TW202345845A - Combination therapy for treating trop-2 expressing cancers - Google Patents

Abstract

The present disclosure relates to methods of treating, mitigating, or preventing or delaying the recurrence or metastasis of, a Trop-2 expressing cancer (e.g., metastatic castrate resistant prostate cancer, non-small cell lung cancer) in a subject by administering an effective amount of: (a) an anti-Trop-2 antibody drug conjugate (ADC) (e.g., sacituzumab govitecan); and (b) an adenosine pathway inhibitor (e.g., etrumadenant, quemliclustat) to the subject. The present disclosure further relates to methods of treating, mitigating, or preventing or delaying the recurrence or metastasis of a tumor antigen (TA) expressing cancer in a subject by administering an effective amount of: (a) a tumor antigen targeted antibody-drug conjugate (ADC) comprising a topoisomerase I inhibitor (TopI ADC); and (b) an adenosine pathway inhibitor.

Description

Combination therapies for treating TROP-2 expressing cancers

Cross-references to related applications

This application claims U.S. Provisional Patent Application No. 63/330,700 filed on April 13, 2022, U.S. Provisional Patent Application No. 63/370,228 filed on August 2, 2022, in accordance with 35 U.S.C. §119(e). and U.S. Provisional Patent Application No. 63/377,918 filed on September 30, 2022, the entire contents of each of which are hereby incorporated by reference.

The present disclosure relates to treating, alleviating, or preventing, or delaying 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: Methods for recurrence or transfer of: (a) anti-Trop-2 antibody drug conjugates (ADCs) (e.g., saxotuzumab govitcan); and (b) adenosine pathway inhibitors (e.g., , Erumeleng, Quilicrustat). The present disclosure further relates to methods of treating, alleviating, or preventing, or delaying the recurrence or metastasis of a tumor antigen (TA)-expressing cancer in a subject by administering an effective amount of: a) including topological isomers Tumor antigen-targeting antibody-drug conjugates (ADCs) of enzyme I inhibitors (TopI ADC); and b) adenosine pathway inhibitors.

Anti-Trop-2 antibody-drug conjugates, such as saxetuzumab, govitcan and datubumab, are in clinical studies for the treatment of various Trop-2-expressing cancers. Although evidence of clinical efficacy has been obtained in the monotherapy setting, further therapeutic benefit to patients is desired.

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

Metastatic or advanced prostate cancer has more complex treatment algorithms. Patients with locally advanced disease initially receive androgen ablation with radiation or prostatectomy, whereas first-line therapy in the metastatic setting is androgen ablation plus systemic therapy (eg, second-generation hormonal therapy or docetaxel-based chemotherapy) . Disease progression in the setting of androgen deprivation is called castrate resistant prostate cancer (CRPC). Specifically, the Prostate Cancer Working Group 2 (PCWG2) defines CRPC as a condition characterized by a persistent increase in serum prostate-specific antigen (PSA) levels, progression of pre-existing local or metastatic disease, and/or castration-resistant serum testosterone levels. New metastases appear under the condition (<50 ng/dL; Scher HI, et al. J Clin Oncol. (2008) 26(7):1148-1159.).

The prognosis of CRPC is related to several factors, including performance status, presence of bone pain, disease extent on bone scan, and serum alkaline phosphatase (ALP) levels. Approximately 80% of men with CRPC will develop bone metastasis, which may result in significant complications, including pain, pathological fractures, spinal cord compression, and bone marrow failure. Paraneoplastic effects are also common and include anemia, weight loss, fatigue, hypercoagulable states, and increased susceptibility to infection (Saad F and Hotte S. Can Urol Assoc J. (2010) 4(6):380-384).

During the past decade, six new agents have been approved by the U.S. Food and Drug Administration (FDA) 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 individual agent is rarely long-lasting, with 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, and novel therapeutic developments are being actively explored.

Lung cancer is the leading cause of cancer-related death worldwide. It is estimated that there will be more than 2 million new cases of lung cancer globally in 2020, with approximately 1.8 million deaths. In the United States (US), more than 235,000 new cases of lung cancer and more than 131,000 deaths are expected in 2021. Approximately 80% to 85% of all lung cancers are non-small cell lung cancer (NSCLC) (Ettinger et al. J Natl Compr Canc Netw (2019);17(12):1464-72), and more than Half were determined to be late stage (Siegel et al. CA Cancer J Clin (2019);69 (1):7-34).

