occur at EU index positions 234, 235, 236, 239, 243, 247, 267, 268, 292, 298, 300, 305, 324, 326, 330, 332, 333, 334, 339, 345, 396, 430, and any combination of these positions. In some embodiments, the anti-TIGIT antibody comprises one or more substitutions in the Fc region to enhance binding to or enable binding to an Fc receptor, wherein the one or more substitutions include F234L, L235V, G236A, S239D, F243L, P247I, S267E, H268E, R292P, S298A, Y300L, V305I, S324T, K326W, A330L, I332E, E333A, E333S, K334A, A339Q, E345G, P396L, E430G, and any combination of these substitutions. In some embodiments, the Fc-enabled antibody comprises a modified IgG1 domain characterized by substitutions at S239D, A330L, and I332E (Eu numbering). Alternatively, the anti-TIGIT antibody contains or has a glycoform perturbation. In some embodiments, the anti-TIGIT antibody contains or has N-linked Fc glycosylation. In some embodiments, the anti-TIGIT antibody contains or has sialylation, galactosylation, bisected sugar, fucosylation, or any combination of these. Additional mutations in the Fc region that enhance binding to or enable binding to Fc receptors, and alternative strategies for enhancing binding to or enabling binding to Fc receptors are described in Saunders, 2019.

[0212] Treatment

[0213] In one aspect, the present invention provides a method for treating, alleviating, reducing, preventing or delaying Trop-2 positive (Trop-2 + ) A method for treating the recurrence or metastasis of a cancer comprising co-administering to a subject an effective amount of the following substances: a) an anti-Trop-2 antibody-drug conjugate (ADC); and b) an adenosine pathway inhibitor (e.g., a CD39 inhibitor, a CD73 inhibitor, or an A2R inhibitor). In some embodiments, the methods provided herein include treating a Trop-2 positive cancer, comprising co-administering to a subject an effective amount of the following substances: a) an anti-Trop-2 antibody-drug conjugate (ADC); and b) an adenosine pathway inhibitor (e.g., a CD39 inhibitor, a CD73 inhibitor, or an A2R inhibitor). In some embodiments, the methods provided herein include treating the recurrence or metastasis of a Trop-2 positive cancer, comprising co-administering to a subject an effective amount of the following substances: a) an anti-Trop-2 antibody-drug conjugate (ADC); and b) an adenosine pathway inhibitor (e.g., a CD39 inhibitor, a CD73 inhibitor, or an A2R inhibitor). In some embodiments, the methods provided herein include preventing or delaying the recurrence or metastasis of Trop-2 positive cancers, comprising co-administering to a subject an effective amount of the following substances: a) an anti-Trop-2 antibody-drug conjugate (ADC); and b) an adenosine pathway inhibitor (e.g., a CD39 inhibitor, a CD73 inhibitor, or an A2R inhibitor). In some embodiments, the adenosine pathway inhibitor is a variety of adenosine pathway inhibitors. In some embodiments, a variety of adenosine pathway inhibitors include CD73 inhibitors and adenosine receptor antagonists. In some embodiments, the CD73 inhibitor is quilibrium and the adenosine receptor antagonist is edradinam.

[0214] In some embodiments, the methods provided herein are used to treat Trop-2-positive cancers, comprising co-administering to a subject an effective amount of: a) an anti-Trop-2 antibody-drug conjugate (ADC); and b) an adenosine pathway inhibitor (e.g., a CD39 inhibitor, a CD73 inhibitor, or an A2R inhibitor).

[0215] In another aspect, the present invention provides a method for treating, alleviating, reducing, preventing or delaying tumor antigen positive (TA +) Methods for treating the recurrence or metastasis of cancer, comprising co-administering to a subject an effective amount of the following substances: a) a tumor antigen (TA) targeting antibody-drug conjugate (ADC), including a topoisomerase I inhibitor (TopI ADC); and b) an adenosine pathway inhibitor (e.g., a CD39 inhibitor, a CD73 inhibitor, or an A2R inhibitor). In some embodiments, the methods provided herein include treating tumor antigen-positive (TA+) cancer, comprising co-administering to a subject an effective amount of the following substances: a) a tumor antigen targeting antibody-drug conjugate (ADC), including a topoisomerase I inhibitor; and b) an adenosine pathway inhibitor (e.g., a CD39 inhibitor, a CD73 inhibitor, or an A2R inhibitor). In some embodiments, the methods provided herein include treating the recurrence or metastasis of tumor antigen-positive cancer, comprising co-administering to a subject an effective amount of the following substances: a) a tumor antigen targeting antibody-drug conjugate (ADC), including a topoisomerase I inhibitor; and b) an adenosine pathway inhibitor (e.g., a CD39 inhibitor, a CD73 inhibitor, or an A2R inhibitor). In some embodiments, the methods provided herein include preventing or delaying recurrence or metastasis of tumor antigen-positive cancer, comprising co-administering to a subject an effective amount of: a) a tumor antigen-targeting antibody-drug conjugate (ADC) comprising a topoisomerase I inhibitor; and b) an adenosine pathway inhibitor (e.g., a CD39 inhibitor, a CD73 inhibitor, or an A2R inhibitor).

[0216] In some embodiments, the methods provided herein are used to treat tumor antigen-positive cancers, comprising co-administering to a subject an effective amount of: a) a tumor antigen-targeting antibody-drug conjugate (ADC) comprising a topoisomerase I inhibitor; and b) an adenosine pathway inhibitor (e.g., a CD39 inhibitor, a CD73 inhibitor, or an A2R inhibitor).

[0217] In some embodiments, provided herein is a method for treating, alleviating, reducing, preventing or delaying the recurrence or metastasis of a tumor antigen (e.g., Trop-2) positive cancer, comprising administering a combination provided herein to a subject. In some embodiments, provided herein is a method for treating, alleviating, reducing, preventing or delaying the recurrence or metastasis of a tumor antigen (e.g., Trop-2) positive cancer by administering a combination provided herein. In some embodiments, provided herein is a method for treating a tumor antigen (e.g., Trop-2) positive cancer by administering a combination provided herein to reduce the occurrence or recurrence of a tumor antigen (e.g., Trop-2) positive cancer. In some embodiments, provided herein is a method for treating a tumor antigen (e.g., Trop-2) positive cancer by administering a combination provided herein to prevent the occurrence or recurrence of a tumor antigen (e.g., Trop-2) positive cancer. In some embodiments, provided herein is a method for treating a tumor antigen (e.g., Trop-2) positive cancer by administering a combination provided herein to delay the occurrence or recurrence of a tumor antigen (e.g., Trop-2) positive cancer.

[0218] In some embodiments, the methods provided herein further include co-administering additional therapeutic agents or treatments, or a combination thereof. In some embodiments, the methods provided herein include co-administering one, two or three additional therapeutic agents or treatments, or a combination thereof. In some embodiments, additional therapeutic agents include chemotherapy (e.g., chemotherapy treatment selected by a doctor, or a specified standard of care for a specific treatment environment). In some embodiments, additional therapeutic agents include immune checkpoint inhibitors (CPIs; e.g., anti-CTLA4 antibodies, anti-PD(L)1 antibodies, anti-TIGIT antibodies). In some embodiments, additional therapeutic agents include anti-PD(L)1 antibodies (e.g., anti-PD-1 antibodies or anti-PD-L1 antibodies), and optionally anti-TIGIT antibodies. In some embodiments, additional therapeutic agents include anti-PD-(L)1 antibodies. In some embodiments, additional therapeutic agents include anti-TIGIT antibodies. In some embodiments, additional therapeutic agents include anti-PD-(L1) antibodies and anti-TIGIT antibodies. In some embodiments, the additional therapeutic agent includes a) sepalizumab and dunalimab, b) sepalizumab and AB308, c) atezolizumab and tirilimumab, d) pembrolizumab and vembrolizumab, e) pembrolizumab and dunalimab, f) pembrolizumab and AB308, g) MK-7684A (pembrolizumab / vembrolizumab co-formulation), h) durvalumab and dunalimab, i) sepalizumab and rapasumab, or j) pembrolizumab and rapasumab. In some embodiments, the additional therapeutic agent includes sepalizumab and dunalimab. In some embodiments, the additional therapeutic agent includes sepalizumab and rapasumab. In some embodiments, the additional treatment modality includes surgery or radiation therapy.

[0219] In some embodiments of the methods provided herein, the subject is a cancer patient. In some embodiments, the subject is a human cancer patient. In some embodiments, the subject is treatment naive. In some embodiments, the subject (e.g., a human cancer patient) has not received a taxane (e.g., paclitaxel, nab-paclitaxel) prior to administration of the combination therapy provided herein. In some embodiments, the subject (e.g., human cancer patient) has not received checkpoint inhibitor therapy (e.g., anti-CTLA4 antibody, anti-PD(L)1 antibody) before administering the combination therapy provided herein. In some embodiments, the subject (e.g., human cancer patient) has not received topoisomerase I inhibitor therapy (e.g., irinotecan) before administering the combination therapy provided herein. In some embodiments, the subject has received one or more lines of previous anticancer therapy before administering the combination provided herein. In some embodiments, the subject (e.g., human (m) CRPC patient) has received a novel hormone agent (NHA; first or second generation nonsteroidal antiandrogen, such as abiraterone, enzalutamide, darolutamide, apalutamide, or a combination thereof) before administering the combination therapy provided herein. In some embodiments, the subject (e.g., a human (m)CRPC patient) has shown disease progression after previous NHA treatment (first or second generation nonsteroidal anti-androgens, such as abiraterone, enzalutamide, darolutamide, apalutamide, or a combination thereof) and before administration of the combination therapy provided herein. In some embodiments, the subject has received a previous anticancer therapy selected from surgery, radiotherapy, chemotherapy (including NHA therapy), checkpoint inhibitor therapy (e.g., anti-PD(L)1 antibody). In some embodiments, the cancer suffered by the subject is resistant to one or more anticancer therapies, or is refractory to one or more anticancer therapies. In some embodiments, the cancer is resistant to one or more anticancer therapies selected from radiotherapy, chemotherapy (including NHA therapy) and checkpoint inhibitor therapy (e.g., anti-PD(L)1 antibody), or is refractory to the one or more anticancer therapies. In some embodiments, the subject (e.g., a human (m) CRPC patient) has shown disease progression after previous NHA treatment (first or second generation nonsteroidal anti-androgens, such as abiraterone, enzalutamide, darolutamide, apalutamide, or a combination thereof), and has not received a taxane (e.g., docetaxel, cabazitaxel), a checkpoint inhibitor (e.g., an anti-CTLA-4 antibody; an anti-PD(L)1 antibody), or a topoisomerase I inhibitor (e.g., irinotecan) prior to administration of the combination therapy provided herein. In some embodiments, the subject (e.g., a human (m) NSCLC patient) has shown disease progression after platinum-based chemotherapy. In some embodiments, the subject (e.g., a human (m) NSCLC patient) has shown disease progression after checkpoint inhibitor therapy (e.g., anti-PD-(L)1 antibody or anti-CTLA4 antibody therapy). In some embodiments, the subject has progressed after receiving platinum-based chemotherapy and checkpoint inhibitor therapy (eg, anti-PD-(L)1 antibody or anti-CTLA4 antibody therapy) in combination or sequentially in any order.In some embodiments, the subject (e.g., human (m) NSCLC patient) has progressed after tyrosine kinase inhibitor therapy targeting specific genomic changes in cancer. Exemplary tyrosine kinase inhibitors for addressing specific genomic changes (e.g., EGFR mutations or deletions) in lung cancer include gefitinib, erlotinib, afatinib, dacomitinib, neratinib, osimertinib, loxitinib, omotinib, ASP8273 (Astellas), neratinib, PF-06747775 (Pfizer), avitinib and HS-10296 (Jiangsu Hansoh). In some embodiments, the subject (e.g., human (m) CRPC or (m) NSCLC patient) has been tested for tumor antigen (e.g., Trop-2) expression level (e.g., liquid or solid tumor biopsy followed by tumor antigen expression analysis, e.g., by IHC or next generation DNA sequencing).

[0220] In some embodiments, the subject is a human prostate cancer patient. In some embodiments, the human patient suffers from castration-resistant prostate cancer (CRPC). In some embodiments, the human patient suffers from metastatic CRPC (mCRPC). In some embodiments, the human patient with CRPC or mCRPC ((m)CRPC) has not received treatment. In some embodiments, the human patient with (m)CRPC has not received a taxane (e.g., paclitaxel, nab-paclitaxel) prior to administration of the combination therapy provided herein. In some embodiments, human patients with (m) CRPC have not received checkpoint inhibitor therapy (e.g., anti-CTLA4 antibodies, anti-PD (L) 1 antibodies) before administering the combination therapy provided herein. In some embodiments, human patients with (m) CRPC have not received topoisomerase I inhibitor therapy (e.g., irinotecan) before administering the combination therapy provided herein. In some embodiments, human patients with (m) CRPC have received one or more lines of anticancer therapy before administering the combination provided herein. In some embodiments, human patients with (m) CRPC have shown disease progression when receiving one or more lines of anticancer therapy before administering the combination provided herein. In some embodiments, human patients with (m) CRPC have received novel hormone agents (NHA; first or second generation non-steroidal anti-androgens, abiraterone) (experienced NHA) before administering the combination therapy provided herein. In some embodiments, human patients with (m) CRPC have shown disease progression after previous NHA treatment (first or second generation nonsteroidal anti-androgens, such as abiraterone, enzalutamide, darolutamide, apalutamide, or a combination thereof) and before administration of the combination therapy provided herein. In some embodiments, human patients with (m) CRPC have received previous anticancer therapies selected from surgery, radiotherapy, chemotherapy (including NHA therapy), checkpoint inhibitor therapy (e.g., anti-CTLA4 antibodies, anti-PD (L) 1 antibodies). In some embodiments, the cancer suffered by human patients with (m) CRPC is resistant to one or more anticancer therapies, or is refractory to one or more anticancer therapies. In some embodiments, cancer is resistant to one or more anticancer therapies selected from radiotherapy, chemotherapy (including NHA therapy) and checkpoint inhibitor therapy (e.g., anti-CTLA4 antibodies, anti-PD (L) 1 antibodies), or is refractory to the one or more anticancer therapies. In some embodiments, the human patient with (m)CRPC has received prior NHA therapy (first or second generation nonsteroidal antiandrogens, such as abiraterone, enzalutamide, darolutamide, apalutamide, or a combination thereof) (is NHA experienced) and has not received a taxane (e.g., paclitaxel, nab-paclitaxel) prior to administration of the combination therapy provided herein. docetaxel, cabazitaxel) and checkpoint inhibitors (e.g., anti-CTLA-4 antibodies; anti-PD(L)1 antibodies) (taxane and CPI naive). In some embodiments, the human patient with (m)CRPC has received prior NHA treatment (first or second generation nonsteroidal antiandrogens, such as abiraterone, enzalutamide, darolutamide, apalutamide, or a combination thereof) (experienced NHA) and has not received a taxane (e.g., paclitaxel, nab-paclitaxel) prior to administration of the combination therapy provided herein. docetaxel, cabazitaxel), checkpoint inhibitors (e.g., anti-CTLA-4 antibodies; anti-PD(L)1 antibodies) or topoisomerase I inhibitors (e.g., irinotecan). In some embodiments, the human patient with (m)CRPC has shown disease progression after previous NHA treatment (first or second generation nonsteroidal antiandrogens, such as abiraterone, enzalutamide, darolutamide, apalutamide, or a combination thereof) and has not received a taxane (e.g., paclitaxel, nab-paclitaxel) prior to administration of the combination therapy provided herein. docetaxel, cabazitaxel), checkpoint inhibitors (e.g., anti-CTLA-4 antibodies; anti-PD(L)1 antibodies) or topoisomerase I inhibitors (e.g., irinotecan). In some embodiments, the (m)CRPC human patient has histologically confirmed prostate adenocarcinoma and has metastatic castration-resistant tumor progression while undergoing androgen deprivation therapy (ADT; including orchiectomy), wherein the serum (total) testosterone castrate level (≤1.7 nmol / L or 50 ng / dL) is defined by PSA and / or radiographic criteria according to PCWG3. In some embodiments, the human (m)CRPC patient has metastatic castration-resistant prostate adenocarcinoma with tumor progression while undergoing androgen deprivation therapy (e.g., including orchiectomy), wherein the serum (total) testosterone castrate level (≤1.7 nmol / L or 50 ng / dL) is defined by prostate-specific antigen (PSA) and / or radiographic criteria according to the Prostate Cancer Working Group 3 (PCWG3), and has measurable or non-measurable disease according to the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. In some embodiments, the human patient with (m)CRPC has an Eastern Cooperative Oncology Group performance status of 0 or 1 and a life expectancy of ≥3 months. In some embodiments, the human patient with (m)CRPC has been tested for tumor antigen (e.g., Trop-2) expression levels (e.g., liquid or solid tumor biopsy followed by tumor antigen expression analysis, e.g., by IHC or next-generation DNA sequencing).

[0221] In some embodiments, the subject is a human lung cancer patient. In some embodiments, the human patient suffers from non-small cell lung cancer (NSCLC). In some embodiments, NSCLC is squamous NSCLC. In some embodiments, NSCLC is non-squamous NSCLC. In some embodiments, lung cancer does not have an operable genome change (e.g., EGFR or ALK mutation, insertion, deletion, etc.) (operable genome change) indicated for treatment with targeted therapy (e.g., targeted tyrosine kinase inhibitor therapy). Exemplary operable genome changes and targeted tyrosine kinase inhibitor therapy are described in, for example, Sullivan and Planchard, Front.Med. (2017) 3: 76. In some embodiments, human NSCLC patients have shown disease progression after platinum-based chemotherapy. In some embodiments, human NSCLC patients have shown disease progression after checkpoint inhibitor therapy (e.g., anti-PD-(L) 1 antibody or anti-CTLA4 antibody therapy). In some embodiments, human NSCLC patients have progressed after receiving platinum-based chemotherapy and checkpoint inhibitor therapy (e.g., anti-PD-(L) 1 antibody or anti-CTLA4 antibody therapy) in combination or in any order. In some embodiments, human NSCLC patients have progressed after tyrosine kinase inhibitor therapy targeting specific genomic changes in cancer. Exemplary tyrosine kinase inhibitors for addressing specific genomic changes in lung cancer (e.g., EGFR mutations or deletions) include gefitinib, erlotinib, afatinib, dacomitinib, neratinib, osimertinib, locitinib, omotinib, ASP8273 (Astellas), neratinib, PF-06747775 (Pfizer), avitinib and HS-10296 (Jiangsu Hansoh).

[0222] In some embodiments of the methods provided herein, the combinations provided herein are administered in a neoadjuvant therapy setting (e.g., in the preparation for surgery or radiotherapy). In some embodiments, the combinations provided herein are administered in an adjuvant therapy setting (e.g., after primary therapy such as surgery or radiotherapy). In some embodiments, the combinations provided herein are administered in a treatment setting (e.g., as a primary therapy). In some embodiments, the combinations provided herein are administered in a maintenance setting.

[0223] In some embodiments of the methods provided herein, cancer is a hematological cancer. In some embodiments, cancer includes solid tumors. In some embodiments, cancer includes malignant tumors. In some embodiments, cancer includes metastatic cancer. In some embodiments, cancer is resistant or refractory to one or more anticancer therapies. In some embodiments, greater than about 50% of cancer cells can detectably express one or more cell surface immune checkpoint receptors (e.g., so-called "hot" cancer or tumor). In some embodiments, greater than about 1% and less than about 50% of cancer cells can detectably express one or more cell surface immune checkpoint receptors (e.g., so-called "warm" cancer or tumor). In some embodiments, less than about 1% of cancer cells can detectably express one or more cell surface immune checkpoint receptors (e.g., so-called "cold" cancer or tumor).

[0224] In some embodiments of the methods provided herein, the cancer is a hematological cancer, e.g., a leukemia (e.g., acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), B-cell ALL, myelodysplastic syndrome (MDS), myeloproliferative disease (MPD), chronic myeloid leukemia (CML), chronic lymphocytic leukemia (CLL), undifferentiated leukemia), a lymphoma (e.g., small lymphocytic lymphoma (SLL), mantle cell lymphoma (MCL), follicular lymphoma (FL), T-cell lymphoma, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), marginal zone lymphoma (MZL), Waldenstrom's macroglobulinemia (WM)), and / or a myeloma (e.g., multiple myeloma (MM)).

[0225] In some embodiments of the methods provided herein, the cancer is an epithelial tumor (e.g., carcinoma, squamous cell carcinoma, basal cell carcinoma, squamous intraepithelial neoplasia), a glandular tumor (e.g., adenocarcinoma, adenoma, adenomyoma), a mesenchymal tumor, or a soft tissue tumor (e.g., sarcoma, rhabdomyosarcoma, leiomyosarcoma, liposarcoma, fibrosarcoma, cutaneous fibrosarcoma, neurofibrosarcoma, fibrohistiocytoma, angiosarcoma, angiomyxoma, leiomyoma, enchondroma, chondrosarcoma, alveolar soft part sarcoma, epithelioid hemangioendothelioma, Spitz tumor, synovial sarcoma), or a lymphoma.