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

Recent advances in immune checkpoint inhibitor (CPI) therapy have significantly improved the prognosis of advanced lung cancer, and these immune-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 performance), mainly used in the frontline metastasis setting based on the results of KEYNOTE-024, KEYNOTE-042, KEYNOTE-189, and KEYNOTE-407 and for patients with no operable genes Similar studies were conducted with altered participants. Regardless of PD-L1 expression, chemotherapy/immunotherapy regimens such as pembrolizumab/(carboplatin or cisplatin)/pemetrexed are recommended for patients with non-squamous NSCLC. 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).

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, the use of single-agent chemotherapy, including taxanes, after failure of platinum-based therapy and/or immune checkpoint therapy, regardless of the presence of genomic alterations and PD-L1 status, is recommended for relapse or Standard treatment for patients with metastatic NSCLC (Ettinger et al. J Natl Compr Canc Netw (2019);17 (12):1464-72). In this setting, the main options for single-agent chemotherapy typically include docetaxel (with or without ramucirumab) and pemetrexed (for nonsquamous tumors, if not previously used). In a study of docetaxel in relapsed NSCLC with best supportive care, the median progression-free survival (PFS) was approximately 3 months and the median overall survival (OS) was approximately 6 months. to 8 months (Shepherd et al. J Clin Oncol (2000);18(10):2095-103). These numbers have been confirmed in more concurrent studies of docetaxel following the failure of platinum-based regimens in NSCLC (Horn et al. J Clin Oncol (2017); 35 (35):3924-33; Mazieres et al. 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 subsequent treatment of advanced or metastatic NSCLC.

Immune checkpoint inhibitors have sparked renewed interest in clinical development of anti-cancer immunotherapies. The latter relies on other forms of treatment in the tumor microenvironment or the immune system to overcome the immunosuppressive mechanism caused by the tumor on the host immune system. Although the approval of nivolumab, pembrolizumab, atezolizumab, and ipilimumab has demonstrated their benefit in multiple tumor types, checkpoint inhibition has not yet proven effective in the treatment of metastatic prostate cancer. The response rate of monotherapy is less than 5% (Antonarakis ES, et al. J Clin Oncol. (2020) 38(5):395-405.).

Antibody-drug conjugates (ADCs) are a rapidly growing drug class 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 typically consist of a monoclonal antibody linked to a cytotoxic drug (payload). ADCs are designed to limit the delivery of cytotoxic drugs to cells expressing the target antigen of the respective antibody (e.g., Trop-2, Her-2, Nectin-4) and in the immediate vicinity of tumor tissue (bystander effect). Tumor-targeted delivery of cytotoxic agents by ADCs generally has a greatly improved therapeutic window compared to systemically administered cytotoxic agents. Examples of ADCs that have received marketing approval from the US Food and Drug Administration (US FDA) include gemtuzumab ozogamicin, brentuximab vedotin, ado-trastuzumab ado-trastuzumab emtansine (T-DM1), inotuzumab ozogamicin, trastuzumab deruxtean (T-DXd), ado-trastuzumab ozogamicin Polatuzumab vedotin, sacituzumab deruxtecan, enfortumab vedotin, and belantamab mafodotin.

The adenosine pathway mediates immunosuppressive effects 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 undergoing clinical research as promising agents for stimulating anti-cancer immune responses.

Despite advances in cancer treatment, many patients remain refractory to currently available therapies or relapse in response to available therapies, resulting in a need for the development of novel agents and agent combinations for the treatment of multiple types of cancer, including mCRPC.

In one aspect, provided herein are methods of 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) anti-Trop- 2 Antibody drug conjugates (ADCs); and b) Adenosine pathway inhibitors.

In some embodiments, methods provided herein are for treating 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) Adenosine pathway inhibitors.

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

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

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

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

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

In some embodiments, the topoisomerase I inhibitor is SN38.

In some embodiments, the anti-Trop-2 ADC has the structural formula of mAb-CL2A-SN-38, which has the structure represented by: (Described, for example, in U.S. Patent No. 7,999,083).

In some embodiments, the anti-Trop-2 ADC includes saxotuzumab (hRS7; described in, eg, WO 2003074566, Figures 3 and 4).

In some embodiments, the anti-Trop-2 ADC is selected from the group consisting of: datopotamab deruxtecan (DS-1062), ESG -401, SKB-264, DAC-02, and BAT-8003.

In some embodiments, the anti-Trop-2 ADC is saxotuzumab govitcan.