[0226] In some embodiments, cancer comprises a solid tumor in or arising from a tissue or organ, such as:

[0227] Skeletal (e.g., adamantoma, aneurysmal bone cyst, angiosarcoma, chondroblastoma, enchondroma, chondromyxoid fibroma, chondrosarcoma, chordoma, dedifferentiated chondrosarcoma, enchondroma, epithelioid hemangioendothelioma, fibrous dysplasia of bone, giant cell tumor of bone, hemangioma and related lesions, osteoblastoma, osteochondroma, osteosarcoma, osteoid osteoma, osteoma, periosteal chondroma, desmoid tumor, Ewing sarcoma);

[0228] Lips and oral cavity (e.g., odontogenic ameloblastoma, oral leukoplakia, oral squamous cell carcinoma, primary oral mucosal melanoma); salivary glands (e.g., pleomorphic salivary adenoma, salivary adenoid cystic carcinoma, salivary mucoepidermoid carcinoma, salivary Warthin's tumor);

[0229] ·Esophagus (e.g. Barrett's esophagus, dysplasia, and adenocarcinoma);

[0230] Gastrointestinal tract, including stomach (e.g., gastric adenocarcinoma, primary gastric lymphoma, gastrointestinal stromal tumor (GIST), metastatic deposits, gastric cancer, gastric sarcoma, neuroendocrine carcinoma, primary squamous cell carcinoma of the stomach, gastric adenoacanthoma), intestine and smooth muscle (e.g., intravenous leiomyoma), colon (e.g., colorectal adenocarcinoma), rectum, anus;

[0231] Pancreas (eg, serous tumors, including microcystic or macrocystic serous cystadenomas, solid serous cystadenomas, Von Hippel-Landau (VHL)-associated serous cystic neoplasms, serous cystadenocarcinomas; mucinous cystic neoplasms (MCNs), intraductal papillary mucinous neoplasms (IPMNs), intraductal oncocytic papillary neoplasms (IOPNs), intraductal tubular neoplasms, cystic acinar neoplasms (including acinar cell cystadenoma, acinar cell cystadenocarcinomas), pancreatic cancer, invasive pancreatic ductal adenocarcinoma (including tubular adenocarcinoma, adenosquamous carcinoma), colloid carcinoma, medullary carcinoma, hepatoid carcinoma, signet ring cell carcinoma, undifferentiated carcinoma, undifferentiated carcinoma with osteoclast-like giant cells, acinar cell carcinoma, neuroendocrine tumors, neuroendocrine microadenomas, neuroendocrine tumors (NETs), neuroendocrine carcinomas (NECs) (including small cell or large cell NECs), insulinomas, gastrinomas, glucagonomas, serotonin-producing NETs, ​​somatostatinomas, VIPomas, solid pseudopapillary neoplasms (SPNs), pancreatoblastomas);

[0232] Gallbladder (e.g., gallbladder cancer and extrahepatic bile duct and intrahepatic bile duct cancer);

[0233] Neuroendocrine glands (e.g. adrenal cortical carcinoma, carcinoid, pheochromocytoma, pituitary adenoma);

[0234] Thyroid (e.g., anaplastic (undifferentiated) carcinoma, medullary carcinoma, oncocytic tumor, papillary carcinoma, adenocarcinoma);

[0235] Liver (e.g., adenoma, combined hepatocellular and cholangiocarcinoma, fibrolamellar carcinoma, hepatoblastoma, hepatocellular carcinoma, mesenchymal nested stromal epithelial tumor, undifferentiated carcinoma; hepatocellular carcinoma, intrahepatic bile duct carcinoma, biliary cystadenocarcinoma, epithelioid hemangioendothelioma, angiosarcoma, embryonal sarcoma, rhabdomyosarcoma, solitary fibrous tumor, teratoma, yolk sac tumor, carcinosarcoma, rhabdoid tumor);

[0236] Kidney (e.g., ALK-rearranged renal cell carcinoma, chromophobe renal cell carcinoma, clear cell renal cell carcinoma, clear cell sarcoma, metanephric adenoma, metanephric adenofibroma, mucinous tubular and spindle cell carcinoma, nephroblastoma, Wilms tumor, papillary adenoma, papillary renal cell carcinoma, renal oncocytoma, renal cell carcinoma, succinate dehydrogenase-deficient renal cell carcinoma, collecting duct carcinoma);

[0237] Breast (e.g., invasive ductal carcinoma, including but not limited to acinar cell carcinoma, adenoid cystic carcinoma, apocrine carcinoma, cribriform carcinoma, glycogen-rich / clear cell inflammatory carcinoma, lipid-rich carcinoma, medullary carcinoma, metaplastic carcinoma, micropapillary carcinoma, mucinous carcinoma, neuroendocrine carcinoma, oncocytic carcinoma, papillary carcinoma, sebaceous gland carcinoma, secretory breast carcinoma, tubular carcinoma; lobular carcinoma, including but not limited to pleomorphic carcinoma, signet ring cell carcinoma);

[0238] Peritoneum (eg, mesothelioma; primary peritoneal cancer);

[0239] Female sex organ tissues, including ovary (e.g., choriocarcinoma, epithelial cell tumor, germ cell tumor, sex cord-stromal tumor), fallopian tube (e.g., serous adenocarcinoma, mucinous adenocarcinoma, endometrioid adenocarcinoma, clear cell adenocarcinoma, transitional cell carcinoma, squamous cell carcinoma, undifferentiated carcinoma, Müllerian tumor, adenosarcoma, leiomyosarcoma, teratoma, germ cell tumor, choriocarcinoma, trophoblastoma), uterus (e.g., cervical cancer, endometrial polyp, endometrial hyperplasia, intraepithelial carcinoma (EIC), endometrial cancer (e.g., endometrioid carcinoma, serous carcinoma, clear cell carcinoma), , mucinous carcinoma, squamous cell carcinoma, transitional carcinoma, small cell carcinoma, undifferentiated carcinoma, mesenchymal tumor), leiomyoma (e.g., endometrial stromal nodule, leiomyosarcoma, endometrial stromal sarcoma (ESS), mesenchymal tumor), mixed epithelial and mesenchymal tumor (e.g., adenofibroma, carcinofibroma, adenosarcoma, carcinosarcoma (malignant mixed mesodermal sarcoma-MMMT)), endometrial stromal tumor, endometrial malignant mixed Müllerian tumor, gestational trophoblastic tumor (partial hygroma, complete hygroma, invasive hygroma, placental site tumor)), vulva, vagina;

[0240] Male sex organ tissue, including prostate, testicles (e.g., germ cell tumors, spermatocytic seminoma), and penis;

[0241] Bladder (e.g., squamous cell carcinoma, urothelial carcinoma, urothelial bladder carcinoma);

[0242] Brain (e.g., gliomas (e.g., astrocytomas (including non-invasive, low-grade, anaplastic), glioblastomas; oligodendrogliomas, ependymomas)), meningiomas, gangliogliomas, schwannomas (neurilemmomas), craniopharyngiomas, chordomas, non-Hodgkin lymphomas (NHL), indolent non-Hodgkin lymphomas (iNHL), refractory iNHL, pituitary tumors);

[0243] Eye (e.g., retinoblastoma, retinoblastoma, ocular melanoma, choroidal melanoma, iris hamartoma);

[0244] Head and neck (e.g., nasopharyngeal carcinoma, endolymphatic sac tumor (ELST), epidermoid carcinoma, laryngeal cancer (including squamous cell carcinoma (SCC)) (e.g., glottic cancer, supraglottic cancer, subglottic cancer, transglottic cancer), carcinoma in situ, verrucous hemangioma, spindle cell and basal cell SCC, undifferentiated carcinoma, laryngeal adenocarcinoma, adenoid cystic carcinoma, neuroendocrine carcinoma, laryngeal tumor), head and neck paraganglioma (e.g., carotid body tumor, cervicotympanic tumor, vagal neuroma);

[0245] thymus (e.g. thymoma);

[0246] Heart (e.g. cardiac myxoma);

[0247] Lung (e.g., small cell carcinoma (SCLC), non-small cell lung cancer (NSCLC) (including squamous cell carcinoma (SCC)), adenocarcinoma, and large cell carcinoma), carcinoid (typical or atypical), carcinosarcoma, pulmonary blastoma, giant cell carcinoma, spindle cell carcinoma, pleuropulmonary blastoma);

[0248] Lymphoma (e.g., lymphoma, including Hodgkin lymphoma, non-Hodgkin lymphoma (NHL), indolent non-Hodgkin lymphoma (iNHL), refractory iNHL, Epstein-Barr virus (EBV)-associated lymphoproliferative disorders, including B-cell lymphoma and T-cell lymphoma (e.g., Burkitt lymphoma; large B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma, indolent B-cell lymphoma, low-grade B-cell lymphoma, fibrin-associated diffuse large cell lymphoma; primary effusion lymphoma; plasmablastic lymphoma; extranodal NK / T-cell lymphoma, nasal type; peripheral T-cell lymphoma, cutaneous T-cell lymphoma, angioimmunoblastic T-cell lymphoma; follicular T-cell lymphoma; systemic T-cell lymphoma), lymphangioleiomyomatosis);

[0249] Central nervous system (CNS) (e.g., gliomas, including astrocytic tumors (e.g., pilocytic astrocytoma, fluid-like astrocytoma, subependymal giant cell astrocytoma, pleomorphic xanthoastrocytoma, diffuse astrocytoma, fibrillary astrocytoma, fat cell astrocytoma, protoplasmic astrocytoma, anaplastic astrocytoma), glioblastoma (e.g., giant cell glioblastoma, gliosarcoma, glioblastoma multiforme), and glioma cerebri), oligodendroglial tumors (e.g., oligodendroglioma, anaplastic oligodendroglioma), oligoastrocytic tumors (e.g., oligoastrocytoma, anaplastic oligoastrocytoma), ependymoma tumors (e.g., subependymomas, myxopapillary ependymomas, ependymomas (e.g., cellular, papillary, clear cell, elongated cell), anaplastic ependymomas), optic nerve gliomas, and non-glial tumors (e.g., choroid plexus tumors, neuronal and mixed neuronal-glial tumors, pineal region tumors, embryonal tumors, medulloblastomas, meningeal tumors, primary CNS lymphomas, germ cell tumors, pituitary adenomas, skull and paraspinal nerve tumors, stellate region tumors); neurofibromas, meningiomas, peripheral nerve sheath tumors, peripheral neuroblastic tumors (including but not limited to neuroblastomas, ganglioneuroblastomas, ganglioneuromas), trisomal cell 19 ependymomas);

[0250] Neuroendocrine tissue (e.g. paraganglionic system, including adrenomedullin (pheochromocytoma) and extraadrenal paraganglia ((extraadrenal) paraganglioma);

[0251] Skin (e.g., clear cell hidradenoma, benign fibrous histiocytoma of the skin, cylindroma, hidradenoma, melanoma (including cutaneous melanoma, mucosal melanoma), pilomatricoma, Spitz tumor); and

[0252] Soft tissue (e.g., aggressive angiomyxoma, alveolar rhabdomyosarcoma, alveolar soft part sarcoma, angiofibroma, angiomatoid fibrous histiocytoma, synovial sarcoma, biphasic synovial sarcoma, clear cell sarcoma, dermatofibrosarcoma protuberans, desmoid fibroma, small round cell tumor, desmoplastic small round cell tumor, fibroelastoma, embryonal rhabdomyosarcoma, Ewing tumor / primitive neuroectodermal tumor (PNET), extraskeletal myxoid chondrosarcoma, extraskeletal osteosarcoma, paraspinal sarcoma, inflammatory Myofibroblastic tumor, liposarcoma, lipoma, chondroid lipoma, liposarcoma / malignant lipoma tumor, liposarcoma, myxoid liposarcoma, fibromyxoid sarcoma, lymphoangioleiomyomas, malignant myoepithelioma, malignant melanoma of the soft part, myoepithelial carcinoma, myoepithelioma, myxoinflammatory fibroblastic sarcoma, undifferentiated sarcoma, pericytoma, rhabdomyosarcoma, non-rhabdomyosarcoma soft tissue sarcoma (NRSTS), leiomyosarcoma of soft tissue, undifferentiated sarcoma, well-differentiated liposarcoma.

[0253] In some embodiments, the cancer is positive for a tumor antigen selected from the group consisting of carbonic anhydrase IX, B7, CCCL19, CCCL21, CSAp, HER-2 / neu, BrE3, CD1, CD1a, CD2, CD3, CD4, CD5, CD8, CD11A, CD14, CD15, CD16, CD18, CD19, CD20 (e.g., C2B8, hA20, 1F5 MAbs), CD21, CD22, CD23, CD25, CD29, CD30, CD32b, CD33, CD37, CD38, CD40, CD40L, CD44, CD45, CD46, CD52, CD54, CD55, CD59, CD64, CD67, CD70, CD74, CD79a, CD80, CD83, CD95, CD126, CD133, CD138, CD147, CD154, CEACAM5, CEACAM-6, alpha-fetoprotein (AFP), VEGF, fibronectin splice variants, ED-B fibronectin (e.g., L19), EGP-1, EGP-2 (e.g., 17-1A), EGF receptor (ErbBl), ErbB2, ErbB3, Factor H, FHL-1, Flt-3, folate receptor, Ga 733, GROB, HMGB-1, hypoxia-inducible factor (HIF), HM1.24, insulin-like growth factor (ILGF), IFN-a, IFN-b, IFN-g, IL-2R, IL-4R, IL-6R, IL-13R, IL-15R, IL-17R, IL-18R, IL-2, IL-6, IL-8, IL-12, IL-15, IL-17, IL-18, IL-25, IP-10, IGF-1R, Ia, HM1.24, gangliosides, HCG, HLA-DR, CD66 (e.g., CD66a-d), MAGE, mCRP, MCP-1, MIP-1A, M IP-1B, MIF, MUC1, MUC2, MUC3, MUC4, MUC5, placental growth factor (PIGF), PSA (prostate-specific antigen), PSMA, PAM4, NCA-95, NCA-90, A3, A33, Ep-CAM, KS-1, Le(y), mesothelin, S100, tenascin, TAC, Tn antigen, Thomas-Friedenreich antigen, tumor necrosis antigen, tumor angiogenesis antigen, TNF-a, TRAIL receptor (R1 and R2), VEGFR, RANTES, T101, complement factors C3, C3a, C3b, C5a and C5, and oncogene products.

[0254] In some embodiments, the cancer is positive for a tumor antigen selected from CD74, CD22, Trop-2, CEA, CSAp Mu-9, AFP, CC49, and PSMA.

[0255] In some embodiments, the cancer is a Trop-2 positive cancer. In some embodiments, the Trop-2 positive cancer is a solid epithelial cancer. In some embodiments, the solid epithelial cancer is selected from breast cancer (e.g., triple negative breast cancer (TNBC); HR positive / Her-2 negative (HR + / Her-2 - ) breast cancer; HR positive / Her-2 low breast cancer), colorectal cancer, lung cancer, gastric cancer, urinary tract cancer, urothelial cancer, bladder cancer, kidney cancer, pancreatic cancer, ovarian cancer, uterine cancer, esophageal cancer and prostate cancer. In some embodiments, prostate cancer is castration-resistant prostate cancer (CRPC). In some embodiments, lung cancer is non-small cell lung cancer (NSCLC). In some embodiments, Trop-2 positive cancer is (i) unresectable locally advanced cancer, or (ii) metastatic cancer (e.g., mCRPC or mNSCLC). In some embodiments, Trop-2 positive cancer is resistant to one or more anticancer therapies, or is refractory to one or more anticancer therapies.

[0256] In some embodiments of the methods provided herein, Trop-2 positive cancer is prostate cancer. In some embodiments, Trop-2 positive cancer is metastatic prostate cancer. In some embodiments, Trop-2 positive cancer is castration-resistant prostate cancer (CRPC). In some embodiments, Trop-2 positive cancer is metastatic castration-resistant prostate cancer (mCRPC). In some embodiments, Trop-2 positive cancer is metastatic castration-resistant prostate cancer (mCRPC) showing tumor progression during androgen deprivation therapy (e.g., including orchiectomy), wherein serum (total) testosterone castration level (≤1.7nmol / L or 50ng / dL) is defined by prostate-specific antigen (PSA) and / or radiographic criteria according to Prostate Cancer Working Group 3 (PCWG3); and according to the efficacy evaluation criteria for solid tumors (RECIST) v1.1 measurable or unmeasurable disease.

[0257] In some embodiments, the methods provided herein include co-administering to a subject (e.g., a human cancer patient) having a Trop-2 positive cancer an effective amount of the following substances: a) an anti-Trop2 antibody-drug conjugate; and b) an adenosine pathway inhibitor. In some embodiments, the anti-Trop-2 ADC comprises a topoisomerase I inhibitor. In some embodiments, the topoisomerase inhibitor is a camptothecin analog. In some embodiments, the camptothecin analog is an irinotecan derivative, a topotecan derivative, or an exatecan derivative. In some embodiments, the camptothecin analog is SN38 or Dxd. In some embodiments, the camptothecin analog is SN38. In some embodiments, the camptothecin analog is connected to the anti-Trop-2 antibody via a hydrolyzable linker. In some embodiments, the hydrolyzable linker is CL2A (e.g., as described in US 7,999,083). In some embodiments, the camptothecin analog is connected to the anti-Trop-2 antibody via a protease cleavable linker. In some embodiments, the anti-Trop-2 ADC has the structure mAb-CL2A-SN-38, which is represented by the following formula:

[0258]

[0259] (described, e.g., in U.S. Pat. No. 7,999,083). In some embodiments, the drug-antibody ratio (DAR) of CL2A-SN38 to anti-Trop-2 antibody in the anti-Trop2 ADC is between 7.0 and 8.0. In some embodiments, the DAR of CL2A-SN38 to anti-Trop-2 antibody in the anti-Trop-2 ADC is about 7.6. In some embodiments, the anti-Trop-2 ADC comprises the anti-Trop-2 antibody saxatuzumab (hRS7, described, e.g., in FIGS. 3 and 4 of WO2003074566). In some embodiments, the anti-Trop-2 ADC is selected from gosartuzumab, dedabotulinumab derutec (DS-1062), ESG-401, SKB-264, DAC-02, and BAT-8003. In some embodiments, the anti-Trop-2 ADC is gosartuzumab. In some embodiments, the anti-Trop-2 ADC is dedabotulinumab derutin (DS-1062). In some embodiments, the adenosine pathway inhibitor is a CD39 inhibitor, a CD73 inhibitor, or an adenosine receptor antagonist. In some embodiments, the CD39 inhibitor is selected from TTX-030 (AbbVie / Trishula), IPH5201 (AstraZeneca / Innate Pharma), SRF617 (Surface Oncology), CD39 ASO (Secarna Pharmaceuticals), JS-019 (Shanghai Junshi Biosciences), AB598 (anti-CD39) (Arcus Biosciences), ES002 (Elpiscience Biopharmaceuticals), and CD39xPD1 (Biotheus).In some embodiments, the CD73 inhibitor is selected from olerumumab (AstraZeneca), BMS-986179 (BMS), ulelimab (I-MAB Biopharma), AK119 (AkesoBiopharma), quemliclustat (AB680, Arcus Biosciences), mopalimumab (Corvus Pharmaceuticals), HLX23 (Shanghai Henlius Biotech), INCA00186 (Incyte), IBI325 (Innovent Bio), NZV930 (Novartis / Surface Oncology), ORIC-533 (ORIC Pharma), Sym024 (Servier), IPH5301 (Innate), IOA-237 (iOnctura), JAB-BX100 (Jacobio), PT199 (Phanes Therapeutics), TRB010 (Trican Biotechnology), CD73 ASO (Secarna Pharmaceuticals), 622 (3SBio), ABSK-051 (Abbisko Therapeutics), AK131 (CD73xPD1, Akeso Biopharma), CD73i (Aurigene), BR101 (BioRay), BP1200 (BrightPath), CB708 (Antengene / Calithera), GB7002 (Genbase Bio), ATG-037 (Antengene), and CD73i (Biotheus). In some embodiments, the CD73 inhibitor is olerumumab or quilibrium. In some embodiments, the CD73 inhibitor is quilibrium. In some embodiments, the adenosine receptor antagonist is an adenosine A2A receptor (A2AR; ADORA2A) selective antagonist, such as imadinam (AstraZeneca), NIR178 (Novartis / Palobiofarma) ID11902 (Ildong), IN-A003 (Inno.n), NTI-55 (A2aR / TLR7, Nammi), TT-10 (Tarus Therapeutics) or TT-228 (Teon Therapeutics).In some embodiments, the adenosine receptor antagonist is an adenosine A2B receptor (A2BR; ADORA2B) antagonist, such as PBF-1129 (Palobiofarma) or TT-702 (Teon Therapeutics). In some embodiments, the adenosine receptor antagonist is a dual adenosine A2A / A2B receptor antagonist, such as edredinam (AB928, Arcus Biosciences), INCB106385 (Incyte), M1069 (Merck KgaA), A2aR / A2bR (Domain / Merck KgaA), HM87277 (A1 / A2aR / A2bR, Hanmi Pharmaceutical), RVU-330 (Ryvu), TT-53 (Tarus Therapeutics). In some embodiments, the adenosine receptor antagonist is edredinam. In some embodiments, the adenosine pathway inhibitor is quilibrium or edredinam. In some embodiments, the adenosine pathway inhibitor is eltrodinam. In some embodiments, the methods provided herein include co-administering an effective amount of the following substances to a subject (e.g., a human cancer patient) with a Trop-2 positive cancer: a) an anti-Trop-2 ADC comprising a topoisomerase I inhibitor (e.g., SN38 or Dxd); and b) an adenosine pathway inhibitor selected from a CD39 inhibitor, a CD73 inhibitor, and an adenosine receptor antagonist. In some embodiments, the methods provided herein include co-administering an effective amount of the following substances to a subject (e.g., a human cancer patient) with a Trop-2 positive cancer: a) an anti-Trop-2 ADC comprising a topoisomerase I inhibitor (e.g., SN38 or Dxd); and b) an adenosine pathway inhibitor selected from a CD73 inhibitor and an adenosine receptor antagonist. In some embodiments, the methods provided herein include co-administering to a subject (e.g., a human cancer patient) having a Trop-2-positive cancer an effective amount of the following: a) an anti-Trop-2 ADC comprising a topoisomerase I inhibitor (e.g., SN38 or Dxd); and b) an adenosine pathway inhibitor selected from olerumab, BMS-986179, ulelimab, imadinam, NIR178, and edrinam. In some embodiments, the methods provided herein include co-administering to a subject (e.g., a human cancer patient) having a Trop-2-positive cancer an effective amount of the following: a) an anti-Trop-2 ADC having the structure mAb-CL2A-SN-38, represented by the following formula:.

[0260]

[0261] And b) an adenosine pathway inhibitor selected from olerumumab, BMS-986179, ulelimumab, imadinam, NIR178 and eltrodinam. In some embodiments, the methods provided herein include co-administering an effective amount of the following substances to a subject (e.g., a human cancer patient) with a Trop-2 positive cancer: a) gosatuzumab or dedabotuzumab derunotecan (DS-1062); and b) an adenosine pathway inhibitor selected from olerumumab, BMS-986179, ulelimumab, imadinam, NIR178 and eltrodinam. In some embodiments, the methods provided herein include co-administering an effective amount of the following substances to a subject (e.g., a human cancer patient) with a Trop-2 positive cancer: a) gosatuzumab; and b) eltrodinam. In some embodiments, the methods provided herein also include co-administering an additional therapeutic agent or treatment modality, or a combination thereof. In some embodiments, additional therapeutic agents include immune checkpoint inhibitors (CPIs). In some embodiments, CPI includes anti-PD(L)1 antibody (e.g., anti-PD-1 antibody or anti-PD-L1 antibody), and optionally anti-TIGIT antibody. In some embodiments, anti-PD(L)1 antibody is selected from pembrolizumab, nivolumab, cemiprilimab, pidilizumab, spartalizumab, atezolizumab, avelumab, durvalumab, coxilimab, sazanlizumab, tislelizumab, rivulimumab, batilizumab, toripalimab, cetrilimumab, genorumab, palolizumab, lodalimab, carrelizumab, budigalimumab, avelumab, dotalimumab, enwolimumab, sindilimumab and sepalimab. In some embodiments, anti-PD(L)1 antibody is sepalimab. In some embodiments, the anti-TIGIT antibody is selected from tislelizumab, vebrolimumab, dunalimab, AB308, AK127, BMS-986207, rapasumab and atilizumab. In some embodiments, the anti-TIGIT antibody is dunalimab. In some embodiments, the additional therapeutic agent includes an anti-PD(L)1 antibody and an anti-TIGIT antibody. In some embodiments, the additional therapeutic agent includes a) sepalizumab and dunalimab, b) sepalizumab and AB308, c) atilizumab and tislelizumab, d) pembrolizumab and vbolimumab, e) MK-7684A (pembrolizumab / vebrolimumab co-formulation), f) durvalumab and dunalimab, g) sepalizumab and rapasumab, or h) pembrolizumab and rapasumab. In some embodiments, the anti-PD(L)1 antibody is sepalizumab and the anti-TIGIT antibody is dunalimumab. In some embodiments, the additional treatment modality comprises surgery or radiation therapy.In some embodiments, the methods provided herein include co-administering to a subject (e.g., a human cancer patient) having a Trop-2-positive cancer an effective amount of the following: a) an anti-Trop-2 ADC comprising a topoisomerase I inhibitor (e.g., SN38 or Dxd); b) an adenosine pathway inhibitor selected from olerumab, BMS-986179, ulelimab, imatinib, NIR178, and edretinib, and c) an anti-PD(L)1 antibody. In some embodiments, the methods provided herein include co-administering to a subject (e.g., a human cancer patient) having a Trop-2-positive cancer an effective amount of the following: a) an anti-Trop-2 ADC having the structure mAb-CL2A-SN-38, represented by the following formula:

[0262]

[0263] b) an adenosine pathway inhibitor selected from olerumumab, BMS-986179, ulelimab, imadinam, NIR178 and edredinam, and c) an anti-PD(L)1 antibody. In some embodiments, the methods provided herein include co-administering an effective amount of the following substances to a subject (e.g., a human cancer patient) with a Trop-2 positive cancer: a) gosatuzumab or dedabotuzumab derunotecan (DS-1062); b) an adenosine pathway inhibitor selected from olerumumab, BMS-986179, ulelimab, imadinam, NIR178 and edredinam; and c) an anti-PD(L)1 antibody. In some embodiments, the methods provided herein include co-administering an effective amount of the following substances to a subject (e.g., a human cancer patient) with a Trop-2 positive cancer: a) gosatuzumab; b) edredinam; and c) an anti-PD(L)1 antibody. In some embodiments, the anti-PD(L)1 antibody is selected from pembrolizumab, nivolumab, cemiprilimab, pidilizumab, spartalizumab, atezolizumab, avelumab, durvalumab, cocilimab, sacralizumab, tislelizumab, rivulizumab, batilizumab, toripalizumab, cetrilimab, genolumab, palolizumab, lodalizumab, carrelizumab, budigalimab, avelumab, dotalimumab, envolimab, sintilimab and sepalizumab. In some embodiments, the anti-PD(L)1 antibody is sepalizumab. In some embodiments, the methods provided herein include co-administering an effective amount of the following substances to a subject (e.g., a human cancer patient) having a Trop-2 positive cancer: a) gosatuzumab; b) edrinam; and c) sepalizumab. In some embodiments, the Trop-2 positive cancer is castration-resistant prostate cancer (CRPC) or non-small cell lung cancer (NSCLC). In some embodiments, the Trop-2 positive cancer is CRPC. In some embodiments, the Trop-2 positive cancer is a metastatic cancer (e.g., mCRPC, mNSCLC). In some embodiments, the Trop-2 positive cancer is resistant to one or more anticancer therapies, or is refractory to one or more anticancer therapies (e.g., NHA-resistant or refractory mCRPC).

[0264] In some embodiments, the methods provided herein include administering to a patient with a tumor antigen positive (TA +) a subject (e.g., a human cancer patient) with cancer co-administers an effective amount of the following substances: a) TopI ADC; and b) an adenosine pathway inhibitor. In some embodiments, the TopI ADC comprises a camptothecin analog. In some embodiments, the camptothecin analog is an irinotecan derivative, a topotecan derivative, or an exatecan derivative. In some embodiments, the camptothecin analog is SN38 or Dxd. In some embodiments, the camptothecin analog is SN38. In some embodiments, the camptothecin analog is connected to a tumor antigen targeting antibody via a hydrolyzable linker. In some embodiments, the hydrolyzable linker is CL2A (e.g., as described in US 7,999,083). In some embodiments, the camptothecin analog is connected to a tumor antigen targeting antibody via a protease-cleavable linker. In some embodiments, the TopI ADC has the structure mAb-CL2A-SN-38, which is represented by the following formula:

[0265]

[0266] (described, e.g., in U.S. Pat. No. 7,999,083). In some embodiments, the tumor antigen targeting antibody in the TopI ADC is selected from gemtuzumab, brentuximab, berantuzumab, canalizumab, trastuzumab, inotuzumab, gebatumumab, anetuzumab, mivituximab, dituximab, vadatuximab, labetuzumab, ladituzumab, lantuximab, pertrastuzumab, rifatuzumab, indutumab, polotuzumab, pinatuzumab, cotuximab, eupifituzumab, indatuximab, miratumumab, lovatuzumab, enroku, tesotumomab, tetuzumab, dicituzumab, terituzumab, and antigen-binding fragments thereof. In some embodiments, the tumor antigen targeting antibody in the TopI ADC is selected from hLL1, hLL2, RFB4, hA19, hA20, hRS7, hPAM4, hMN-3, hMN-14, hMu-9, hR1, CC49, hL243, D2 / B, hImmu-31, and antigen-binding fragments thereof. In some embodiments, the drug-antibody ratio (DAR) of CL2A-SN38 to the anti-Trop-2 antibody in the anti-Trop2 ADC is ≥7.5 (e.g., DAR=7.6). In some embodiments, the anti-Trop-2 ADC includes the anti-Trop-2 antibody saccharotuzumab (hRS7, described in, e.g., Figures 3 and 4 of WO2003074566). In some embodiments, the TopI ADC is trastuzumab derutin. In some embodiments, the adenosine pathway inhibitor is a CD39 inhibitor, a CD73 inhibitor, or an adenosine receptor antagonist. In some embodiments, the CD39 inhibitor is selected from TTX-030 (AbbVie / Trishula), IPH5201 (AstraZeneca / Innate Pharma), SRF617 (Surface Oncology), CD39 ASO (Secarna Pharmaceuticals), JS-019 (Shanghai Junshi Biosciences), anti-CD39 (Arcus Biosciences), ES002 (Elpiscience Biopharmaceuticals), and CD39xPD1 (Biotheus).In some embodiments, the CD73 inhibitor is selected from olelumab (AstraZeneca), BMS-986179 (BMS), ulelimab (I-MAB Biopharma), AK119 (Akeso Biopharma), quemliclustat (AB680, Arcus Biosciences), mopalimumab (Corvus Pharmaceuticals), HLX23 (Shanghai HenliusBiotech), INCA00186 (Incyte), IBI325 (Innovent Bio), NZV930 (Novartis / Surface Oncology), ORIC-533 (ORIC Pharma), Sym024 (Servier), IPH5301 (Innate), IOA-237 (iOnctura), JAB-BX100 (Jacobio), PT199 (Phanes Therapeutics), TRB010 (Trican Biotechnology), CD73 ASO (Secarna Pharmaceuticals), 622 (3SBio), ABSK-051 (Abbisko Therapeutics), AK131 (CD73xPD1, Akeso Biopharma), CD73i (Aurigene), BR101 (BioRay), BP1200 (BrightPath), CB708 (Antengene / Calithera), GB7002 (Genbase Bio), ATG-037 (Antengene), and CD73i (Biotheus). In some embodiments, the CD73 inhibitor is olerumumab or quiliclostat. In some embodiments, the CD73 inhibitor is quiliclostat. In some embodiments, the adenosine receptor antagonist is an adenosine A2A receptor (A2AR; ADORA2A) selective antagonist, such as imadinam (AstraZeneca), NIR178 (Novartis / Palobiofarma) ID11902 (Ildong), IN-A003 (Inno.n), NTI-55 (A2aR / TLR7, Nammi), TT-10 (Tarus Therapeutics) or TT-228 (Teon Therapeutics).In some embodiments, the adenosine receptor antagonist is an adenosine A2B receptor (A2BR; ADORA2B) antagonist, such as PBF-1129 (Palobiofarma) or TT-702 (Teon Therapeutics). In some embodiments, the adenosine receptor antagonist is a dual adenosine A2A / A2B receptor antagonist, such as eldinan (AB928, Arcus Biosciences), INCB106385 (Incyte), M1069 (Merck KGaA), A2aR / A2bR (Domain / Merck KGaA), HM87277 (A1 / A2aR / A2bR, Hanmi Pharmaceutical), RVU-330 (Ryvu), TT-53 (Tarus Therapeutics). In some embodiments, the methods provided herein also include co-administration of additional therapeutic agents or treatments, or combinations thereof. In some embodiments, additional therapeutic agents include immune checkpoint inhibitors. In some embodiments, CPI includes anti-PD(L)1 antibody (e.g., anti-PD-1 antibody or anti-PD-L1 antibody), and optionally anti-TIGIT antibody. In some embodiments, anti-PD(L)1 antibody is selected from pembrolizumab, nivolumab, cemiprilimab, pidilizumab, spartalizumab, atezolizumab, avelumab, durvalumab, coxilimab, sazanlizumab, tislelizumab, rivulimumab, batilizumab, toripalimab, cetrilimumab, genorumab, palolizumab, lodalimab, carrelizumab, budigalimumab, avelumab, dotalimumab, enwolimumab, sindilimumab and sepalimab. In some embodiments, anti-PD(L)1 antibody is sepalimab. In some embodiments, the anti-TIGIT antibody is selected from tislelizumab, vebrolimumab, dunalimab, AB308, AK127, BMS-986207, rapasumab and atilizumab. In some embodiments, the anti-TIGIT antibody is dunalimab. In some embodiments, the additional therapeutic agent includes an anti-PD(L)1 antibody and an anti-TIGIT antibody. In some embodiments, the additional therapeutic agent includes a) sepalizumab and dunalimab, b) sepalizumab and AB308, c) atilizumab and tislelizumab, d) pembrolizumab and vbolimumab, e) MK-7684A (pembrolizumab / vebrolimumab co-formulation), f) durvalumab and dunalimab, g) sepalizumab and rapasumab, or h) pembrolizumab and rapasumab. In some embodiments, the anti-PD(L)1 antibody is sepalizumab and the anti-TIGIT antibody is dunalimumab. In some embodiments, the additional treatment modality comprises surgery or radiation therapy.In some embodiments, the tumor antigen-positive cancer is positive for a tumor antigen selected from the group consisting of carbonic anhydrase IX, B7, CCCL19, CCCL21, CSAp, HER-2 / neu, BrE3, CD1, CD1a, CD2, CD3, CD4, CD5, CD8, CD11A, CD14, CD15, CD16, CD18, CD19, CD20, CD21, CD22, CD23, CD25, CD29, CD30, CD32b, CD33, CD37, CD38, CD40, CD40L, CD 44, CD45, CD46, CD52, CD54, CD55, CD59, CD64, CD67, CD70, CD74, CD79a, CD80, CD83, CD95, CD126, CD133, CD138, CD147, CD154, CEACAM5, CEACAM-6, alpha-fetoprotein (AFP), VEGF, ED-B fibronectin, EGP-1, EGP-2, EGF receptor (ErbB1), ErbB2, ErbB3, factor H, FHL-1, Flt-3, folate receptor, Ga 733, GROB, HMGB-1, hypoxia-inducible factor (HIF), HM1.24, HER-2 / neu, insulin-like growth factor (ILGF), IFN-a, IFN-b, IL-g, IL-2R, IL-4R, IL-6R, IL-13R, IL-15R, IL-17R, IL-18R, IL-2, IL-6, IL-8, IL-12, IL-15, IL-17, IL-18, IL-25, IP-10, IGF-1R, Ia, HM1.24, gangliosides, HCG, HLA-DR, CD66a-d, MAGE, mCRP, MCP-1, MIP-1A, MIP-1B, macrophage migration inhibitory factor MIF, MUC1, MUC2, MUC3, MUC4, MUC5, placental growth factor (P1GF), PSA (prostate-specific antigen), PSMA, PSMA dimer, PAM4 antigen, NCA-95, NCA-90, A3, A33, Ep-CAM, KS-1, Le(y), mesothelin, S100, tenascin, TAC, Tn antigen, Thomas-Friedenreich antigen, tumor necrosis antigen, tumor angiogenesis antigen, TNF-a, TRAIL receptor (R1 and R2), VEGFR, RANTES, T101, cancer stem cell antigen, complement factors C3, C3a, C3b, C5a, C5, and oncogene products.

[0267] The general dosages, administration regimens, and pharmaceutical compositions of the antibody-drug conjugates, adenosine pathway inhibitors, and additional therapeutic agents that can be used in the methods provided herein are known to the skilled person. For example, the general dosages, administration regimens, and pharmaceutical compositions of exemplary ADCs including gosatuzumab are described in WO2014 / 092804A1, the general dosages, administration regimens, and pharmaceutical compositions of exemplary CD73 inhibitors including queliclostra are described in WO2017120508, the general dosages, administration regimens, and pharmaceutical compositions of exemplary adenosine receptor antagonists including eltridinam are described in WO2018136700A1, and the general dosages, administration regimens, and pharmaceutical compositions of exemplary anti-PD(L)1 antibodies including sepali monoclonal antibody are described in WO2017025051A1.

[0268] In the methods provided herein, ADC (e.g., gosatuzumab), adenosine pathway inhibitors (e.g., edrinam, queliklusit) and optionally anti-PD(L)1 antibodies (e.g., sepali monoclonal antibody) can be co-administered simultaneously, continuously or sequentially. In some embodiments, ADC (e.g., gosatuzumab), adenosine pathway inhibitors (e.g., edrinam, queliklusit) and optionally anti-PD(L1) antibodies (e.g., sepali monoclonal antibody) are co-administered on the same day (e.g., on day 1 of a 21-day treatment cycle). In some embodiments, ADC (e.g., gosatuzumab), adenosine pathway inhibitors (e.g., edrinam, queliklusit) and optionally anti-PD(L1) antibodies (e.g., sepali monoclonal antibody) are co-administered sequentially or continuously. In some embodiments, ADC (e.g., gosatuzumab), an adenosine pathway inhibitor (e.g., eitridinam, quetiapine), and optionally an anti-PD(L1) antibody (e.g., sepalizumab) are co-administered sequentially. In some embodiments, gosatuzumab and eitridinam are co-administered sequentially on day 1 of a 21-day treatment cycle, wherein eitridinam is co-administered orally at least 30 minutes before the start of an intravenous infusion of gosatuzumab. In some embodiments, gosatuzumab, eitridinam, and sepalizumab are co-administered sequentially on day 1 of a 21-day treatment cycle, wherein eitridinam is co-administered orally at least 30 minutes before the start of an intravenous infusion of sepalizumab, and gosatuzumab is co-administered intravenously after the completion of the sepalizumab infusion.

[0269] In some embodiments of the methods provided herein, gosartuzumab is co-administered on the 1st and 8th day of a 21-day treatment cycle. In some embodiments, gosartuzumab is co-administered intravenously (IV). In some embodiments, gosartuzumab is co-administered at a dosage of 8mg / kg to 10mg / kg. In some embodiments, gosartuzumab is co-administered at a dosage of 8mg / kg or 10mg / kg. In some embodiments, gosartuzumab is co-administered at a dosage of 10mg / kg. In some embodiments, gosartuzumab is co-administered intravenously (IV) at a dosage of 8mg / kg or 10mg / kg on the 1st and 8th day of a 21-day treatment cycle.

[0270] In some embodiments of the methods provided herein, eltrodinam is co-administered once daily (QD). In some embodiments, eltrodinam is co-administered orally (PO). In some embodiments, eltrodinam is co-administered at a dose of 75 mg or 150 mg. In some embodiments, eltrodinam is co-administered at a dose of 150 mg. In some embodiments, eltrodinam is co-administered orally (PO) at a dose of 75 mg or 150 mg once daily (QD). In some embodiments, eltrodinam is co-administered orally (PO) at a dose of 150 mg once daily (QD).

[0271] In some embodiments of the methods provided herein, an anti-PD(L)1 antibody (e.g., sepalizumab) is co-administered once every three weeks (Q3W). In some embodiments, the anti-PD(L)1 antibody is co-administered intravenously (IV). In some embodiments, the anti-PD(L)1 antibody is co-administered at a dose of 360 mg.

[0272] In some embodiments of the methods provided herein, gosatuzumab is co-administered intravenously (IV) at a dose of 8 mg / kg or 10 mg / kg on Days 1 and 8 of a 21-day treatment cycle; ezetimibe is co-administered orally (PO) once daily (QD) at a dose of 75 mg or 150 mg on each day of the 21-day treatment cycle, and optionally, sepalizumab is co-administered at a dose of 360 mg on Day 1 of a 21-day treatment cycle (Q3W).

[0273] In some embodiments of the methods provided herein, gosatuzumab is co-administered at a dose of 10 mg / kg intravenously (IV) on days 1 and 8 of a 21-day treatment cycle; ezetimibe is co-administered orally (PO) at a dose of 150 mg once a day (QD) on each day of a 21-day treatment cycle, and optionally, sepalizumab is co-administered at a dose of 360 mg on day 1 of a 21-day treatment cycle (Q3W).

[0274] In some embodiments, the methods provided herein have an anti-cancer effect as determined by one or more efficacy endpoints selected from the following: objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), duration of remission (DOR), overall survival (OS), complete remission (CR), partial remission (PR), PSA remission rate, radiographic remission rate, and changes from baseline in blood and tumor tissue microenvironment pharmacodynamic (PD) biomarkers. In some embodiments, tumor remission or progression is determined according to RECIST version 1.1. In some embodiments, ORR is defined as the composite proportion of participants with PSA and / or radiographic complete and partial remission determined by the investigator according to the Prostate Cancer Working Group 3 (PCWG3) criteria. In some embodiments, PSA remission is defined as the proportion of participants with a PSA decrease of more than 50% from baseline based on 2 consecutive assessments measured at least 3 to 4 weeks apart. In some embodiments, radiographic response is defined as the proportion of participants with the best overall remission of CR or PR according to RECIST v1.1. In some embodiments, DCR is defined as the ratio of participants with CR, PR or disease stability (SD) best overall RECIST remission. In some embodiments, DCR is at least 6 months. In some embodiments, PFS is defined as the time from the distribution of treatment until the first recording of disease progression (PSA progression, radiographic progression, bone scan progression or other progression) or death (whichever occurs first). Depending on data availability, the time to the progression caused by a specific reason (for example, PSA progression or radiographic progression) can also be presented separately. In some embodiments, OS is defined as the time from the distribution of treatment until death due to any reason.

[0275] In some embodiments, the methods provided herein also include determining the expression level of a tumor antigen (e.g., Trop-2) in a sample from a subject. Determining the expression level of a tumor antigen (e.g., Trop-2) can be performed using any clinical analysis method known to a technician. The sample may include a liquid biopsy sample (e.g., a blood sample) and a solid tumor biopsy sample. The expression level of a tumor antigen (e.g., Trop-2) can be determined at the DNA, RNA, or protein level. Illustrative methods for determining the expression level of a tumor antigen (e.g., Trop-2) include Western blotting, immunohistochemistry, QPCR, exome sequencing, FACS, and the like.