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

In some embodiments, the adenosine pathway inhibitor is a plurality of adenosine pathway inhibitors. In some embodiments, the plurality of adenosine pathway inhibitors include CD73 inhibitors and adenosine receptor antagonists. In some embodiments, the CD73 inhibitor is quiclocrustat and the adenosine receptor antagonist is elumelon.

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

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

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 alumilan (AB928; GS-0928), taminadenant, TT-10, TT-4, or M1069.

In some embodiments, the adenosine pathway inhibitor is elumelon.

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

In some embodiments, the CD73 inhibitor is oleclumab, BMS-986179, uliledlimab, AK119, quilicrustat, mupadolimab, 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 quiclocrustat (AB680, GS-0680), ulelelimab, mupadolizumab, ORIC-533, ATG-037, PT-199, AK131, NZV930, BMS-986179, or olerumab.

In some embodiments, the CD73 inhibitor is quiclocrustat.

In some embodiments, the method further comprises co-administering additional therapeutic agents or treatment modalities.

In some embodiments, the additional therapeutic agents or treatment modes include one, two, three, or four additional therapeutic agents and/or treatment modes.

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

In some embodiments, the anti-PD-(L)1 antibody system is pembrolizumab, nivolumab, cemiplimab, pidilizumab, spartalizumab, atezolizumab, avelumab, durvalumab, cosibelimab, sasanlimab ), tislelizumab, retifanlimab, balstilimab, toripalimab, cetrelimab, Genolizumab, prolgolimab, lodapolimab, camrelizumab, budigalimab, avelumab ( avelumab), dostarlimab (dostarlimab), envafolimab (envafolimab), sintilimab (sintilimab), or zimberelimab (zimberelimab).

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

In some embodiments, the additional therapeutic agent includes an anti-TIGIT antibody.

In some embodiments, the anti-TIGIT antibodies are tiragolumab, vibostolimab, domvanalimab, AB308, AK127, BMS-986207, rapsutta monoclonal antibody (ralzapastotug), or etigilimab (etigilimab).

In some embodiments, the anti-TIGIT antibody is dovanalimab. In some embodiments, the anti-TIGIT antibody is rapasutalumab.

In some embodiments, additional therapeutic agents include anti-PD-(L1) antibodies and anti-TIGIT antibodies.

In some embodiments, the additional therapeutic agents include a) sepalizumab and dovanalizumab, b) sepalizumab and AB308, c) atezolizumab and tisrelumab, d) Pembrolizumab and Weibolizumab, e) Pembrolizumab and Dovanalumab, f) Pembrolizumab and AB308, g) MK-7684A (Pembrolizumab/Weibolizumab co-formulation), h) durvalumab and dovanalumab, i) cepalizumab and rapasutalumab, or j) pembrolizumab and rapasutalumab.

In some embodiments, additional therapeutic agents include cepalizumab and dovanalizumab.

In some embodiments, the Trop-2 positive cancer is solid epithelial cancer.

In some embodiments, the solid epithelial cancer is selected from the group consisting of breast cancer (e.g., triple negative breast cancer (TNBC), HR ⁺ /Her2 ⁻ breast cancer, HR ⁺ /Her2 ^low breast cancer), colorectal cancer, lung cancer, gastric cancer, urethral cancer, urothelial cancer cancer, bladder cancer, kidney cancer, pancreatic cancer, ovarian cancer, uterine cancer, esophageal cancer, and prostate cancer. In some embodiments, the breast cancer is triple negative breast cancer (TNBC), HR ⁺ /Her2 ⁻ breast cancer, or HR ⁺ /Her2 ^low breast cancer.

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

In some embodiments, the lung cancer is non-small lung cancer (NSCLC).

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

In some embodiments, the lung cancer line does not have EGFR, ALK, or other actionable genomic alterations.

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

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

In some embodiments, the cancer has progressed following prior treatment with a new hormonal agent (NHA; first or second generation nonsteroidal antiandrogen, abiraterone).

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

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

In some embodiments, the cancer has progressed or recurred after receiving platinum-based chemotherapy and anti-PD-(L)1 antibody therapy in any order, in combination or sequentially.

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

In some embodiments, the subject is treatment naïve.

In some embodiments, the subject does not receive a treatment selected from the group consisting of taxane therapy (not receiving a taxane), checkpoint inhibitor therapy (not receiving a CPI), and topoisomerase I inhibitor therapy Previous therapy.

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

In some embodiments, taxane therapy includes paclitaxel, albumin-bound paclitaxel ( ^ABRAXANE® ), docetaxel, or cabazitaxel.

In some embodiments, checkpoint inhibitor therapy includes an anti-CTLA4 antibody or an anti-PD(L)1 antibody.

In some embodiments, topoisomerase I inhibitor therapy includes topotecan, irinotecan, bellotecan, or ixotecan.

In some embodiments, the anti-Trop-2 ADC and the adenosine pathway inhibitor are co-administered concurrently.

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

In some embodiments, the subject is a human being.

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

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

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

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

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

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

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

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

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

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

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

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

In some embodiments, saxetuzumab govitcan is administered intravenously (IV) at a dose of 10 mg/kg on days 1 and 8 of a 21-day treatment cycle, and elumelon is administered on day 21 A dose of 150 mg is administered orally (PO) once daily (QD) on each day of the 21-day treatment cycle, and optionally, cepalizumab is administered intravenously (IV) on Day 1 of the 21-day treatment cycle (Q3W). ) invest.

In some embodiments, the anti-cancer effect is measured by objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), duration of response (duration of response) , DOR), overall survival (OS), complete response (CR), partial response (PR), PSA response rate, radiation response rate, blood and tumor tissue microenvironment pharmacodynamics ( PD) biomarkers are observed as determined by changes from baseline, or combinations thereof. In some embodiments, tumor response or progression is determined according to RECIST version 1.1.

In some embodiments, provided herein are methods of 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) saxetuzumab Anti-govitkan; and b) Arumeleng. In some embodiments, provided herein is a method of treating metastatic castration-resistant prostate (mCRPC), the method comprising co-administering to a human patient an effective amount of a) saxetulizumab govitcan; and b) ellu Beautiful cold. 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 system is selected from the group consisting of: pembrolizumab, nivolumab, cemiplimab, pidilizumab, spartalizumab, atezolizumab, avelumab, durvalumab, coxilizumab ( cosibelimab), sasanlimab, tislelizumab, retifanlimab, balstilimab, toripalimab, cetrelimab, genolimzumab, prolgolimab, lodapolimab, camrelizumab, brigalizumab budigalimab, avelumab, dostarlimab, envafolimab, sintilimab, and zimberelimab. In some embodiments, the method further comprises co-administering cepalizumab to the human patient. In some embodiments, the human mCRPC patient has previously progressed on ADT. In some embodiments, the human mCRPC patient has previously progressed on NHA. In some embodiments, human mCRPC patients do not receive CPIs and taxanes. In some embodiments, the human mCRPC patient has RECIST 1.1 measurable or non-measurable disease.

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

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

In some embodiments, CRPC has progressed following prior NHA therapy (first or second generation nonsteroidal antiandrogen, abiraterone).

In some embodiments, the human patient has not received prior therapy selected from the group consisting of taxane therapy (not receiving a taxane), checkpoint inhibitor therapy (not receiving a CPI), and topoisomerase I inhibitor therapy.

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

In some embodiments, taxane therapy includes paclitaxel, albumin-bound paclitaxel ( ^ABRAXANE® ), docetaxel, or cabazitaxel.

In some embodiments, checkpoint inhibitor therapy includes an anti-CTLA4 antibody or an anti-PD(L)1 antibody.

In some embodiments, topoisomerase I inhibitor therapy includes topotecan, irinotecan, bellotecan, or ixotecan.

In some embodiments, provided herein are methods of treating, alleviating, reducing, preventing, or delaying recurrence or metastasis of non-small cell lung cancer (NSCLC), comprising co-administering to a human patient an effective amount of: a) Sa Cituzumab Govitcan; b) elumelon; and c) anti-PD-(L)1 antibody. In some embodiments, the anti-PD-(L)1 antibody system is selected from the group consisting of: pembrolizumab, nivolumab, cemiplimab, pidilizumab, spartalizumab, atezolizumab, avelumab, durvalumab, coxilizumab ( cosibelimab), sasanlimab, tislelizumab, retifanlimab, balstilimab, toripalimab, cetrelimab, genolimzumab, prolgolimab, lodapolimab, camrelizumab, brigalizumab budigalimab), avelumab, dostarlimab, envafolimab, sintilimab, and zimberelimab. In some embodiments, the anti-PD-(L)1 antibody is sepalizumab. In some embodiments, NSCLC has progressed or recurred following platinum-based chemotherapy. In some embodiments, NSCLC has progressed or recurred following checkpoint inhibitor therapy (CPI) therapy. In some embodiments, NSCLC has progressed or recurred after receiving platinum-based chemotherapy and anti-PD-(L)1 antibody therapy in any order, in combination or sequentially. In some embodiments, NSCLC has progressed or recurred following tyrosine kinase inhibitor therapy. In some embodiments, the NSCLC is (i) unresectable locally advanced or (ii) metastatic.