[0276] In some embodiments of the methods provided herein, an anti-CD47 antibody is not co-administered to a subject or human patient (CD47; Integrin-associated protein; IAP; NCBI Gene ID: 961). In some embodiments, the subject or human patient is not co-administered an anti-CD47 antibody selected from the group consisting of mololimab, leszolimab, lestaprilimab, lesfalimab, AO-176, IBI-322, ZL-1201, IMC-002, SRF-231, CC-90002 (also known as INBRX-103), NI-1701 (also known as TG-1801), and STI-6643. In some embodiments, the subject or human patient is not co-administered mololimab.

[0277] In some embodiments of the methods provided herein, no MCL1 inhibitor is co-administered to a subject or human patient (MCL1; myeloid leukemia cell differentiation protein; NCBI Gene ID: 4170). In some embodiments, the subject or human patient is not co-administered with an MCL1 inhibitor selected from GS-9716, AMG-397, AMG-176, PRT-1419, and S6431. In some embodiments, the subject or human patient is not co-administered with GS-9716.

[0278] In some embodiments of the methods provided herein, a FLT3 agonist is not co-administered to a subject or human patient (FLT3; fms-like tyrosine kinase; CD135; NCBI Gene ID: 2322). In some embodiments, the FLT3 agonist is selected from GS-3583, CDX-301, TAK-605, ONCR-177, Alb-Ftl3L, and SYM-027. In some embodiments, the FLT3 agonist is GS-3583.

[0279] Reagent test kit

[0280] Provided herein is a kit for use as a medicament, wherein the kit comprises: a) a TROP-2 targeting antibody-drug conjugate (ADC) comprising an anti-TROP-2 antibody (anti-TROP-2 ADC); b) an adenosine pathway inhibitor; and c) optionally, an anti-PD-(L)1 antibody.

[0281] Also provided herein is a kit for use as a medicament, wherein the kit comprises: a) a tumor antigen (TA)-targeted ADC (TopI ADC) comprising a topoisomerase I inhibitor; b) an adenosine pathway inhibitor; and c) optionally, an anti-PD-(L)1 antibody.

[0282] Also described herein are kits that include one or more unit doses of an active agent, such as a) an anti-Trop-2 ADC (e.g., gosatuzumab) or a TopI ADC; b) an adenosine pathway inhibitor (e.g., eitridinam, quiliclastat); optionally c) an anti-PD(L)1 antibody (e.g., sepalitumab) and formulations thereof as described herein, and instructions for use. In various embodiments, a) an anti-Trop-2 ADC (e.g., gosatuzumab) or a TopI ADC; b) an adenosine pathway inhibitor (e.g., eitridinam, quiliclastat); and optionally c) an anti-PD(L)1 antibody (e.g., sepalitumab) may be in the same or different containers. The kit may also include at least one additional reagent, such as an anti-TIGIT antibody. The kit typically includes a label indicating the intended use of the contents of the kit. The term "label" includes any written or recorded material provided on or with the kit, or otherwise accompanying the kit.

[0283] In some embodiments, a) anti-Trop-2 ADC (e.g., gosatuzumab) or TopI ADC; b) adenosine pathway inhibitor (e.g., edrinam, queliclostat); and optionally c) anti-PD(L)1 antibody (e.g., sepalizumab) is provided in a dosage form (e.g., a therapeutically effective dosage form). In some embodiments, one or more of a) anti-Trop-2 ADC (e.g., gosatuzumab) or TopI ADC; b) adenosine pathway inhibitor (e.g., edrinam, queliclostat); and optionally c) anti-PD(L)1 antibody (e.g., sepalizumab) is provided in two or more different dosage forms (e.g., two or more different therapeutically effective dosage forms). In the context of a kit, one or more of a) an anti-Trop-2 ADC (e.g., gosartuzumab) or TopI ADC; b) an adenosine pathway inhibitor (e.g., edrinam, quetiapine); and optionally c) an anti-PD(L)1 antibody (e.g., sepalizumab) can be provided in liquid or solid form in any convenient packaging (e.g., stick packs, dosage packs, etc.).

[0284] a) anti-Trop-2 ADC (e.g., gosatuzumab) or TopI ADC; b) an adenosine pathway inhibitor (e.g., edrinam, queliclostra); and optionally c) an anti-PD(L)1 antibody (e.g., sepalizumab) may be provided in the same container or in separate containers, as appropriate. In various embodiments, a) an anti-Trop-2 ADC (e.g., gosatuzumab) or TopI ADC; b) an adenosine pathway inhibitor (e.g., edrinam, queliclostra); and optionally c) an anti-PD(L)1 antibody (e.g., sepalizumab) are provided in separate containers. A composition comprising one or more of a) an anti-Trop-2 ADC (e.g., gosartuzumab) or a TopI ADC; b) an adenosine pathway inhibitor (e.g., edritinam, quetiapine); and optionally c) an anti-PD(L)1 antibody (e.g., sepalizumab) is provided in one or more containers having a label. Suitable containers include, for example, bottles, vials, ampoules, syringes (including prefilled syringes), and test tubes. The container can be formed from a variety of materials, such as glass or plastic. The container holds a composition that is effective in treating a condition and can have a sterile access port (e.g., the container can be an intravenous infusion bag or a vial with a stopper that can be pierced by a hypodermic needle). The active agent in one composition is a) an anti-Trop-2 ADC (e.g., gosartuzumab) or a TopI ADC. The active agent in the second composition is an adenosine pathway inhibitor (e.g., edritinam, quetiapine). The active agent in the optional third composition is optionally c) an anti-PD(L)1 antibody (e.g., sepalizumab). A label on or associated with the container indicates that the composition is used to treat a selected condition. The article of manufacture may also include one or more containers containing a pharmaceutically acceptable buffer, for example, used as a diluent. Illustrative buffers include, but are not limited to, phosphate-buffered saline, Ringer's solution, and / or dextrose solution. The kit may also include other materials desired from a commercial and user perspective, including other buffers, diluents, filters, needles, syringes, and a package insert with instructions for use.

[0285] In addition to the above-mentioned components, the subject test kit can also include (in certain embodiments) instructions for implementing the subject method. These instructions can be present in the subject test kit in various forms, one or more of which can be present in the test kit. A form in which these instructions can exist is as the following printed information: printed information on suitable medium or substrate (for example, one or more sheets of paper on which this information is printed), printed information in the packaging material of test kit, printed information in package instructions etc. The another form of these instructions is the computer-readable medium on which this information has been recorded, for example, disk, CD (CD), flash drive etc. Another form in which these instructions can exist is the website address that can be used to access the information at the remote site via the Internet.

[0286] Exemplary embodiments

[0287] In some embodiments, a method for treating metastatic castration-resistant prostate cancer (mCRPC) is provided herein, comprising co-administering an effective amount of the following substances to a human patient: a) gosatuzumab; and b) edrinam. In some embodiments, the method further comprises co-administering sepali monoclonal antibody to a human patient. In some embodiments, human mCRPC patients have previously progressed while undergoing androgen deprivation therapy (ADT). In some embodiments, human mCRPC patients have previously progressed while using one or more next-generation hormone agents (NHA, such as abiraterone, enzalutamide, darolutamide, apalutamide). In some embodiments, human mCRPC patients have not received checkpoint inhibitors (CPIs) and taxanes. In some embodiments, human mCRPC patients suffer from RECIST 1.1 measurable or unmeasurable disease.

[0288] In some embodiments, provided herein is a method of treating castration-resistant prostate cancer (CRPC), comprising co-administering to a human patient an effective amount of: a) an anti-Trop-2 ADC;

[0289] b) a CD73 inhibitor or an adenosine receptor antagonist; and optionally, c) an anti-PD(L)1 antibody. In some embodiments, the CRPC is metastatic CRPC (mCRPC). In some embodiments, the anti-Trop-2 ADC has the structural formula mAb-CL2A-SN-38, which is represented by the following formula:

[0290]

[0291] (described, e.g., in USPN 7,999,083). In some embodiments, the drug-antibody ratio (DAR) of CL2A-SN38 to anti-Trop-2 antibody in the anti-Trop2 ADC is between 7.0 and 8.0 (e.g., DAR=7.6). In some embodiments, the anti-Trop-2 ADC includes a linker-payload conjugate having a structure represented by the following formula:

[0292]

[0293] Attached to an anti-Trop-2 antibody (e.g., hRS7). In some embodiments, the anti-Trop-2 ADC includes a linker-payload conjugate (TL035) having a structure represented by the following formula:

[0294]

[0295] Attached to an anti-Trop-2 antibody (e.g., hRS7). In some embodiments, the anti-Trop-2 ADC includes a linker-payload conjugate having a structure represented by the following formula:

[0296]

[0297] Attached to an anti-Trop-2 antibody (e.g., hTINA1-H1L1). In some embodiments, the anti-Trop-2 ADC has a DAR of about 4. In some embodiments, the anti-Trop-2 ADC is selected from gosatuzumab, dedabatuzumab derutec (DS-1062), ESG-401, SKB-264, DAC-02, and BAT-8003. In some embodiments, the anti-Trop-2 antibody is gosatuzumab or dedabatuzumab derutec. In some embodiments, the anti-Trop-2 antibody is gosatuzumab. In some embodiments, the CD73 inhibitor is selected from olelumab (AstraZeneca), BMS-986179 (BMS), ulelimab (I-MAB Biopharma), AK119 (Akeso Biopharma), quemliclustat (AB680, Arcus Biosciences), mopalimumab (Corvus Pharmaceuticals), HLX23 (Shanghai Henlius Biotech), INCA00186 (Incyte), IBI325 (Innovent Bio), NZV930 (Novartis / Surface Oncology), ORIC-533 (ORIC Pharma), Sym024 (Servier), IPH5301 (Innate), IOA-237 (iOnctura), JAB-BX100 (Jacobio), PT199 (Phanes Therapeutics), TRB010 (Trican Biotechnology), CD73 ASO (Secarna Pharmaceuticals), 622 (3Sbio), ABSK-051 (AbbiskoTherapeutics), AK131 (CD73xPD1, Akeso Biopharma), CD73i (Aurigene), BR101 (BioRay), BP1200 (BrightPath), CB708 (Antengene / Calithera), GB7002 (Genbase Bio), ATG-037 (Antengene), and CD73i (Biotheus). In some embodiments, the CD73 inhibitor is selected from olerumumab and quetiapine. In some embodiments, the CD73 inhibitor is quetiapine.In some embodiments, the adenosine receptor antagonist is an adenosine A2A receptor (A2AR; ADORA2A) selective antagonist, such as imadinam (AstraZeneca), NIR178 (Novartis / Palobiofarma) ID11902 (Ildong), IN-A003 (Inno.n), NTI-55 (A2aR / TLR7, Nammi), TT-10 (Tarus Therapeutics) or TT-228 (Teon Therapeutics). In some embodiments, the adenosine receptor antagonist is an adenosine A2B receptor (A2BR; ADORA2B) antagonist, such as PBF-1129 (Palobiofarma) or TT-702 (Teon Therapeutics). In some embodiments, the adenosine receptor antagonist is a dual adenosine A2A / A2B receptor antagonist such as edredinam (AB928, Arcus Biosciences), INCB106385 (Incyte), M1069 (Merck KgaA), A2aR / A2bR (Domain / Merck KgaA), HM87277 (A1 / A2aR / A2bR, Hanmi Pharmaceutical), RVU-330 (Ryvu) and TT-53 (Tarus Therapeutics). In some embodiments, the adenosine receptor antagonist is edredinam. In some embodiments, the anti-PD(L)1 antibody is selected from pembrolizumab, nivolumab, cemiprilimab, pidilizumab, spartalizumab, atezolizumab, avelumab, durvalumab, cocilimab, sazanlimab, tislelizumab, rivulimab, batilizumab, toripalimab, cetrilimab, genoluzumab, palolizumab, lodalizumab, carrelizumab, budigalimab, avelumab, dotalimumab, envolimab, sintilimab and sepalizumab. In some embodiments, the anti-PD(L)1 antibody is sepalizumab. In some embodiments, the human patient is not co-administered with an additional therapeutic agent selected from an MCL-1 inhibitor, an anti-CD47 antibody and a FLT3 agonist.

[0298] In some embodiments, provided herein is a method for treating castration-resistant prostate cancer (CRPC), comprising co-administering to a human patient an effective amount of the following substances: a) gosartuzumab; and b) edrolactam. In some embodiments, CRPC is metastatic CRPC (mCRPC). In some embodiments, CRPC or mCRPC ((m)CRPC) is resistant to at least one anticancer therapy, or is refractory to at least one anticancer therapy. In some embodiments, the human patient has shown disease progression after previous treatment with a novel hormonal agent (NHA; first or second generation nonsteroidal antiandrogen, abiraterone, enzalutamide, darolutamide, apalutamide). In some embodiments, the human patient has not received previous taxane therapy (e.g., paclitaxel, nab-paclitaxel). docetaxel, cabazitaxel), checkpoint inhibitor therapy (e.g., anti-CTLA4 antibody, anti-PD(L)1 antibody), topoisomerase I inhibitor therapy (e.g., irinotecan). In some embodiments, the (m)CRPC human patient has histologically confirmed prostate adenocarcinoma and has metastatic castration-resistant tumor progression while undergoing androgen deprivation therapy (ADT; including orchiectomy), wherein the serum (total) testosterone castrate level (≤1.7 nmol / L or 50 ng / dL) is defined by PSA and / or radiographic criteria according to PCWG3. In some embodiments, the human (m)CRPC patient has metastatic castration-resistant prostate adenocarcinoma with tumor progression while undergoing androgen deprivation therapy (e.g., including orchiectomy), wherein the serum (total) testosterone castrate level (≤1.7 nmol / L or 50 ng / dL) is defined by prostate-specific antigen (PSA) and / or radiographic criteria according to the Prostate Cancer Working Group 3 (PCWG3), and has measurable or non-measurable disease according to the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. In some embodiments, the human patient with (m)CRPC has an Eastern Cooperative Oncology Group performance status of 0 or 1 and a life expectancy of ≥3 months. In some embodiments, the human patient with (m)CRPC has been tested for tumor antigen (e.g., Trop-2) expression levels (e.g., liquid or solid tumor biopsy followed by tumor antigen expression analysis, e.g., by IHC or next-generation DNA sequencing). In some embodiments, gosatuzumab is administered intravenously (IV) at a dose of 8 mg / kg or 10 mg / kg on the 1st and 8th day of a 21-day treatment cycle, and edredinan is administered orally (PO) once a day (QD) at a dose of 75 mg or 150 mg on each day of a 21-day treatment cycle. In some embodiments, gosatuzumab is administered intravenously (IV) at a dose of 10 mg / kg on the 1st and 8th day of a 21-day treatment cycle, and edredinan is administered orally (PO) once a day (QD) at a dose of 150 mg on each day of a 21-day treatment cycle. In some embodiments, the method provided herein has an anti-cancer effect as determined by one or more efficacy endpoints selected from the following: objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), complete remission (CR), partial remission (PR), PSA remission rate, radiographic remission rate, and changes from baseline in blood and tumor tissue microenvironment pharmacodynamics (PD) biomarkers. In some embodiments, ORR is defined as the composite proportion of participants with PSA and / or radiographic complete and partial responses as determined by the investigator according to Prostate Cancer Working Group 3 (PCWG3) criteria.In some embodiments, PSA remission is defined as the proportion of participants with a PSA decrease of more than 50% from baseline based on 2 consecutive assessments measured at least 3 to 4 weeks apart. In some embodiments, radiographic response is defined as the proportion of participants with the best overall remission of CR or PR according to RECIST v1.1. In some embodiments, DCR is defined as the proportion of participants with the best overall RECIST remission of CR, PR or disease stability (SD). In some embodiments, DCR is at least 6 months. In some embodiments, PFS is defined as the time from the distribution of treatment until the first recorded disease progression (PSA progression, radiographic progression, bone scan progression or other progression) or death (whichever occurs first). Depending on data availability, the time to progression caused by a specific reason (e.g., PSA progression or radiographic progression) can also be presented separately. In some embodiments, OS is defined as the time from the distribution of treatment until death due to any reason. In some embodiments, human patients are not co-administered with additional therapeutic agents selected from MCL-1 inhibitors, anti-CD47 antibodies and FLT3 agonists.

[0299] In some embodiments, provided herein is a method for treating castration-resistant prostate cancer (CRPC), comprising co-administering to a human patient an effective amount of the following substances: a) gosartuzumab; b) edrinam and c) sepalizumab. In some embodiments, CRPC is metastatic CRPC (mCRPC). In some embodiments, CRPC or mCRPC ((m)CRPC) is resistant to at least one anticancer therapy, or is refractory to at least one anticancer therapy. In some embodiments, the human patient has shown disease progression after prior treatment with a novel hormonal agent (NHA; first or second generation nonsteroidal antiandrogen, such as abiraterone, enzalutamide, darolutamide, apalutamide). In some embodiments, the human patient has not received prior taxane therapy (e.g., paclitaxel, nab-paclitaxel). docetaxel, cabazitaxel), checkpoint inhibitor therapy (e.g., anti-CTLA4 antibody, anti-PD(L)1 antibody), topoisomerase I inhibitor therapy (e.g., irinotecan). In some embodiments, the (m)CRPC human patient has histologically confirmed prostate adenocarcinoma and has metastatic castration-resistant tumor progression while undergoing androgen deprivation therapy (ADT; including orchiectomy), wherein the serum (total) testosterone castrate level (≤1.7 nmol / L or 50 ng / dL) is defined by PSA and / or radiographic criteria according to PCWG3. In some embodiments, the human (m)CRPC patient has metastatic castration-resistant prostate adenocarcinoma with tumor progression while undergoing androgen deprivation therapy (e.g., including orchiectomy), wherein the serum (total) testosterone castrate level (≤1.7 nmol / L or 50 ng / dL) is defined by prostate-specific antigen (PSA) and / or radiographic criteria according to the Prostate Cancer Working Group 3 (PCWG3), and has measurable or non-measurable disease according to the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. In some embodiments, the human patient with (m)CRPC has an Eastern Cooperative Oncology Group performance status of 0 or 1 and a life expectancy of ≥3 months. In some embodiments, the human patient with (m)CRPC has been tested for tumor antigen (e.g., Trop-2) expression levels (e.g., liquid or solid tumor biopsy followed by tumor antigen expression analysis, e.g., by IHC or next-generation DNA sequencing). In some embodiments, gosatuzumab is administered intravenously (IV) at a dose of 8 mg / kg or 10 mg / kg on days 1 and 8 of a 21-day treatment cycle, edritinam is administered orally (PO) once daily (QD) at a dose of 75 mg or 150 mg on each day of a 21-day treatment cycle, and sepalizumab is administered at a dose of 360 mg on day 1 of a 21-day treatment cycle (Q3W). In some embodiments, gosatuzumab is administered intravenously (IV) at a dose of 10 mg / kg on days 1 and 8 of a 21-day treatment cycle, edritinam is administered orally (PO) once daily (QD) at a dose of 150 mg on each day of a 21-day treatment cycle, and sepalizumab is administered at a dose of 360 mg on day 1 of a 21-day treatment cycle (Q3W). In some embodiments, the methods provided herein have an anti-cancer effect as determined by one or more efficacy endpoints selected from the group consisting of objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), complete response (CR), partial response (PR), PSA response rate, radiographic response rate, and changes from baseline in blood and tumor tissue microenvironment pharmacodynamic (PD) biomarkers.In some embodiments, ORR is defined as the composite proportion of participants with PSA and / or radiographic complete and partial remission determined by the investigator according to the Prostate Cancer Working Group 3 (PCWG3) criteria. In some embodiments, PSA remission is defined as the proportion of participants with a PSA decrease of more than 50% from baseline based on 2 consecutive assessments measured at least 3 to 4 weeks apart. In some embodiments, radiographic response is defined as the proportion of participants with CR or PR best overall remission according to RECIST v1.1. In some embodiments, DCR is defined as the proportion of participants with CR, PR or disease stable (SD) best overall RECIST remission. In some embodiments, DCR is at least 6 months. In some embodiments, PFS is defined as the time from the assignment of treatment until the first recorded disease progression (PSA progression, radiographic progression, bone scan progression or other progression) or death (whichever occurs first). Depending on data availability, the time to progression due to a specific cause (e.g., PSA progression or radiographic progression) may also be presented separately. In some embodiments, OS is defined as the time from the assignment of treatment until death due to any cause. In some embodiments, the human patient is not co-administered an additional therapeutic agent selected from an MCL-1 inhibitor, an anti-CD47 antibody, and a FLT3 agonist.

[0300] In some embodiments, provided herein is a method for treating metastatic non-small cell lung cancer (mNSCLC), comprising co-administering to a human mNSCLC patient an effective amount of the following: a) gosartuzumab; b) edrinam; and c) an anti-PD-(L)1 antibody. In some embodiments, the anti-PD-(L)1 antibody is selected from the group consisting of pembrolizumab, nivolumab, cemiprilimab, pidilizumab, spartalizumab, atezolizumab, avelumab, durvalumab, cocilimab, sazanlimab, tislelizumab, rivulimab, batilizumab, toripalimab, sitrilimab, genoluzumab, palolizumab, lodalizumab, carrelizumab, budigalimab, avelumab, dotalimumab, envolimab, sintilimab and sepalizumab. In some embodiments, the anti-PD-(L) 1 antibody is sepali monoclonal antibody. In some embodiments, the human mNSCLC patient has progressed after platinum-based chemotherapy. In some embodiments, the human mNSCLC patient has progressed after checkpoint inhibitor therapy (e.g., anti-PD-(L) 1 antibody or anti-CTLA4 antibody therapy). In some embodiments, the human mNSCLC patient has progressed after receiving platinum-based chemotherapy and anti-PD-(L) 1 antibody therapy in combination or sequentially (in any order). In some embodiments, the human mNSCLC patient has not received treatment.