In some embodiments, saxetuzumab govitcan 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 Lumereng was administered orally (PO) at a dose of 75 mg or 150 mg once daily (QD) on each day of the 21-day treatment cycle.

In some embodiments, saxetuzumab govitcan is administered intravenously (IV) at a dose of 10 mg/kg on Days 1 and 8 of a 21-day treatment cycle, and elumelon is administered on 150 mg was administered orally (PO) once daily (QD) on each day of the 21-day treatment cycle.

In some embodiments, cepalizumab is administered intravenously (IV) on Day 1 of a 21-day treatment cycle (Q3W).

In some embodiments, the anti-cancer effect is measured by objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), duration of response (DOR), overall survival (OS), complete response Observe changes from baseline (CR), partial response (PR), PSA response rate, radiation response rate, blood and tumor tissue microenvironment pharmacodynamics (PD) biomarkers, or a combination thereof. In some embodiments, the anti-cancer effect is measured by objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), complete response (CR), partial response (PR). ), PSA response rate, radiation response rate, or changes from baseline in pharmacodynamic (PD) biomarkers of the blood and tumor tissue microenvironment.

In some embodiments of the methods provided herein, the anti-CD47 antibody (eg, magrolumab) is not co-administered with the subject or human patient.

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

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.

In one aspect, provided herein are methods of treating, alleviating, reducing, preventing, or delaying the recurrence or metastasis of tumor antigen-positive (TA ⁺ ) cancer, comprising co-administering to a subject an effective amount of: a) A tumor antigen (TA) targeting ADC comprising a topoisomerase I inhibitor (TopI ADC); b) an adenosine pathway inhibitor; and c) optionally an anti-PD-(L)1 antibody.

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 for treating, ameliorating, reducing, preventing, or delaying A method of recurrence or metastasis of 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.

In another aspect, provided herein is 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 positivity (TA ⁺ ) A method of recurrence or metastasis of cancer, wherein the method comprises administering to a subject a TopI ADC, an adenosine pathway inhibitor, and optionally an anti-PD(L)1 antibody.

Provided herein are combination therapies for treating, alleviating, reducing, preventing, or delaying the recurrence or metastasis of Trop-2 positive (Trop-2 ⁺ ) cancers by co-administering to a subject an effective amount of a) anti-Trop-2 Antibody drug conjugates (anti-Trop-2 ADC) and b) adenosine pathway inhibitors. Also provided herein are combination therapies for treating, alleviating, reducing, preventing, or delaying the recurrence or metastasis of tumor antigen-positive (TA ⁺ ) cancers by co-administering to a subject an effective amount of a) comprising a topoisomerase I inhibitor (TopI ADC) tumor antigen (TA) targeting ADC and b) an effective amount of adenosine pathway inhibitor. In some embodiments, combination therapies provided herein further comprise co-administration of additional therapeutic agents, such as checkpoint inhibitors, or additional treatment modalities (eg, surgery, radiation). In some embodiments, the anti-Trop-2 ADC is saxotuzumab govitcan. In some embodiments, the TopI ADC is trastuzumab delutecan (T-DXd). In some embodiments, the adenosine pathway inhibitor is a CD39 inhibitor (e.g., TTX-030, IPH5201, SRF617), a CD73 inhibitor (e.g., quicrustat, olelutumab), or an adenosine receptor body antagonists (e.g., elumelen, emarelen, NIR178). In some embodiments, the checkpoint inhibitor is an anti-PD(L)1 antibody (eg, cepalizumab, 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).

In another aspect, the present invention provides a method for use with an adenosine pathway inhibitor (e.g., elumelon) and optionally an additional therapeutic agent (such as a checkpoint inhibitor (e.g., anti-PD(L)1 antibody)). Anti-Trop-2 ADCs (e.g., saxetuzumab govitcan) used in combination with additional treatment modalities (e.g., surgery, radiation) to treat, mitigate, reduce, prevent, or delay the recurrence of Trop-2-positive cancers Methods for the development or metastasis of cancer, wherein the method includes administering to a subject (e.g., a human cancer patient) an anti-Trop-2 ADC, an adenosine pathway inhibitor, and optionally additional therapeutic agents or additional treatment modalities. In some embodiments, the anti-Trop-2 ADC is saxotuzumab govitcan. In some embodiments, the adenosine pathway inhibitor is a CD39 inhibitor (e.g., TTX-030, IPH5201, SRF617), a CD73 inhibitor (e.g., quicrustat, olelutumab), or an adenosine receptor body antagonists (e.g., elumelen, emarelen, NIR178). In some embodiments, the checkpoint inhibitor is an anti-PD(L)1 antibody (eg, cepalizumab, 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).