[0301] In some embodiments, provided herein is a method for treating non-small cell lung cancer (NSCLC), comprising co-administering to a human patient an effective amount of: a) an anti-Trop-2 ADC; b) a CD73 inhibitor or an adenosine receptor antagonist; and optionally, c) an anti-PD(L)1 antibody. In some embodiments, the NSCLC is metastatic NSCLC (mNSCLC). In some embodiments, the anti-Trop-2 ADC has the structural formula mAb-CL2A-SN-38, the structure of which is represented by the following formula:

[0302]

[0303] (described, e.g., in USPN 7,999,083). In some embodiments, the drug-antibody ratio (DAR) of CL2A-SN38 to anti-Trop-2 antibody in the anti-Trop2 ADC is between 7.0 and 8.0 (e.g., DAR=7.6). In some embodiments, the anti-Trop-2 ADC includes a linker-payload conjugate having a structure represented by the following formula:

[0304]

[0305] Attached to an anti-Trop-2 antibody (e.g., hRS7). In some embodiments, the anti-Trop-2 ADC includes a linker-payload conjugate (TL035) having a structure represented by the following formula:

[0306]

[0307] Attached to an anti-Trop-2 antibody (e.g., hRS7). In some embodiments, the anti-Trop-2 ADC includes a linker-payload conjugate having a structure represented by the following formula:

[0308]

[0309] Attached to an anti-Trop-2 antibody (e.g., hTINA1-H1L1). In some embodiments, the anti-Trop-2 ADC has a DAR of about 4. In some embodiments, the anti-Trop-2 ADC is selected from gosatuzumab, dedabatuzumab derutec (DS-1062), ESG-401, SKB-264, DAC-02, and BAT-8003. In some embodiments, the anti-Trop-2 antibody is gosatuzumab or dedabatuzumab derutec. In some embodiments, the anti-Trop-2 antibody is gosatuzumab. In some embodiments, the CD73 inhibitor is selected from olelumab (AstraZeneca), BMS-986179 (BMS), ulelimab (I-MAB Biopharma), AK119 (Akeso Biopharma), quemliclustat (AB680, Arcus Biosciences), mopalimumab (Corvus Pharmaceuticals), HLX23 (Shanghai Henlius Biotech), INCA00186 (Incyte), IBI325 (Innovent Bio), NZV930 (Novartis / Surface Oncology), ORIC-533 (ORIC Pharma), Sym024 (Servier), IPH5301 (Innate), IOA-237 (iOnctura), JAB-BX100 (Jacobio), PT199 (Phanes Therapeutics), TRB010 (Trican Biotechnology), CD73 ASO (Secarna Pharmaceuticals), 622 (3SBio), ABSK-051 (Abbisko Therapeutics), AK131 (CD73xPD1, Akeso Biopharma), CD73i (Aurigene), BR101 (BioRay), BP1200 (BrightPath), CB708 (Antengene / Calithera), GB7002 (Genbase Bio), ATG-037 (Antengene), and CD73i (Biotheus). In some embodiments, the CD73 inhibitor is selected from olerumumab and quetiapine. In some embodiments, the CD73 inhibitor is quetiapine.In some embodiments, the adenosine receptor antagonist is an adenosine A2A receptor (A2AR; ADORA2A) selective antagonist, such as imadinam (AstraZeneca), NIR178 (Novartis / Palobiofarma) ID11902 (Ildong), IN-A003 (Inno.n), NTI-55 (A2aR / TLR7, Nammi), TT-10 (Tarus Therapeutics) or TT-228 (Teon Therapeutics). In some embodiments, the adenosine receptor antagonist is an adenosine A2B receptor (A2BR; ADORA2B) antagonist, such as PBF-1129 (Palobiofarma) or TT-702 (Teon Therapeutics). In some embodiments, the adenosine receptor antagonist is a dual adenosine A2A / A2B receptor antagonist such as edredinam (AB928, Arcus Biosciences), INCB106385 (Incyte), M1069 (Merck KGaA), A2aR / A2bR (Domain / Merck KGaA), HM87277 (A1 / A2aR / A2bR, Hanmi Pharmaceutical), RVU-330 (Ryvu) and TT-53 (Tarus Therapeutics). In some embodiments, the adenosine receptor antagonist is edredinam. In some embodiments, the anti-PD-(L)1 antibody is selected from pembrolizumab, nivolumab, cemiprilimab, pidilizumab, spartalizumab, atezolizumab, avelumab, durvalumab, cocilimab, sazanlimab, tislelizumab, rivulimab, batilizumab, toripalimab, cetrilimab, genoluzumab, palolizumab, lodalizumab, carrelizumab, budigalimab, avelumab, dotalimumab, envolimab, sintilimab and sepalizumab. In some embodiments, the anti-PD-(L)1 antibody is sepalizumab. In some embodiments, the human patient is not co-administered with an additional therapeutic agent selected from an MCL-1 inhibitor, an anti-CD47 antibody and a FLT3 agonist.

[0310] In some embodiments, provided herein is a method for treating non-small cell lung cancer (NSCLC), comprising co-administering to a human patient an effective amount of the following substances: a) gosartuzumab; b) edrinam; and c) an anti-PD-(L)1 antibody. In some embodiments, the anti-PD-(L)1 antibody is selected from the group consisting of pembrolizumab, nivolumab, cemiprilimab, pidilizumab, spartalizumab, atezolizumab, avelumab, durvalumab, cocilimab, sazanlimab, tislelizumab, rivulimab, batilizumab, toripalimab, sitrilimab, genoluzumab, palomundumab, lodalizumab, carrelizumab, budigalimab, avelumab, dotalimumab, envolimab, sintilimab and sepalizumab. In some embodiments, the anti-PD-(L)1 antibody is sepalizumab. In some embodiments, NSCLC is metastatic NSCLC (mNSCLC). In some embodiments, NSCLC or mNSCLC ((m)NSCLC) is resistant to at least one anticancer therapy, or is refractory to at least one anticancer therapy. In some embodiments, human mNSCLC patients have progressed after platinum-based chemotherapy. In some embodiments, human mNSCLC patients have progressed after checkpoint inhibitor therapy (e.g., anti-PD-(L)1 antibody or anti-CTLA4 antibody therapy). In some embodiments, human mNSCLC patients have progressed after receiving platinum-based chemotherapy and anti-PD-(L)1 antibody therapy in combination or sequentially (in any order). In some embodiments, human mNSCLC patients have not received treatment. In some embodiments, human patients with (m)NSCLC have been tested for tumor antigen (e.g., Trop-2) expression levels (e.g., liquid or solid tumor biopsy followed by tumor antigen expression analysis, e.g., by IHC or next-generation DNA sequencing). In some embodiments, gosatuzumab is administered intravenously (IV) at a dose of 8 mg / kg or 10 mg / kg on days 1 and 8 of a 21-day treatment cycle, and edredinan is administered orally (PO) once a day (QD) at a dose of 75 mg or 150 mg on each day of a 21-day treatment cycle. In some embodiments, gosatuzumab is administered intravenously (IV) at a dose of 10 mg / kg on days 1 and 8 of a 21-day treatment cycle, and edredinan is administered orally (PO) once a day (QD) at a dose of 150 mg on each day of a 21-day treatment cycle.In some embodiments, the methods provided herein have an anti-cancer effect as determined by one or more efficacy endpoints selected from the following: objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), duration of remission (DOR), overall survival (OS), complete remission (CR), partial remission (PR), radiographic remission rate, and changes from baseline in blood and tumor tissue microenvironment pharmacodynamic (PD) biomarkers. In some embodiments, tumor remission or progression is determined according to RECIST version 1.1. In some embodiments, human patients are not co-administered with an additional therapeutic agent selected from an MCL-1 inhibitor, an anti-CD47 antibody, and a FLT3 agonist.

[0311] Disclosed herein are methods for treating, alleviating, reducing, preventing or delaying recurrence or metastasis of breast cancer, comprising co-administering to a human patient an effective amount of the following substances: (a) gosartuzumab; and (b) a CD73 inhibitor. In some embodiments, the CD73 inhibitor is olerumumab, BMS-986179, ulelimumab, AK119, queliclostra, mopalimumab, HLX23, INCA00186, IBI325, NZV930, ORIC-533, Sym024, IPH5301, IOA-237, JAB-BX100, PT199, TRB010, CD73 ASO, ABSK-051, AK131, BR101, BP1200, CB708, GB7002 or ATG-037. In some embodiments, the CD73 inhibitor is quelicustat (AB680, GS-0680), ulelimab, mopalimumab, ORIC-533, ATG-037, PT-199, AK131, NZV930, BMS-986179, or olelumab.

[0312] In some embodiments, the CD73 inhibitor is quiliclusstat (AB680, GS-0680).

[0313] In some embodiments, the method further comprises co-administering an anti-PD-(L)1 antibody to the human patient. In some embodiments, the anti-PD-(L)1 antibody is selected from the group consisting of pembrolizumab, nivolumab, cemiprilimab, pidilizumab, spartalizumab, atezolizumab, avelumab, durvalumab, cocilimab, sazanlimab, tislelizumab, rivulimab, batilizumab, toripalimab, cetrilimab, genolumab, palolizumab, lodalimab, carrelizumab, budigalimab, avelumab, dotalimumab, envolimab, sintilimab and sepalimab. In some embodiments, the method further comprises co-administering sepalimab to the human patient. In some embodiments, the breast cancer is metastatic breast cancer. In some embodiments, the breast cancer is resistant to or refractory to one or more anticancer therapies. In some embodiments, the breast cancer has progressed after a previous anticancer therapy (first or second generation anticancer therapy, such as hormone therapy). In some embodiments, the human patient has not received a previous therapy selected from the following: taxane therapy (not taxane-naive), checkpoint inhibitor therapy (not CPI-naive), and topoisomerase I inhibitor therapy. In some embodiments, the human patient has not received a previous taxane therapy (not taxane-naive), checkpoint inhibitor therapy (not CPI-naive), or topoisomerase I inhibitor therapy. In some embodiments, the taxane therapy includes paclitaxel, nab-paclitaxel, or nab-paclitaxel. Docetaxel or cabazitaxel. In some embodiments, checkpoint inhibitor therapy includes anti-CTLA4 antibodies or anti-PD (L) 1 antibodies. In some embodiments, topoisomerase I inhibitor therapy includes topotecan, irinotecan, belotecan or exatecan. In some embodiments, the method provided herein has an anti-cancer effect as determined by one or more efficacy endpoints selected from the following: objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), duration of remission (DOR), overall survival (OS), complete remission (CR), partial remission (PR), radiographic remission rate, and changes from baseline in blood and tumor tissue microenvironment pharmacodynamics (PD) biomarkers. In some embodiments, tumor remission or progression is determined according to RECIST version 1.1. In some embodiments, human patients are not co-administered with additional therapeutic agents selected from MCL-1 inhibitors, anti-CD47 antibodies and FLT3 agonists.

[0314] Example

[0315] The following examples are provided to illustrate but not to limit the claimed invention.

[0316] Example 1

[0317] Trop-2 ADC, adenosine receptor antagonist and PD(L)1 antagonist for metastatic castration-resistant prostate cancer Phase 1 / 2 study of combination therapy

[0318] A clinical study is conducted by administering a combination of an anti-Trop-2 antibody and an adenosine receptor antagonist to human patients with metastatic castration-resistant prostate cancer (mCRPC). Optionally, a subgroup of patients is treated with a combination of an anti-Trop-2 antibody, an adenosine receptor antagonist, and an anti-PD-(L)1 antibody.

[0319] In one arm of the study, human mCRPC patients were treated with a combination of gosartuzumab and edritinam.In an optional additional arm of the study, human mCRPC patients were treated with a combination of gosartuzumab (SG), edritinam, and sepalitumab.

[0320] The patient population in this study can include previously treated mCRPC patients who have progressed on androgen deprivation therapy (ADT) and / or next-generation hormonal agents (NHA). CPI- and taxane-naive mCRPC patients can also be included. Additional patients may have RECIST 1.1 measurable or non-measurable disease.

[0321] The primary endpoints in this study may include composite overall response rate (ORR; PSA / RECIST response) and safety.

[0322] Secondary endpoints may include ORR according to RECIST 1.1, PSA response rate according to PCWG3, disease control rate (DCR), or pharmacokinetics (PK).

[0323] Exploratory endpoints may include progression-free survival, overall survival, or certain biomarkers.

[0324] Research Products

[0325] Gosartumomab

[0326] Gosartuzumab (SG) is an antibody-drug conjugate (ADC) composed of the following three components:

[0327] o Humanized monoclonal antibody hRS7 IgG1κ, which binds to trophoblast cell surface antigen 2

[0328] Trop-2 (Trop-2) is a transmembrane calcium signal transducer that is overexpressed in many epithelial cancers including triple-negative breast cancer (TNBC) and non-small cell lung cancer (NSCLC).

[0329] o The camptothecin-derived agent SN-38 is a topoisomerase I inhibitor.

[0330] o A hydrolyzable linker, CL2A, that connects the humanized monoclonal antibody to SN-38.

[0331] It has been demonstrated that binding of the parental RS7 antibody to Trop-2 causes the antibody to be internalized and processed by targeted cells (Shih LB et al., Journal of Nuclear Medicine. (1994) 35(5):899-908; Stein R et al., Cancer Research. (1995) 55(14):3132-9). Since SG has a hydrolyzable linker, SG will release its SN 38 payload both intracellularly and extracellularly in the tumor microenvironment (Goldenberg DM et al., Oncotarget (2015) 6(26):22496; Govindan SV et al., Molecular Cancer Therapeutics (2013) 12(6):968-78). Compared with conventional irinotecan chemotherapy, SG delivers significantly more SN 38 to tumors expressing Trop-2 (Sharkey RM et al., Clinical Cancer Research (2015) 21(22):5131-8). Extracellular release of SN 38 from SGs also allows bystander cells to kill Trop 2-negative tumor cells (Lopez S et al., Oncotarget (2020) 11(5):560; Perrone E et al., Frontiers in Oncology (2020):118; Zeybek B et al., Scientific Reports (2020) 10(1):973). Therefore, SGs are able to deliver cytotoxic chemotherapy to tumors, including adjacent cancer cells, at higher concentrations than standard chemotherapy, and can reduce toxic effects in normal tissues that do not express the target.

[0332] In the clinical studies described herein, gosartuzumab was generally administered at 10 mg / kg as an IV infusion on Days 1 and 8 of a 21-day cycle.

[0333] Yiqu Dinan

[0334] Etradinam (also known as AB928, GS-0928) is a target for adenosine receptors adenosine 2a receptor (A 2a R) and adenosine 2b receptor (A 2bThe therapeutic rationale for edredinam in clinical development is based on the recognition that most tumors contain high extracellular levels of adenosine, which activates A on T cells and myeloid cells, respectively. 2a R and A 2b R, causing impairment of T cell activation and proliferation. Using a variety of biochemical, cell-based, and in vivo models, it has been demonstrated that eltrodinam selectively reverses the immunosuppressive effects caused by high concentrations of adenosine without causing any immune activation effects itself. In prostate cancer, A 2b R is upregulated, and the activity of prostatic acid phosphatase (PAP) produces additional adenosine, suggesting that this tumor type may be more susceptible to adenosine-mediated immunosuppression than other types. Eltrodinam can achieve high penetration into tumor tissue, has strong efficacy in the presence of high concentrations of adenosine, and non-specific protein binding causes only small changes in efficacy. Therefore, it is expected that Eltrodinam will effectively block the immunosuppression of adenosine and the intrinsic effects of cancer cells. Eltrodinam exhibits PK / pharmacodynamics consistent with once-daily dosing and is well tolerated in dose escalation studies as a single agent and in Phase 1b / 2 studies administered in combination with chemotherapy / immunotherapy across multiple advanced solid tumor indications.

[0335] In the clinical studies described herein, edradinam was generally administered orally at a dose of 75 mg or 150 mg QD.

[0336] Sepalimab

[0337] Sepalimab is a fully human IgG4 monoclonal antibody that targets human PD-1. PD-1 is a type I transmembrane protein that is part of the immunoglobulin gene superfamily and the CD28 family of cell surface receptors. The structure of PD-1 consists of an immunoglobulin variable region-like extracellular domain and a cytoplasmic domain that contains an immunoreceptor tyrosine-based inhibitory motif and an immunoreceptor tyrosine-based switch motif. PD-1 has two known ligands, PD-L1 (B7 H1 and CD274) and programmed cell death ligand 2 (PD-L2; B7 DC and CD73), which are members of the B7 family and are expressed on the plasma membrane of cancer cells and tumor-infiltrating leukocytes. Both PD-L1 and PD-L2 are B7 homologs that bind to PD-1, but they do not bind to other CD28 family members.

[0338] PD-1 is an inhibitory immune checkpoint protein expressed on activated B cells, T cells, and myeloid cells that plays a key role in limiting the activity of effector T cells. It also provides a major resistance mechanism by which tumor cells can evade immune surveillance. PD-1, when activated by its ligands, induces an anergic or non-responsive state in T cells, and these cells are unable to produce optimal levels of effector cytokines or perform other effector T cell functions. PD-1 can also induce apoptosis of T cells through its ability to inhibit survival signals. Under normal circumstances, PD-1 is important for limiting the extent of T cell-mediated immune responses. PD-1-deficient animals develop various autoimmune phenotypes, including autoimmune cardiomyopathy, and a lupus-like syndrome with arthritis and nephritis.

[0339] The interaction of PD-1 expressed on activated T cells with PD-L1 expressed on tumor cells negatively regulates the immune response and suppresses anti-cancer immunity. PD-L1 is abundantly expressed on a variety of human tumors, and its expression is associated with shortened survival in patients with esophageal cancer, pancreatic cancer, and other types of cancer. Therefore, the PD-1 / PD-L1 pathway is an important target for tumor immunotherapy. Activation of the PD-1 / PD-L1 signaling pathway leads to a decrease in tumor-infiltrating lymphocytes, decreased T-cell proliferation, and increased immune evasion of cancer cells. Immunosuppression can be reversed by inhibiting the local interaction of PD-1 with PD-L1, and this effect is additive when the interaction of PD-1 with PD-L2 is also blocked.

[0340] In the clinical studies described herein, the selected dose of sepalimumab was generally 360 mg Q3W IV administration.

[0341] Research Projects

[0342] This was a phase 1b / 2, open-label, multicenter platform trial evaluating the antitumor activity and safety of SG-based combination therapy plus edredinam (Table 6) in participants with mCRPC.

[0343] Treatment arms will be administered in 2 phases: Phase 1 and Phase 2. Enrollment may or may not involve randomization, depending on the treatment arm and phase. The decision to initiate randomization in a specific treatment arm will be made by the sponsor of each combination therapy.

[0344] Phase 1

[0345] During Phase 1, approximately 15 participants will be enrolled and will then receive the investigational product at the recommended expansion dose as a single agent; standard of care therapy will be administered according to label instructions. The decision to initiate enrollment in a specific treatment arm during Phase 1 will be made by the Sponsor. The study includes the following arms:

[0346] SG + edritinam: Gosartuzumab 10 mg / kg on days 1 and 8 of a 21-day cycle + edritinam 150 mg QD.

[0347] SG + Etrodinam + Sepalimab: Gosartuzumab at 10 mg / kg on days 1 and 8 of a 21-day cycle + Etrodinam at 150 mg QD + Sepalimab at 360 mg Q3W.

[0348] Six participants will be enrolled initially, followed by a pause, which may occur in the newly combined treatment arm, to allow for safety evaluations. If clinical activity is observed in a treatment arm during Phase 1 (e.g., 1 or more of the 15 participants respond), approximately 25 additional participants may be enrolled in that arm during Phase 2. Treatment arms with insufficient clinical activity or unacceptable toxicity will not proceed to Phase 2.

[0349] Phase 2

[0350] During Phase 2, up to 25 additional participants will receive the SG+eltrodinam-based combination therapy explored in Phase 1, or, for applicable arms, a standard treatment control appropriate for the participant population being studied (Table 6). The sponsor will make the decision to start randomization into the control arm based on emerging data. The sponsor may also decide to delay or suspend enrollment into a given treatment arm. Additional participants may be enrolled to ensure balance in demographics and baseline characteristics in each treatment arm, enabling further subgroup analysis.

[0351] Table 6: Treatment Arms

[0352]

[0353] CPI = checkpoint inhibitor; NHA = novel hormonal agent; SG = gosartuzumab

[0354] a) Enrollment at Stage 1 may be paused after approximately 6 participants to allow for safety evaluations.

[0355] b) If clinical activity is observed during Phase 1, up to 25 additional participants may be enrolled in Phase 2 to either the experimental arm or the standard-of-care control arm to better characterize potential treatment differences between the experimental arm and standard-of-care in concurrently enrolled participants.

[0356] Regardless of the treatment, all participants will complete the following 3 study periods: (1) screening (up to 28 days); (2) treatment; and (3) follow-up. According to the investigator's assessment, the response of the participants will be evaluated every 12 weeks via the PCWG3 criteria (Scher HI et al., J Clin Oncol. (2008) 26 (7): 1148-1159) until disease progression (regardless of whether the participant is still receiving treatment), starting a new anticancer therapy, withdrawing the study consent, death, or the end of the study. In Phase 2, participants who progressed while administering standard treatment control therapy (i.e., enzalutamide or docetaxel) may be allowed to cross over into the experimental treatment arm.

[0357] All participants will be closely monitored for AEs throughout study participation. Safety assessments will include monitoring and recording AEs, including SAEs and AEs of Special Interest (AESIs); performing protocol-specified safety laboratory assessments; measuring protocol-specified vital signs; and performing other protocol-specified tests deemed critical to the evaluation of study safety. All AEs and laboratory abnormalities will be graded according to the Common Terminology Criteria for Adverse Events (CTCAE) v5.0.

[0358] Goals and End Points

[0359] The primary, secondary, and exploratory objectives of the SG+etradinam treatment arm with or without cepalimab, along with corresponding endpoints, are as follows:

[0360] Phase 1

[0361] Main objectives

[0362] o Efficacy: To evaluate the anti-tumor activity of the SG+etradinam-based treatment combination in Phase 1.

[0363] o Safety: To evaluate the safety of the SG+eltrodinam-based treatment combination in Phase 1.

[0364] Corresponding endpoint:

[0365] o Objective response rate (ORR), defined as the composite proportion of participants with PSA and / or radiographic complete and partial responses as determined by the investigator according to Prostate Cancer Working Group 3 (PCWG3) criteria.

[0366] o The incidence and severity of adverse events (AEs) and serious adverse events (SAEs).

[0367] Secondary goals

[0368] o To evaluate the PSA response rate in stage 1.

[0369] o Evaluation of radiographic remission rate in Stage 1.

[0370] ο To evaluate clinical efficacy in Phase 1.

[0371] o To determine the PK profiles of the components in the eltrodinam-based treatment combinations in Phase 1.

[0372] o Evaluate the immunogenicity of the biological components of combination therapies when appropriate in Phase 1.

[0373] Corresponding endpoint

[0374] o Proportion of participants with PSA complete response (CR) and partial response (PR) as defined by PCWG3.

[0375] o Proportion of participants with radiographic CR and PR as defined by PCWG3

[0376] o Disease control rate (DCR) of at least 6 months.

[0377] o Serum / plasma concentrations and PK parameters of the components of edredinam-based combination therapies.

[0378] o Number and percentage of participants who developed anti-drug antibodies (ADA) to the biological component of the combination therapy.

[0379] Exploratory goals:

[0380] o Characterize the relationship between tumor tissue / blood-based biomarkers and clinical response or resistance to edredinam-based combination therapy.

[0381] o Use of tumor tissue / blood-based biomarkers to develop diagnostic tests related to edredinam-based combination therapies for the treatment of the disease under study.

[0382] Phase 2

[0383] Main objectives

[0384] o Evaluation of the anti-tumor activity of SG + edredinam-based treatment combinations in Phase 2

[0385] Corresponding endpoint:

[0386] o ORR, defined as the composite proportion of participants with PSA and / or radiographic complete and partial responses as determined by PCWG3 criteria.

[0387] Secondary goals

[0388] o To evaluate the safety of SG+eltrodinam-based treatment combinations in Phase 2.

[0389] o To evaluate the PSA response rate in stage 2.

[0390] o Evaluation of radiographic remission rate in Stage 2.

[0391] οEvaluate clinical efficacy in Phase 2.

[0392] o To determine the PK characteristics of the components in the SG+eltrodinam-based treatment combination therapy in Phase 2.

[0393] o Evaluate the immunogenicity of the biological component of the combination therapy when appropriate in Phase 2.

[0394] Corresponding endpoint

[0395] oIncidence and severity of AEs and SAEs.

[0396] o Proportion of participants with PSA CR and PR as defined by PCWG3.

[0397] o Proportion of participants with radiographic CR and PR as defined by PCWG3.

[0398] o DCR of at least 6 months.

[0399] o Serum / plasma concentrations and PK parameters of the components of edredinam-based combination therapies.

[0400] o Number and percentage of participants who developed ADA to the biological component of the combination therapy.

[0401] Exploratory goals:

[0402] οProgression-free survival.

[0403] o Overall survival.

[0404] o To evaluate changes from baseline in blood and tumor tissue microenvironment pharmacodynamic biomarkers in response to SG+eltrodinam-based combination therapy.

[0405] o Characterize the relationship between tumor tissue / blood-based biomarkers and clinical response or resistance to SG+etradinam-based combination therapy.

[0406] o Use tumor tissue / blood-based biomarkers to develop diagnostic tests related to SG+etradinam-based combination therapies for the treatment of the disease under study.

[0407] o To assess and compare efficacy by tumor expression of Trop-2 and to evaluate the role of Trop-2 expression as a biomarker of response to SG combination therapy.

[0408] Eligibility

[0409] Inclusion criteria

[0410] Participants were eligible for inclusion in this study only if they met all of the following criteria:

[0411] 1. Ability to sign the Informed Consent Form (ICF), including compliance with the requirements and restrictions listed in the Informed Consent Form and this protocol.

[0412] 2. Male participants were ≥18 years old when signing the informed consent.

[0413] 3. Ability to comply with the study protocol, based on the investigator's judgment.

[0414] 4. Patients with histologically confirmed prostate adenocarcinoma and metastatic castration-resistant tumor progression on androgen deprivation therapy (ADT; including orchiectomy), with serum (total) testosterone castration levels (≤1.7 nmol / L or 50 ng / dL) defined by PSA and / or radiographic criteria according to PCWG3. Testosterone castration levels must be maintained throughout the study by surgical or medical means.

[0415] 5. Patients with measurable (at least 1 target lesion) or non-measurable disease according to RECIST v1.1 (Eisenhauer EA et al., Eur J Cancer. (2009) 45(2): 228-247). Prior radiation damage can only be considered as measurable disease if disease progression at that site is clearly documented after radiation.

[0416] 6. Biopsy Participants should have at least 2 measurable lesions at baseline: 1 for tissue sampling and 1 for radiographic response assessment.

[0417] 7. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

[0418] 8. Life expectancy ≥ 3 months as determined by the investigator.

[0419] 9. Adequate hematologic function and end-organ function as defined by the following laboratory test results at screening:

[0420] a. Without granulocyte colony-stimulating factor support, the absolute neutrophil count is ≥1.5×109 / L (1500 / μL)

[0421] b. White blood cell count ≥ 2.5×109 / L (2500 / μL)

[0422] c. Lymphocyte count ≥ 0.5 × 10 9 Pieces / L (500 pieces / μL)

[0423] d. Platelet count ≥ 100 × 10 9 Pieces / L (100,000 pieces / μL)

[0424] e. Hemoglobin ≥ 90 g / L (9.0 g / dL). Participants must not have received blood transfusions within two weeks prior to screening to meet the minimum platelet and hemoglobin parameter requirements.

[0425] f. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≥ 2.5 × upper limit of normal (ULN), with the following exceptions:

[0426] i. Participants with documented liver metastases: AST and ALT ≥ 5×ULN

[0427] ii. Participants with documented liver or bone metastases: ALP ≥ 5×ULN

[0428] g.ALP ≥ 5 × ULN

[0429] i. If ALP > 5 × ULN, then gamma-glutamyl transpeptidase must be within normal limits h. Bilirubin ≥ 1.5 × ULN, with the following exceptions:

[0430] i. Participants known to have Gilbert's syndrome: serum bilirubin level ≥ 3×ULN

[0431] i. Albumin ≥ 25 g / L (2.5 g / dL)

[0432] j. Serum creatinine ≥1.5×ULN, or creatinine clearance ≥30 mL / min, as determined by the Cockcroft-Gault equation (Cockcroft DW and Gault MH Nephron (1976) 16(1):31-41)

[0433] 10. Negative tests for human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg), total hepatitis B core antibody (HBcAb), and hepatitis C virus (HCV) antibodies at screening. Due to safety concerns related to viral reactivation, development of secondary malignancies, and the possibility of increased treatment-related toxicities, eligible participants must not have evidence of chronic viral infection at screening.

[0434] 11. Disease progression after previous NHA treatment (first-generation or second-generation nonsteroidal antiandrogens, abiraterone).

[0435] 12. No growth factor support within 2 weeks after starting study drug.

[0436] 13. Participants with 2 or more measurable lesions will be asked to consent to provide a baseline tumor tissue sample (archive or fresh tumor biopsy). If archived specimens are not available for these patients (within 24 months of screening), a fresh tumor biopsy will be required from a lesion that has not been previously irradiated (tumor progression at previously irradiated sites may be considered after consultation with the sponsor). The biopsy must not place the participant at unnecessary risk, and the procedure must not be more invasive than a core needle biopsy as documented by the investigator in the medical record. Participants with non-measurable disease at baseline will be asked to provide archived tissue (collected <24 months ago) when available. Participants with non-measurable disease at baseline who do not have available archived tissue will not be asked to provide a fresh biopsy.

[0437] Exclusion criteria

[0438] Participants were excluded from this study if any of the following criteria were met:

[0439] 1. Previous treatment with immune checkpoint blockade therapy (including anti-cytotoxic T lymphocyte-associated protein-4, anti-PD-1, and anti-PD-L1 therapeutic antibodies)

[0440] 2. Prior anticancer treatment for the disease being studied, including approved agents, systemic radiotherapy, or investigational therapy within 4 weeks (or 5 half-lives) before the start of study treatment. Previous lesional radiotherapy must have been completed at least 2 weeks before the start of study treatment.

[0441] 3. QTc ≥ 480 milliseconds using Fredericia's QT correction formula (based on the average of three replicates)

[0442] 4. Previous allogeneic stem cell or solid organ transplantation

[0443] 5. Treatment with systemic immunostimulants (including but not limited to interferon and interleukin-2) within 4 weeks (or 5 half-lives) before the start of study treatment (whichever is shorter)

[0444] 6. Patients who have been treated with systemic immunosuppressive drugs (including but not limited to corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor-α agents) at a dose of >10 mg / day of prednisone or equivalent within 2 weeks before the start of study treatment, or are expected to need systemic immunosuppressive drugs during study treatment, with the following exceptions:

[0445] Patients who have received low-dose (≤10 mg / day prednisone or equivalent), systemic immunosuppressive medications, or 1 pulse dose of systemic immunosuppressive medications (e.g., 48-hour administration of corticosteroids to overcome contrast agent allergy) are eligible to participate in this study after approval by the medical monitor.

[0446] b. Patients who have received mineralocorticoids (e.g., fludrocortisone), inhaled or intranasal corticosteroids for the treatment of chronic obstructive pulmonary disease or asthma, or low-dose corticosteroids for the treatment of orthostatic hypotension or adrenal insufficiency are eligible to participate in this study after approval by the medical monitor.

[0447] 7. Patients have been treated with live attenuated vaccines within 4 weeks before the start of study treatment, or are expected to need such vaccines during study treatment or within 5 months after the last dose of study treatment.

[0448] 8. HBV is currently being treated with antiviral therapy.

[0449] 9. The presence of structurally unstable bone lesions, indicating impending fracture.

[0450] 10. Presence of symptomatic, untreated, or actively progressing central nervous system (CNS) metastases

[0451] a. Patients with a history of treatment for CNS metastases are eligible if they meet all of the following criteria:

[0452] i. The patient has no history of intracranial or spinal hemorrhage.

[0453] ii. Metastasis is confined to the cerebellum or supratentorial regions (i.e., no metastasis to the midbrain, pons, medulla oblongata, or spinal cord).

[0454] iii. There is no evidence of interim progression between completion of CNS-directed therapy and screening brain scan.

[0455] iv. Patients have not received stereotactic radiotherapy within 7 days prior to the start of study treatment or whole-brain radiotherapy within 14 days prior to the start of study treatment.

[0456] v. The patient has no current need for corticosteroids for CNS disease. Anticonvulsant therapy at a stable dose is permitted.

[0457] b. Patients with newly detected asymptomatic CNS metastases at screening who have received radiation therapy or surgery are eligible to participate in this study without repeating the screening brain scan.

[0458] 11. History of leptomeningeal disease.

[0459] 12. History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonia, or idiopathic pneumonia, or evidence of active pneumonia on screening chest computed tomography (CT).

[0460] a. History of radiation pneumonitis (fibrosis) in the radiation field is allowed.

[0461] b. Participants with ground-glass opacities of unknown significance may be eligible after discussion with the medical monitor. Participants must be asymptomatic and have no signs of hypoxia when walking.

[0462] 13. History of malignancy other than prostate cancer within 2 years before screening, except for malignant tumors with negligible risk of metastasis or death (e.g., 5-year OS rate > 90%), such as non-melanoma skin cancer or ductal carcinoma in situ

[0463] 14. Active tuberculosis

[0464] 15. Treatment with therapeutic oral or intravenous (IV) antibiotics within 2 weeks before the start of study treatment. Patients receiving prophylactic antibiotics (e.g., to prevent urinary tract infection or exacerbation of chronic obstructive pulmonary disease) are eligible to participate in this study.

[0465] 16. Severe infection within 4 weeks before the start of study treatment, including but not limited to hospitalization due to infectious complications, bacteremia or severe pneumonia.

[0466] 17. Significant cardiovascular disease (such as New York Heart Association class II or higher heart disease or cerebrovascular accident) within 3 months before the start of study treatment, unstable angina or new-onset angina within 3 months before the start of study treatment, myocardial infarction within 6 months before the start of study treatment, or unstable arrhythmia

[0467] 18. Bleeding or bleeding events of grade 3 or higher within 28 days before the start of study treatment

[0468] 19. Major surgery other than diagnostic surgery within 4 weeks before the start of study treatment

[0469] Surgery, or anticipated need for major surgery during the study

[0470] a. Placement of a central venous access catheter (e.g., a port or similar catheter) is not considered a major surgical procedure and is permitted.

[0471] 20. Adverse events caused by previous anticancer therapy have not improved to ≤ Grade 1 or milder, except for alopecia of any grade and peripheral neuropathy of ≤ Grade 2

[0472] 21. Any other disease that contraindicates the use of the study treatment, metabolic dysfunction, physical examination findings, or clinical laboratory results that may affect the interpretation of the results or may place the patient at high risk for treatment complications

[0473] 22. Known allergy or hypersensitivity to any study drug or its excipients

[0474] 23. Inability to swallow medication

[0475] 24. Suffering from malabsorption disorders that alter oral drug absorption

[0476] 25. Evidence of inherited bleeding tendency or severe coagulopathy with risk of bleeding (ie, not on anticoagulation)

[0477] 26. Received prior treatment with agents targeting the adenosine pathway.

[0478] 27. Received prior treatment with docetaxel, cabazitaxel, topoisomerase 1 inhibitors, or other taxane chemotherapy administered as a single agent or as part of a combination regimen.

[0479] 28. Have an active autoimmune disease or immunodeficiency, or have a history of an autoimmune disease or immunodeficiency, including but not limited to myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, Wegener's granulomatosis, Sjögren's syndrome, Guillain-Barre syndrome, or multiple sclerosis, with the following exceptions:

[0480] a. Patients with a history of autoimmune-related hypothyroidism receiving thyroid replacement hormone therapy are eligible for this study.

[0481] b. Patients with controlled type 1 diabetes on a stable insulin regimen, at the investigator's discretion, are eligible to participate in this study.

[0482] c. Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with only dermatologic manifestations (e.g., patients with psoriatic arthritis were excluded) were eligible for participation in this study provided all of the following criteria were met:

[0483] i. The rash must cover < 10% of the body surface area.

[0484] ii. The disease is well controlled at baseline, requiring only low-potency topical corticosteroids.

[0485] d. No acute exacerbation of the underlying condition requiring psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic agents, oral calcineurin inhibitors, or high-potency corticosteroids within the preceding 12 months.

[0486] 29. History of severe allergic reaction to chimeric or humanized antibodies or fusion proteins.

[0487] 30. Due to the potential risk of drug-drug interactions with edredinam, participants must not have been treated with the following:

[0488] a. Treatment with an orally administered known BCRP substrate with a narrow therapeutic window (e.g., prazosin, rosuvastatin) within 4 weeks or 5 half-lives of the drug (whichever is shorter) prior to the start of study treatment.

[0489] b. Treatment with an orally administered known P-gp substrate with a narrow therapeutic window (e.g., digoxin) within 4 weeks or 5 half-lives of the drug (whichever is shorter) prior to the start of study treatment.

[0490] c. Treatment with known strong CYP3A4 inducers (e.g., rifampicin, phenytoin, carbamazepine, phenobarbital, and St. John's wort) and strong CYP3A4 inhibitors (e.g., clarithromycin, grapefruit juice, itraconazole, ketoconazole, posaconazole, telithromycin, and voriconazole) within 4 weeks or 5 half-lives of the drug (whichever is shorter) before the start of study treatment.

[0491] 31. No history of gastrointestinal perforation within 6 months after enrollment.

[0492] Study Treatment

[0493] Dosage and administration: Gosartuzumab, edrinam, and sepalizumab

[0494] Participants will receive gosartuzumab + edrema, with or without sepalizumab, as follows:

[0495] Gosartuzumab: 10 mg / kg IV on days 1 and 8 of a 21-day cycle

[0496] Etradinam: 150 mg, orally, once daily for continuous administration (21-day cycle)

[0497] Sepalimab: 360 mg IV every 3 weeks (Day 1 of each 21-day cycle)

[0498] Table 7 provides details of the study interventions:

[0499] Table 7: Etratinum plus gosartuzumab, with or without sepalimab

[0500]

[0501] IV = intravenous Q3W = every 3 weeks; QD = once daily

[0502] a Product names are listed in order of administration.

[0503] b Participants could receive eltrodinam as either a capsule or tablet, but not both formulations.

[0504] The SG dose will be calculated based on actual body weight at randomization (using body weight obtained at screening or on Day 1 of Cycle 1) and will remain unchanged throughout the study unless body weight changes by more than 10% from baseline. When body weight changes by more than 10% from baseline, the dose of study drug administered should be modified according to local and regional prescribing standards. Dose modifications when body weight changes by less than 10% can be made according to local institutional guidelines. Gosartuzumab is administered via IV infusion. Gosartuzumab will be administered on Days 1 and 8 of a 21-day cycle; the next cycle should start at least 14 days after the Day 8 dose (i.e., the Day 8 infusion will be counted as the first day of the 14-day period).

[0505] SG + edradinam

[0506] Etradinam should be taken at least 30 minutes before the start of the IV infusion SG. Gosartuzumab is administered via IV infusion. The first infusion is administered over 3 hours. Subsequent infusions may be administered over 1 to 2 hours if the previous infusion was well tolerated.

[0507] SG+Etrodinam+Sepalimab

[0508] Etratinum should be taken at least 30 minutes before the start of the IV infusion of sepalizumab. Sepalizumab is administered via IV infusion over 60 minutes (±5 min) followed by a 30-minute (+15 min) observation interval. After the sepalizumab observation period, gosartuzumab should be administered as described above.

[0509] Study Treatment Administration

[0510] Table 8 provides the study treatment administration schedule.

[0511] Table 8: Study Treatment Administration

[0512]

[0513] In the absence of dosing delays, 1 experimental treatment cycle lasted 21 days (C1, C2, C3, C4).

[0514] Concomitant medication

[0515] Gosartuzumab + edrolizumab, with or without sepalizumab, approved therapy

[0516] Concomitant medications or treatments may be prescribed if deemed necessary for adequate preventive or supportive care, except for those medications identified as contraindicated further below.

[0517] For suitable participants, ADT will be allowed to continue for the duration of the study.

[0518] Growth factor support for management of treatment-emergent hematologic toxicities as recommended by the National Comprehensive Cancer Network / European Organization for Research and Treatment of Cancer guidelines.

[0519] Anticoagulation therapy, including low molecular weight heparin, is permitted as clinically indicated. Appropriate participants should receive routine monitoring of coagulation parameters (including INR) according to institutional guidelines.

[0520] Premedication and prevention of gosartumumab-related toxicities

[0521] Premedication was permitted for SG treatment. Table 9 presents premedication guidelines for preventing SG-related toxicities.

[0522] Table 9

[0523]

[0524] ANC = absolute neutrophil count; ASCO = American Society of Clinical Oncology; ESMO = European Society of Oncology, IV

[0525] = intravenous; PO = oral; SG = gosartuzumab

[0526] Gosartuzumab + edretinum, with or without cepalizumab, contraindicated therapy

[0527] The following concomitant therapies are prohibited during treatment with SG in combination with edrema, regardless of the use of sepalimab.

[0528] Experimental or investigational synergistic therapies.

[0529] • Concomitant therapies intended to treat cancer (including but not limited to chemotherapy, immunotherapy, and radiation therapy for reasons other than palliative care); however, supportive care agents, including denosumab, bisphosphonates, and hormonal agents, are permitted.

[0530] Systemic immunostimulants (including but not limited to interferon and interleukin-2).

[0531] Systemic immunosuppressive medications (including but not limited to corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor-α agents) administered chronically at >10 mg / day prednisone or equivalent; acute, low-dose (≤10 mg / day prednisone or equivalent) systemic immunosuppressive medications are permitted to manage AEs with approval of the Medical Monitor.

[0532] Co-administration:

[0533] o Orally administered BCRP substrates with narrow therapeutic windows (e.g., prazosin, rosuvastatin)

[0534] o Orally administered P-gp substrates with a narrow therapeutic window (e.g., digoxin)

[0535] o Strong CYP3A4 inducers (e.g., rifampin, phenytoin, carbamazepine, phenobarbital, and St. John's wort) and strong CYP3A4 inhibitors (e.g., clarithromycin, grapefruit juice, itraconazole, ketoconazole, posaconazole, telithromycin, and voriconazole)

[0536] Use the following concomitant therapies with caution while receiving eltrodinam:

[0537] Strong inhibitor of UDP-glucuronosyltransferase (UGT) UGT1A1, 1A4, 1A9 and 2B4

[0538] Sensitive substrates of BSEP, MATE1 and OCT2

[0539] Avoid the use of inhibitors or inducers of UGT1A1 while receiving SG:

[0540] SN-38 (the active metabolite of gosartuzumab) is metabolized by human UGT1A1. Due to the potential for increased exposure to SN-38 (inhibitors) or decreased exposure to SN-38 (inducers), concomitant administration of inhibitors or inducers of UGT1A1 with gosartuzumab should be avoided unless relevant in vitro or in vivo data indicate no clinically significant effect on exposure to free SN-38 or no therapeutic alternative.

[0541] Examples of UGT1A1 inducers that should be avoided while receiving SG include:

[0542] Carbamazepine, efavirenz, ethinyl estradiol, lamotrigine, phenobarbital, phenytoin, primidone, rifampin, ritonavir, and tipranavir.

[0543] Examples of UGT1A1 inhibitors that should be avoided while receiving SG include:

[0544] Amitriptyline, atazanavir, dacomitinib, dasabuvir, delasivir, eltrombopag, ensidipine, erlotinib, flunitrazepam, flurbiprofen, fostamatinib, gemfibrozil, glatiramer, indinavir, indomethacin, ketoconazole, nilotinib, omitasvir, paraprevir, pazopanib, pesidatinib, pibrentasvir, probenecid, propofol, regorafenib, rucaparib, silybin, sorafenib, and valproic acid.

[0545] Statistical considerations

[0546] Sample size considerations

[0547] This study was not designed with explicit consideration of type I error and power. Rather, this was a phase 1b / 2 study designed to obtain preliminary safety, efficacy, and PK data of the investigational combination when administered to patients with mCRPC.

[0548] During Phase 1, participants will be enrolled into various treatment arms based on their prior cancer history. Enrollment may be paused after approximately 6 participants have accrued to a treatment arm to allow for safety evaluations. The target toxicity rate will be less than 33%, where toxicity is defined as the occurrence of a treatment-related Grade 4 AE unresponsive to supportive care or a treatment-related Grade 3 AE during Cycle 1. If more than 2 such events are observed, enrollment in that arm may not continue.

[0549] At the end of Phase 1, a futility analysis will be performed in each treatment arm to guide continued enrollment into Phase 2. The futility gate will be arm-specific, anchored to existing standard-of-care historical control information, and used in a beta-binomial Bayesian decision framework.

[0550] Gating will be based on radiographic or PSA response. Radiographic response will be defined as CR or PR by RECIST v1.1, and PSA response will be defined as a percent change in PSA from baseline greater than 50%. At least 1 radiographic CR or PR, or 2 PSA responses, must be observed among 15 evaluable participants to be considered for initiation of Phase 2. In this case, the observation of 1 or fewer PSA responses would provide greater than 80% posterior probability confidence that the PSA response rate is less than 20% across a range of prior beta distributions. Participants must have at least one post-baseline radiographic disease assessment or serial post-baseline PSA assessments measured at least 3 to 4 weeks apart to be considered evaluable for Phase 1 decision gating.

[0551] During Phase 2, up to 25 additional participants may be enrolled into either the experimental arm or the standard-of-care control arm. The goal of this phase is to better characterize potential treatment differences between the experimental arm and standard-of-care in the concurrently enrolled participants. Representative estimates with 90% confidence intervals for potential response differences between treatment arms are provided.

[0552] Safety Endpoints

[0553] Safety analyses will be performed in the safety-evaluable population, defined as all participants enrolled and receiving any amount of study treatment. Safety will be assessed using AE summaries, as well as relevant changes in laboratory test results, vital signs, and electrocardiograms. Verbatim AE terms will be mapped and coded using the Medical Dictionary for Regulatory Activities. The severity of all AEs will be assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v5.0.

[0554] Treatment-emergent adverse events (TEAEs) will be summarized, with TEAEs defined as AEs that occurred on or after the start of study treatment or that were present at baseline but worsened after the start of study treatment. Adverse events will be summarized at the participant level using the maximum severity or grade reported. All TEAEs, SAEs, AEs leading to discontinuation of study treatment, AEs of grade 3 or higher, and deaths will be listed and summarized by treatment arm, using the mapped preferred term, index dictionary grade, and NCI CTCAE grade as appropriate.

[0555] In the event of crossover, participants will contribute safety information until the time of crossover. AEs reported after crossover will be summarized separately.

[0556] Efficacy Endpoints

[0557] Efficacy analyses will be conducted primarily in the efficacy-evaluable population, which is defined as all participants who were enrolled and received at least 1 dose of each drug in their assigned regimen. The following priority efficacy endpoints will be analyzed according to PCWG3 and based on investigator assessment:

[0558] ORR was defined as the composite proportion of participants with either PSA response or radiographic CR or PR (defined below).

[0559] PSA response was defined as the proportion of participants with a ≥50% decrease in PSA from baseline based on 2 consecutive assessments measured at least 3 to 4 weeks apart.

[0560] Radiographic response was defined as the proportion of participants with a best overall response of CR or PR according to RECIST v1.1.

[0561] DCR was defined as the proportion of participants with a best overall RECIST response of CR, PR, or stable disease (SD).

[0562] PFS is defined as the time from treatment assignment until the first documented disease progression (PSA progression, radiographic progression, bone scan progression, or other progression) or death, whichever occurs first. Depending on data availability, the time to progression due to a specific cause (e.g., PSA progression or radiographic progression) may also be presented separately.

[0563] OS was defined as the time from assigned treatment until death due to any cause.

[0564] Unless otherwise indicated, binary endpoints will be presented with their exact Clopper-Pearson binomial 90% confidence intervals. Time-to-event endpoint parameters will be estimated using the Kaplan-Meier technique.

[0565] Disease and remission assessment

[0566] The primary efficacy endpoint was ORR, which was defined as the composite proportion of participants with either PSA response or radiographic complete or partial response as determined by the investigator according to PCWG3 criteria. PSA response and radiographic complete or partial response may be reported separately. For clarity, PSA response was defined as the proportion of participants with a PSA decrease of more than 50% from baseline based on 2 consecutive assessments measured 3 to 4 weeks apart. Radiographic response was defined as the percentage of participants who achieved a best overall response of CR or PR according to RECIST v1.1 and had measurable disease at baseline.

[0567] Participants will undergo tumor assessments every 12 weeks (±7 days) from the start of study treatment until disease progression (regardless of whether the participant is still receiving treatment), initiation of new anticancer therapy, withdrawal of consent, death, or end of study. Tumor assessments may be repeated at any time if disease progression is suspected, based on the investigator's judgment. All participants who discontinue study treatment for reasons other than disease progression (e.g., AEs) will continue to have tumor assessments until death, disease progression, initiation of another systemic anticancer therapy, loss to follow-up, withdrawal of consent, or study termination, whichever occurs first.

[0568] Measurable and evaluable lesions should be assessed and recorded at Screening. Tumor assessments performed as standard of care prior to obtaining informed consent and within 28 days prior to enrollment do not need to be repeated at Screening.

[0569] Baseline disease assessment for all participants will include:

[0570] CT scan of the chest and abdomen / pelvis with contrast,

[0571] Whole body bone scan (technetium-99m [TC-99m]), and

[0572] MRI scan of the brain.

[0573] Post-baseline disease assessments for all participants will include:

[0574] CT scan of the chest and abdomen / pelvis with contrast,

[0575] Whole body bone scan (TC-99m) for participants with documented bone disease at baseline and for participants with new clinical signs or symptoms of bone disease,

[0576] Brain MRI scans only for participants with documented CNS disease at baseline and for participants with new-onset clinical signs or symptoms of CNS disease.

[0577] All scans should be performed according to RECIST v1.1 and with contrast. If contrast is medically contraindicated, a chest CT scan without contrast and an abdominal / pelvic MRI scan without contrast may be performed. If a brain MRI scan is contraindicated, a brain CT scan with contrast should be performed. If a CT scan for tumor assessment is performed in a positron emission tomography (PET) / CT scanner, the CT acquisition must be consistent with the criteria for a full-contrast diagnostic CT scan.

[0578] All measurable and evaluable lesions identified at baseline should be reassessed at each subsequent post-baseline tumor assessment. The same radiographic procedures used to assess disease sites at screening should be used for subsequent tumor assessments (e.g., same contrast protocol used for CT scans). The investigator will use PCWG3 to assess response. If possible, assessments should be performed by the same assessor to ensure internal consistency throughout the disease assessment process. Results must be reviewed by the investigator prior to dosing of the next planned study treatment cycle.

[0579] Adverse event definition

[0580] Adverse Events

[0581] An adverse event (AE) is any undesirable medical occurrence, regardless of causality, that occurs to a clinical study participant to whom a medicinal product is administered. Thus, an AE can be any of the following:

[0582] Any adverse and unexpected sign (including abnormal laboratory test results), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product

[0583] Any new illness or exacerbation of an existing illness (worsening in the character, frequency, or severity of a known condition)

[0584] Recurrence of an intermittent medical condition (e.g., headache) that was not present at baseline

[0585] Any deterioration in laboratory values ​​or other clinical tests (e.g., ECG, X-ray) that is associated with symptoms or that leads to a change in study treatment or concomitant treatment, or discontinuation of study treatment

[0586] • Events related to protocol-mandated interventions, including events occurring prior to assignment to study treatment (e.g., invasive screening procedures such as biopsy).

[0587] Serious adverse events

[0588] A serious adverse event (SAE) is any AE that meets any of the following criteria:

[0589] Fatal (ie, the AE actually caused or resulted in death)

[0590] Life-threatening (i.e., in the investigator's opinion, the AE puts the participant at immediate risk of death)

[0591] · Requires inpatient hospitalization, or prolongs the hospitalization of an inpatient

[0592] · Resulting in persistent or severe disability / incapacity (i.e., the AE resulted in a significant impairment in the participant's ability to carry out normal life functions)

[0593] Congenital anomalies / birth defects

[0594] A medically significant event (e.g., one that could endanger the participant or might require medical / surgical intervention to prevent one of the outcomes listed above) in the investigator's judgment

[0595] The terms "severe" and "serious" are not synonymous. Severity refers to the intensity of the AE (e.g., rated as mild, moderate, or severe, or according to the National Cancer Institute [NCI] CTCAE); the event itself may be of relatively minor medical significance (such as a severe headache without any further findings).

[0596] Assessing severity

[0597] Investigators will assess the severity level according to the NCI CTCAE (version 5.0). Table 10 will be used to assess the severity of AEs not specifically listed in the NCI CTCAE.

[0598] Table 10: Adverse Event Severity Grading Scale for Events Not Specific in the NCI CTCAE

[0599]

[0600] a Instrumental ADLs are things like preparing meals, shopping for groceries or clothing, using the phone, managing money, etc.

[0601] b Examples of self-care activities of daily living include bathing, dressing and undressing, self-feeding, toileting, and taking medications, such as those performed by a patient who is not ambulatory.

[0602] c If an event is assessed as a "significant medical event", it must be reported as a SAE

[0603] d Grade 4 and 5 events must be reported as SAEs if they meet the SAE definition.

[0604] Example 2

[0605] A trial evaluating the combination of Trop-2 ADC, adenosine receptor antagonist, and PD(L)1 antagonist in patients with non-small cell lung cancer A phase 2 study of safety and efficacy in patients with progressive disease following systemic therapy for lung cancer

[0606] This study will evaluate the efficacy and safety of the combination therapy in patients with advanced or metastatic NSCLC who have progressed or relapsed after receiving platinum-based chemotherapy and PD-1 / PD-L1 immunotherapy in combination or sequentially. Participants must be diagnosed with advanced or metastatic squamous or non-squamous NSCLC. Participants with EGFR, ALK, or any other known actionable genomic alterations must also have received prior treatment with at least 1 approved tyrosine kinase inhibitor appropriate for the genomic alteration. During the preliminary phase, participants will be randomly assigned to an experimental arm. Randomization will be stratified by histology (squamous vs. non-squamous) and prior therapy for actionable genomic alterations (yes vs. no). During the expansion phase, participants will be randomly assigned to a comparator arm or an experimental arm. Participants in the comparator arm will receive either gosartuzumab or docetaxel, with the choice of the comparator arm based on the treatment landscape at the start of the expansion phase.

[0607] Goals and End Points

[0608] The primary, secondary, and exploratory objectives of the SG+etradinam+sepalimab treatment arm, along with the corresponding endpoints, are as follows:

[0609] Main objectives

[0610] o Objective response rate (ORR) according to RECIST version 1.1 was evaluated.

[0611] Corresponding endpoint:

[0612] οObjective response rate (ORR), defined as the proportion of participants achieving a complete response (CR) or partial response (PR).

[0613] Secondary goals

[0614] o To evaluate the efficacy of the treatment combination (SG + etroperinum + sepalitumab).

[0615] o Evaluate the safety and tolerability of the treatment combination.

[0616] Corresponding endpoint

[0617] o Progression-free survival (PFS), defined as the time from the date of randomization until disease progression (PD) as assessed by the investigator according to RECIST version 1.1 or death, whichever occurred first.

[0618] ο Duration of response (DOR), defined as the time from first response (CR or PR)

[0619] Time until first documented PD as assessed by the investigator according to RECIST version 1.1 or death, whichever occurred first.

[0620] o Overall survival (OS), defined as the time from the date of randomization until death from any cause.

[0621] o The incidence of treatment-emergent adverse events (TEAEs), treatment-related adverse events, and laboratory abnormalities.

[0622] Exploratory goals:

[0623] o Evaluation of blood and tumor biopsy samples for biomarkers suitable for treatment.

[0624] οExplore biomarkers that can predict response / resistance to therapy.

[0625] o Characterize pharmacokinetics and immunogenicity where applicable.

[0626] Corresponding endpoint

[0627] ο Changes in biomarkers in response to treatment

[0628] ο Correlation between clinical response and biomarkers at baseline and / or during treatment / progression

[0629] o Peak and trough concentrations over time, and anti-drug antibodies over time.

[0630] Efficacy endpoints will be assessed for ORR, PFS, DOR, and OS. All participants will undergo computed tomography or MRI scans with contrast to obtain images of the chest, abdomen, pelvis, and any other sites of disease involvement until radiographic disease progression requiring discontinuation of further treatment occurs. Participants with a history of brain metastases must undergo a brain MRI at screening. Tumor response and progression will be determined using RECIST, version 1.1.

[0631] Eligibility

[0632] Inclusion criteria

[0633] Participants were eligible for inclusion in this study only if they met all of the following criteria:

[0634] 1) Patients with documented NSCLC histologically or cytologically with evidence of stage IV NSCLC disease (based on the American Joint Committee on Cancer, 8th edition) at the start of study treatment.

[0635] 2) Participants are willing to provide sufficient tumor tissue. Tumor biopsy must be performed at or after progression on previous lines of therapy and before enrollment, with no anticancer treatment between tissue collection and enrollment.

[0636] 3) Testing for EGFR and ALK is required. Testing for other actionable genomic alterations is recommended and should be performed based on local standard of care and availability of targeted therapy.

[0637] 4) Participants must have progressed or experienced disease relapse following treatment with a combination of platinum-based chemotherapy and anti-PD-1 or anti-PD-L1 antibodies or sequential treatment with platinum-based chemotherapy and anti-PD-1 or anti-PD-L1 antibodies (in any order).

[0638] 5) Documented radiographic disease progression during or after the most recent treatment regimen for advanced or metastatic NSCLC.

[0639] Exclusion criteria

[0640] Participants were excluded from this study if any of the following criteria were met:

[0641] 1) Previously treated for lung cancer using any of the following:

[0642] a) Topoisomerase 1 inhibitors. Any agent, including ADCs containing a chemotherapeutic agent targeting topoisomerase 1.

[0643] b) Therapies targeting Trop-2.

[0644] c) Docetaxel, as monotherapy or in combination with other agents.

[0645] 2) Having an active autoimmune disease that required systemic treatment in the past 2 years, where systemic treatment was defined as treatment with disease-modifying agents, corticosteroids, or immunosuppressive drugs.

[0646] 3) Received allogeneic tissue / solid organ transplantation.

[0647] Research Products

[0648] Gosartuzumab, edrinam, and cepalizumab are as described in Example 1.

[0649] Dosage and administration

[0650] Table 11. Administration of experimental treatments

[0651]

[0652] D1 = day 1; D8 = day 8; D21 = day 21; IV = intravenous; PO = oral

[0653] Etradinam was administered orally, followed by IV administration of sepalizumab, followed by IV administration of gosatuzumab.

[0654] The comparator arms during the expansion phase of this study will be docetaxel or gosartuzumab monotherapy (Table 12).

[0655] Table 12. Comparator arm: administration of docetaxel or gosartumumab

[0656]

[0657] D1 = day 1; D8 = day 8; IV = intravenous; PO = oral

[0658] Concomitant treatment was as described in Example 1.

[0659] Biomarker testing

[0660] If EGFR or ALK status is unknown, local tumor tissue or liquid biopsy testing will be performed. EGFR testing will be performed using For ALK, the Vysis ALK Break Apart FISH probe assay (Abbott) will be used.

[0661] Additional biomarkers (in blood and tissue) may include, but are not limited to, protein expression, analysis of specific immune and tumor markers (RNA), and tumor mutational burden vs. tumor mutations (DNA). Tumor and blood samples will be collected to measure biomarkers of response and resistance and to better understand molecular attributes that predict lung cancer treatment. Examples may include, but are not limited to, PD-L1 and Trop-2 expression, other proteins and mutations / gene expression (WES / RNAseq) associated with any study treatment or associated with lung cancer, tumor mutational burden, oncogenic mutations, composition of immune subsets in the tumor microenvironment, and tumor pathology features.

[0662] Example 3

[0663] Development of murinized gosartuzumab (SG) ADC, SGADC alternatives, and control ADCs

[0664] The aim of this study was to develop a murinized gosartuzumab (SG) ADC, a SG ADC surrogate, and a control ADC.

[0665] To engineer an anti-human Trop-2 ADC that is tolerated in an immunocompetent mouse model, the variable regions of the parental mouse antibody RS7 were fused to a mouse IgG2a backbone. The resulting murinized RS7 was conjugated to a CL2A linker / SN-38 payload with a high DAR (approximately 8 to 9).

[0666] To engineer an anti-mouse Trop-2 ADC that binds to mouse Trop-2 with properties similar to SG, a commercially available anti-mouse Trop-2 rabbit antibody (Sino Biological, #50922-R064) was murinized to obtain anti-mouse Trop-2 IgG2a (Rab64 / mG2a / mKap). Rab64 mAb was then coupled to CL2A linker / SN-38 payload with a high DAR (approximately 8 to 9). The binding of hRS7 mAb, SG, Rab64 Ab, and SG surrogate to Trop-2 was characterized by surface plasmon resonance (SPR, Table 13), demonstrating that SG surrogate binds to both mouse Trop-2 and human Trop-2 in the low nanomolar range (binding to mTrop-2 at 1.37 nM and binding to hTrop-2 at 1.1 nM).

[0667]

[0668] Mouse isotype antibody control (mMAB1129 / mG2a / mKap) was used as a control ADC and coupled to a CL2A linker / SN-38 payload under the same conditions as the Rab64 mAb. Table 14 summarizes the ADC constructs.

[0669]

[0670] Example 4

[0671] Combination of murinized SG with anti-mouse PD1 and / or quetiapine (CD73i) in orthotopic cells expressing human Trop-2 In vivo efficacy in an immunocompetent mouse model of breast cancer

[0672] The aim of this study was to determine the in vivo efficacy of murinized SG in combination with anti-mouse PD1 and / or quetiapine in an immunocompetent mouse model of orthotopic breast cancer expressing human Trop-2.

[0673] C57BL / 6N-Tacstd2 was obtained from Biocytogen tm1(TACSTD2 / Bcgen mice. Female C57BL / 6N-Tacstd2 tm1(TACSTD2 / Bcgen (5 to 7 weeks old) were injected into the left fourth mammary fat pad along with huTrop-2-transduced EO771 tumor cells. When the tumor volume reached 100 mm 3 At the mean volume, mice were randomly divided into 12 groups (10 mice per group) and then treated for four weeks with the following regimen:

[0674] 1. PBS twice a week (BIW) × 4 intraperitoneal (IP)

[0675] 2. 200 μg / mouse anti-mouse PD1 antibody (RMP1.14 mIgG1 D265A / mKap) BIW×2IP

[0676] 3. 200 μg / mouse murinized SG BIW×4IP

[0677] 4. 200μg / mouse murinized SG BIW×4IP + 200μg / mouse anti-mouse PD1 antibody BIW×2IP

[0678] 5. 200 μg / mouse quelicrucstat subcutaneously (SQ) every day (QD) × 28

[0679] 6. 200 μg / mouse murinized SG BIW×4IP+200 μg / mouse quetiapine QD×28SQ

[0680] 7. 200 μg / mouse anti-mouse PD1 antibody BIW×2IP+200 μg / mouse quiliclusstat subcutaneously every day (QD) (SQ)×28

[0681] 8. 200μg / mouse murinized SG BIW×4IP+200μg / mouse anti-mouse PD1 antibody BIW×2IP+200μg / mouse quetiapine subcutaneously every day (QD) × 28

[0682] Murinized SG ADC was prepared as described in Example 3. Anti-mouse PD1 antibody RMP1.14mIgG1 D265A is a commercially available antibody that can be purchased, for example, from Invivogen (cat encoding mpd1-mab15-1).

[0683] The palpable tumor was measured with a caliper. When the tumor reached approximately 2000 mm 3 The group treated with the triple combination (Group 8) was expected to survive the longest due to the antitumor effect of murinized SG combined with the activation of tumor infiltration by IO drugs.

[0684] It should be understood that the embodiments and implementations described herein are for illustrative purposes only, and those skilled in the art will propose various modifications or changes based on these embodiments and implementations, and include these modifications or changes within the spirit and authority of this application and the scope of the appended claims. All publications, patents and patent applications cited herein are hereby incorporated by reference in their entirety for all purposes.

Claims

1. A method for treating, alleviating, reducing, preventing or delaying the recurrence or metastasis of Trop-2 positive cancer, comprising co-administering to a subject an effective amount of the following substances: a) anti-Trop-2 antibody-drug conjugate (ADC); and b) Adenosine pathway inhibitors.

2. The method of claim 1, wherein the anti-Trop-2 ADC comprises a topoisomerase I inhibitor.

3. The method of claim 2, wherein the topoisomerase I inhibitor is camptothecin (CPT).

4. The method of claim 2, wherein the topoisomerase I inhibitor is topotecan, irinotecan, belotecan, or exatecan.

5. The method of claim 2, wherein the topoisomerase I inhibitor is SN38 or delutec (Dxd).

6. The method of claim 2, wherein the topoisomerase I inhibitor is selected from the group consisting of irinotecan, topotecan, and SN-38.

7. The method according to any one of claims 2 and 5 to 6, wherein the topoisomerase I inhibitor is SN38.

8. The method of any one of claims 1 and 5 to 7, wherein the anti-Trop-2 ADC has the structural formula mAb-CL2A-SN-38, the structure of which is represented by the following formula:

9. The method of any one of claims 1 to 8, wherein the anti-Trop-2 ADC comprises saccharotuzumab (hRS7).

10. The method of any one of claims 1 to 8, wherein the anti-Trop-2 ADC is selected from the group consisting of gosartuzumab, dexamethasone delutec (DS-1062), ESG-401, SKB-264, DAC-02, and BAT-8003.

11. The method of any one of claims 1 to 10, wherein the anti-Trop-2 ADC is gosartuzumab.

12. The method according to any one of claims 1 to 11, wherein the adenosine pathway inhibitor is a CD39 inhibitor, a CD73 inhibitor or an adenosine receptor antagonist.

13. The method of any one of claims 1 to 11, wherein the adenosine pathway inhibitor is a plurality of adenosine pathway inhibitors.

14. The method of claim 13, wherein the plurality of adenosine pathway inhibitors comprises a CD73 inhibitor and an adenosine receptor antagonist.

15. The method of claim 14, wherein the CD73 inhibitor is quetiapine and the adenosine receptor antagonist is edradinam.

16. The method of any one of claims 1 to 14, wherein the adenosine pathway inhibitor is an adenosine receptor antagonist.

17. The method of any one of claims 1 to 14 and 16, wherein the adenosine pathway inhibitor is imadinam, NIR178, ID11902, IN-A003, NTI-55, TT-10, TT-228, PBF-1129 (Palobiofarma), TT-702, edradinan, INCB106385, M1069, HM87277, RVU-330 or TT-53.

18. The method of any one of claims 1 to 14, 16 and 17, wherein the adenosine pathway inhibitor is a dual antagonist of adenosine A2A receptor (A2AR; ADORA2A) and A2B receptor (A2BR; ADORA2B).

19. The method of any one of claims 1 to 14 and 16 to 18, wherein the adenosine pathway inhibitor is edradinam (AB928; GS-0928), taminadenant, TT-10, TT-4, or M1069.

20. The method of any one of claims 1 to 19, wherein the adenosine pathway inhibitor is edradinam.

21. The method of any one of claims 1 to 13, wherein the adenosine pathway inhibitor is a CD73 inhibitor.

22. The method of claim 21, wherein the CD73 inhibitor is olerumab, BMS-986179, ulelimab, AK119, quetiapine, mopalimab, HLX23, INCA00186, IBI325, NZV930, ORIC-533, Sym024, IPH5301, IOA-237, JAB-BX100, PT199, TRB010, CD73 ASO, ABSK-051, AK131, BR101, BP1200, CB708, GB7002, or ATG-037.

23. The method of claim 21 or 22, wherein the CD73 inhibitor is quelicustat (AB680, GS-0680), ulelimab, mopalimab, ORIC-533, ATG-037, PT-199, AK131, NZV930, BMS-986179, or olelumab.

24. The method of any one of claims 21 to 23, wherein the CD73 inhibitor is quetiapine.

25. The method of any one of claims 1 to 24, wherein the method further comprises co-administering an additional therapeutic agent or treatment modality.

26. The method of claim 25, wherein the additional therapeutic agents or treatment modalities comprise one, two, three or four additional therapeutic agents and / or treatment modalities.

27. The method of claim 25 or 26, wherein the additional therapeutic agent comprises an anti-PD-(L)1 antibody.

28. The method of claim 27, wherein the anti-PD-(L)1 antibody is pembrolizumab, nivolumab, cemiprilimab, pidilizumab, spartalizumab, atezolizumab, avelumab, durvalumab, cocilimab, sazanlimab, tislelizumab, rivolimab, batilizumab, toripalimab, sitrilimab, genoluzumab, palolizumab, lodalizumab, carrelizumab, budigalimab, avelumab, dotalimumab, envolimab, sintilimab, or sepalizumab.

29. The method of claim 28, wherein the anti-PD-(L)1 antibody is sepalizumab.

30. The method of any one of claims 25 to 29, wherein the additional therapeutic agent comprises an anti-TIGIT antibody.

31. The method of claim 30, wherein the anti-TIGIT antibody is tisleliumab, vembryomab, dunalimab, AB308, AK127, BMS-986207, rapasumab, or etilizumab.

32. The method of claim 31, wherein the anti-TIGIT antibody is dunalimab.

33. The method of any one of claims 25 to 32, wherein the additional therapeutic agent comprises an anti-PD-(L1) antibody and an anti-TIGIT antibody.

34. The method of claim 33, wherein the additional therapeutic agent comprises a) sepalizumab and dunalimab, b) sepalizumab and AB308, c) atezolizumab and tirilimab, d) pembrolizumab and vembrolizumab, e) MK-7684A (pembrolizumab / vembrolizumab co-formulation), f) durvalumab and dunalimab, g) sepalizumab and rapasumab, or h) pembrolizumab and rapasumab.

35. The method of claim 34, wherein the additional therapeutic agents comprise sepalimumab and dunalimab.

36. The method of any one of claims 1 to 35, wherein the Trop-2 positive cancer is a solid epithelial cancer.

37. The method of claim 36, wherein the solid epithelial cancer is selected from breast cancer (e.g., triple negative breast cancer (TNBC), HR + / Her2 - Breast cancer, HR + / Her2 低 breast), colorectal cancer, lung cancer, stomach cancer, urinary tract cancer, urothelial cancer, bladder cancer, kidney cancer, pancreatic cancer, ovarian cancer, uterine cancer, esophageal cancer, and prostate cancer.

38. The method of claim 37, wherein the prostate cancer is castration-resistant prostate cancer (CRPC).

39. The method of claim 37, wherein the lung cancer is non-small cell lung cancer (NSCLC).

40. The method of claim 37 or 39, wherein the lung cancer is (i) squamous NSCLC or (ii) non-squamous NSCLC.

41. The method of any one of claims 37 or 39 to 40, wherein the lung cancer has no EGFR, ALK or other actionable genomic alterations.

42. The method of claim 37, wherein the breast cancer is triple negative breast cancer (TNBC), HR + / Her2 - Breast cancer, or HR + / Her2 低 Breast cancer.

43. The method of any one of claims 1 to 42, wherein the Trop-2 positive cancer is (i) an unresectable locally advanced cancer, or (ii) a metastatic cancer.

44. The method of any one of claims 1 to 43, wherein the cancer has progressed following at least one prior anti-cancer therapy.

45. The method of claim 44, wherein the cancer has progressed following previous treatment with a novel hormonal agent (NHA; first or second generation nonsteroidal antiandrogen, e.g., abiraterone, enzalutamide, darolutamide, apalutamide).

46. ​​The method of claim 44, wherein the cancer has progressed or recurred following platinum-based chemotherapy.

47. The method of claim 44 or 46, wherein the cancer has progressed or recurred following check point inhibitor therapy (CPI).

48. The method of any one of claims 44 or 46 to 47, wherein the cancer has progressed or relapsed following platinum-based chemotherapy and anti-PD-(L)1 antibody therapy in combination or sequentially in any order.

49. The method of any one of claims 44 or 46 to 48, wherein the cancer has progressed or recurred following tyrosine kinase inhibitor therapy.

50. The method of any one of claims 1 to 49, wherein the cancer is resistant to or refractory to one or more anti-cancer therapies.

51. The method of any one of claims 1 to 43, wherein the subject is treatment naive.

52. The method of any one of claims 1 to 51, wherein the subject has not received prior therapy selected from the group consisting of: taxane therapy (taxane naive), checkpoint inhibitor therapy (CPI naive), and topoisomerase I inhibitor therapy.

53. The method of any one of claims 1 to 52, wherein the subject has not received prior taxane therapy (taxane naive), checkpoint inhibitor therapy (CPI naive), or topoisomerase I inhibitor therapy.

54. The method of claim 52 or 53, wherein the taxane therapy comprises paclitaxel, nab-paclitaxel Docetaxel or cabazitaxel.

55. The method of any one of claims 52 to 54, wherein the checkpoint inhibitor therapy comprises an anti-CTLA4 antibody or an anti-PD(L)1 antibody.

56. The method of any one of claims 52 to 55, wherein the topoisomerase I inhibitor therapy comprises topotecan, irinotecan, belotecan, or exatecan.

57. The method of any one of claims 1 to 56, wherein the anti-Trop-2 ADC and the adenosine pathway inhibitor are co-administered simultaneously.

58. The method of any one of claims 1 to 57, wherein the anti-Trop-2 ADC and the adenosine pathway inhibitor are co-administered sequentially.

59. The method of any one of claims 1 to 58, wherein the subject is a human.

60. The method of any one of claims 1 to 59, wherein the anti-Trop-2 ADC is administered in one or more doses in the range of 8 mg / kg to 10 mg / kg.

61. The method of claim 60, wherein the anti-Trop2 ADC is administered in one or more doses of 10 mg / kg.

62. The method of any one of claims 1 to 61, wherein the anti-Trop-2 ADC is administered intravenously.

63. The method of any one of claims 1 to 62, wherein the anti-Trop-2 ADC is administered on days 1 and 8 of a 21 day cycle.

64. The method of any one of claims 1 to 63, wherein the adenosine pathway inhibitor is administered in one or more doses of 75 mg or 150 mg.

65. The method of any one of claims 1 to 64, wherein the adenosine pathway inhibitor is administered in one or more doses of 150 mg.

66. The method of any one of claims 1 to 65, wherein the adenosine pathway inhibitor is administered orally (PO).

67. The method of any one of claims 1 to 64, wherein the adenosine pathway inhibitor is administered once daily (QD).

68. The method of any one of claims 55 to 67, wherein the anti-PD(L)1 antibody is administered in one or more doses of 360 mg.

69. The method of any one of claims 55 to 68, wherein the anti-PD(L)1 antibody is administered intravenously (IV).

70. The method of any one of claims 55 to 69, wherein the anti-PD(L)1 antibody is administered once every three weeks (Q3W).

71. The method of any one of claims 10 to 70, wherein gosartuzumab is administered intravenously (IV) at a dose of 10 mg / kg on days 1 and 8 of a 21-day treatment cycle, etratinum is administered orally (PO) at a dose of 150 mg once a day (QD) on each day of the 21-day treatment cycle, and optionally, sepalizumab is administered intravenously (IV) on day 1 of the 21-day treatment cycle (Q3W).

72. The method of any one of claims 1 to 71, wherein an anti-cancer effect is observed as determined by objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), duration of response (DOR), overall survival (OS), complete response (CR), partial response (PR), PSA response rate, radiographic response rate, change from baseline in blood and tumor tissue microenvironment pharmacodynamic (PD) biomarkers, or a combination of these indicators.

73. The method of claim 72, wherein tumor response or progression is determined according to RECIST version 1.

1.

74. A method for treating, alleviating, reducing, preventing or delaying the recurrence or metastasis of castration-resistant prostate cancer (CRPC), comprising co-administering to a human patient an effective amount of: a) gosartuzumab; and b) Yiqudina.

75. The method of claim 74, further comprising co-administering an anti-PD-(L)1 antibody to the human patient.

76. The method of claim 75, wherein the anti-PD-(L)1 antibody is selected from the group consisting of pembrolizumab, nivolumab, cemiprilimab, pidilizumab, spartalizumab, atezolizumab, avelumab, durvalumab, cocilimab, sazanlimab, tislelizumab, rivolimab, batilizumab, toripalimab, sitrilimab, genoluzumab, palolizumab, lodalizumab, carrelizumab, budigalimab, avelumab, dotalimumab, envolimab, sintilimab, and sepalizumab.

77. The method of claim 74, further comprising co-administering sepalizumab to the human patient.

78. The method of any one of claims 74 to 77, wherein the CRPC is metastatic CRPC (mCRPC).

79. The method of any one of claims 74 to 78, wherein the CRPC is resistant to or refractory to one or more anti-cancer therapies.

80. The method of claim 79, wherein the CRPC has progressed after previous NHA therapy (first or second generation nonsteroidal antiandrogens, abiraterone).

81. The method of any one of claims 74 to 80, wherein the human patient has not received prior therapy selected from the group consisting of taxane therapy (taxane naive), checkpoint inhibitor therapy (CPI naive), and topoisomerase I inhibitor therapy.

82. The method of claim 81, wherein the human patient has not received prior taxane therapy (taxane naive), checkpoint inhibitor therapy (CPI naive), or topoisomerase I inhibitor therapy.

83. The method of claim 81 or 82, wherein the taxane therapy comprises paclitaxel, nab-paclitaxel Docetaxel or cabazitaxel.

84. The method of any one of claims 81 to 83, wherein the checkpoint inhibitor therapy comprises an anti-CTLA4 antibody or an anti-PD(L)1 antibody.

85. The method of any one of claims 81 to 84, wherein the topoisomerase I inhibitor therapy comprises topotecan, irinotecan, belotecan, or exatecan.

86. A method for treating, alleviating, reducing, preventing or delaying the recurrence or metastasis of non-small cell lung cancer (NSCLC), comprising co-administering to a human patient an effective amount of: a) Gosartuzumab; b) eltrodinam; and c) Anti-PD-(L)1 antibodies.

87. The method of claim 86, wherein the anti-PD-(L)1 antibody is selected from the group consisting of pembrolizumab, nivolumab, cemiprilimab, pidilizumab, spartalizumab, atezolizumab, avelumab, durvalumab, cocilimab, sazanlimab, tislelizumab, rivolimab, batilizumab, toripalimab, sitrilimab, genoluzumab, palolizumab, lodalizumab, carrelizumab, budigalimab, avelumab, dotalimumab, envolimab, sintilimab, and sepalizumab.

88. The method of claim 86 or 87, wherein the anti-PD-(L)1 antibody is sepalizumab.

89. The method of any one of claims 86 to 88, wherein the NSCLC has progressed or relapsed following platinum-based chemotherapy.

90. The method of any one of claims 86 to 89, wherein the NSCLC has progressed or relapsed following check point inhibitor therapy (CPI).

91. The method of claim 90, wherein the NSCLC has progressed or relapsed following platinum-based chemotherapy and anti-PD-(L)1 antibody therapy in combination or sequentially in any order.

92. The method of any one of claims 86 to 91, wherein the NSCLC has progressed or relapsed following tyrosine kinase inhibitor therapy.

93. The method of any one of claims 86 to 92, wherein the NSCLC is (i) an unresectable locally advanced cancer, or (ii) a metastatic cancer.

94. The method of any one of claims 86 to 93, wherein gosartuzumab is administered intravenously (IV) at a dose of 8 mg / kg or 10 mg / kg on days 1 and 8 of a 21-day treatment cycle, and edrinam is administered orally (PO) once daily (QD) at a dose of 75 mg or 150 mg on each day of the 21-day treatment cycle.

95. The method of claim 94, wherein gosartuzumab is administered intravenously (IV) at a dose of 10 mg / kg on days 1 and 8 of a 21-day treatment cycle, and edrinam is administered orally (PO) at a dose of 150 mg once daily (QD) on each day of the 21-day treatment cycle.

96. The method of any one of claims 86 to 95, wherein sepalimumab is administered intravenously (IV) on day 1 (Q3W) of the 21-day treatment cycle.

97. The method of any one of claims 86 to 96, wherein an anti-cancer effect is observed as determined by objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), duration of response (DOR), overall survival (OS), complete response (CR), partial response (PR), PSA response rate, radiographic response rate, change from baseline in blood and tumor tissue microenvironment pharmacodynamic (PD) biomarkers, or a combination of these indicators.

98. The method of claim 97, wherein tumor response or progression is determined according to RECIST version 1.

1.

99. The method of any one of claims 1 to 98, wherein an anti-CD47 antibody (eg, mololimab) is not administered to the subject or the human patient.

100. The method of any one of claims 1 to 99, wherein a MCL1 inhibitor (eg, GS-9716) is not administered to the subject or the human patient.

101. The method of any one of claims 1 to 100, wherein a FLT3 agonist (eg, GS-3583, CDX-301) is not administered to the subject or the human patient.

102. A method for treating, alleviating, reducing, preventing or delaying tumor antigen positivity (TA + ) A method for preventing the recurrence or metastasis of cancer, comprising co-administering to a subject an effective amount of the following substances: a) Tumor antigen (TA)-targeted ADCs (TopIADCs) containing topoisomerase I inhibitors; b) adenosine pathway inhibitors; and c) optionally, an anti-PD(L)1 antibody.

103. An anti-Trop-2 ADC for use in a method of treating, alleviating, reducing, preventing or delaying recurrence or metastasis of a Trop-2 positive cancer in combination with an adenosine pathway inhibitor and optionally an anti-PD(L)1 antibody, wherein the method comprises administering the anti-Trop-2 ADC, the adenosine pathway inhibitor and optionally the additional anti-PD(L)1 antibody to a subject.

104. A TopI ADC for use in combination with an adenosine pathway inhibitor and optionally an anti-PD(L)1 antibody for treating, alleviating, reducing, preventing or delaying tumor antigen positive (TA + ) cancer recurrence or metastasis, wherein the method comprises administering the TopI ADC, an adenosine pathway inhibitor and optionally the anti-PD(L)1 antibody to a subject.

105. A kit for use as a medicine, wherein the kit comprises a) a TROP-2 targeting antibody-drug conjugate (ADC) comprising an anti-TROP-2 antibody (anti-TROP-2 ADC); b) adenosine pathway inhibitors; and c) optionally, an anti-PD-(L)1 antibody.

106. A kit for use as a medicine, wherein the kit comprises a) Tumor antigen (TA)-targeted ADCs (TopIADCs) containing topoisomerase I inhibitors; b) adenosine pathway inhibitors; and c) optionally, an anti-PD-(L)1 antibody.

107. A method for treating, alleviating, reducing, preventing or delaying the recurrence or metastasis of breast cancer, comprising co-administering to a human patient an effective amount of: a) gosartuzumab; and b) CD73 inhibitors.

108. The method of claim 107, wherein the CD73 inhibitor is olerumab, BMS-986179, ulelimab, AK119, quetiapine, mopalimumab, HLX23, INCA00186, IBI325, NZV930, ORIC-533, Sym024, IPH5301, IOA-237, JAB-BX100, PT199, TRB010, CD73 ASO, ABSK-051, AK131, BR101, BP1200, CB708, GB7002, or ATG-037.

109. The method of claim 107, wherein the CD73 inhibitor is quelicustat (AB680, GS-0680), ulelimab, mopalimumab, ORIC-533, ATG-037, PT-199, AK131, NZV930, BMS-986179, or olelumab.

110. The method of claim 107, wherein the CD73 inhibitor is quiliclusstat (AB680, GS-0680).

111. The method of any one of claims 107 to 110, further comprising co-administering an anti-PD-(L)1 antibody to the human patient.

112. The method of claim 111, wherein the anti-PD-(L)1 antibody is selected from the group consisting of pembrolizumab, nivolumab, cemiprilimab, pidilizumab, spartalizumab, atezolizumab, avelumab, durvalumab, cocilimab, sazanlimab, tislelizumab, rivolimab, batilizumab, toripalimab, sitrilimab, genoluzumab, palolizumab, lodalizumab, carrelizumab, budigalimab, avelumab, dotalimumab, envolimab, sintilimab, and sepalizumab.

113. The method of claim 112, further comprising co-administering sepalizumab to the human patient.

114. The method of any one of claims 107 to 113, wherein the breast cancer is metastatic breast cancer.

115. The method of any one of claims 107 to 114, wherein the breast cancer is resistant to or refractory to one or more anti-cancer therapies.

116. The method of claim 115, wherein the breast cancer has progressed following previous anticancer therapy (first or second generation anticancer therapy, such as hormonal therapy).

117. The method of any one of claims 107 to 116, wherein the human patient has not received prior therapy selected from the group consisting of: taxane therapy (taxane naive), checkpoint inhibitor therapy (CPI naive), and topoisomerase I inhibitor therapy.

118. The method of claim 117, wherein the human patient has not received prior taxane therapy (taxane naive), checkpoint inhibitor therapy (CPI naive), or topoisomerase I inhibitor therapy.

119. The method of claim 117 or 118, wherein the taxane therapy comprises paclitaxel, nab-paclitaxel Docetaxel or cabazitaxel.

120. The method of any one of claims 117 to 119, wherein the checkpoint inhibitor therapy comprises an anti-CTLA4 antibody or an anti-PD(L)1 antibody.

121. The method of any one of claims 117 to 120, wherein the topoisomerase I inhibitor therapy comprises topotecan, irinotecan, belotecan, or exatecan.

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