In another aspect, provided herein are methods for use with adenosine pathway inhibitors (e.g., CD39 inhibitors, CD73 inhibitors, adenosine receptor antagonists) and optional additional therapeutic agents (such as checkpoint inhibitors (e.g., CD39 inhibitors, CD73 inhibitors, adenosine receptor antagonists) TopI ADCs used in combination with (e.g., anti-PD(L)1 antibodies)) or additional treatment modalities (e.g., surgery, radiation) are used to treat, alleviate, reduce, prevent, or delay the recurrence or metastasis of TA-positive cancers, wherein The method includes administering to a subject (eg, a human cancer patient) a TopI ADC, an adenosine pathway inhibitor, and optionally additional therapeutic agents or additional treatment modalities. In some embodiments, the TopI ADC is trastuzumab delutecan (T-DXd). In some embodiments, the adenosine pathway inhibitor is a CD39 inhibitor (e.g., TTX-030, IPH5201, SRF617), a CD73 inhibitor (e.g., quicrustat, olelutumab), or an adenosine receptor body antagonists (e.g., elumelen, emarelen, NIR178). In some embodiments, the checkpoint inhibitor is an anti-PD(L)1 antibody (eg, cepalizumab, 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).

The present disclosure is based, at least in part, on the understanding that combination therapy involving co-administration of a) an anti-Trop2 ADC or TopI ADC and b) an adenosine pathway inhibitor is comparable to single-agent therapy using one of the combination agents a) and b) ratio, may have improved anti-cancer effects. Improved anti-cancer effects may include, for example, improved overall response rate (ORR), improved partial response rate (PR), improved complete response rate (CR), improved duration of response (DOR), improved overall survival (OS) ), improved progression-free survival (PFS), improved quality of life (QoL) measures, or similar. Combination therapies described herein generally have a tolerable safety profile, as determined, for example, by the observed incidence and/or severity of adverse events (AEs) or serious adverse events (SAEs). In some embodiments, combination therapies described herein have an improved safety profile, e.g., compared to monotherapy involving co-administration of agents, or relative to standards of care for a given indication (e.g., physician's choice of chemotherapy plan). definition

As used herein, the term "antibody" refers to a polypeptide that includes typical immunoglobulin sequence elements sufficient to confer specific binding to a particular target antigen (e.g., heavy chain variable domain, light chain variable domain, and/or or one or more CDRs sufficient to confer specific binding to a specific target antigen). Thus, the term antibody includes, for example, but is not limited to, human antibodies, non-human antibodies, antibody fragments, and antigen-binding agents including antibody fragments, including synthetic, engineered, and modified forms thereof. The term antibody includes, for example, naturally occurring and non-naturally occurring antibodies. Generally, an antibody may comprise at least two heavy (H) chains and two light (L) chains interconnected by disulfide bonds, or antigen-binding molecules 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 contains 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 contains one constant domain, CL. The VH and VL regions can be further subdivided into highly variable regions called complementarity determining regions (CDRs), interspersed with more conservative regions called framework regions (FRs). Each VH and VL contains three CDRs and four FRs, arranged from the amine 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 the antigen. The constant region of an antibody (Ab) mediates the binding of immunoglobulins to host tissues or factors, including various cells of the immune system (eg, effector cells) and the first component (C1q) of the typical complement system. Naturally produced antibodies are glycated, typically 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 containing two heavy chain and two light chain molecules, antibody light chain monomers, antibody heavy chain monomers, antibody light chain dimers, antibody heavy chain dimers, antibodies Light chain-antibody heavy chain pair, intrabody, antibody fusion (sometimes referred to herein as "antibody conjugate"), heteroconjugate antibody, single domain antibody, monovalent antibody, single chain Antibody or single chain Fv (scFv), camelized antibody, affinity antibody (affybody), Fab fragment, Fab' fragment, F(ab')2 fragment, Fd' fragment, Fd fragment, isolated CDR, single chain Fv , polypeptide-Fc fusion, single domain antibody (such as shark single domain antibody, such as IgNAR or its fragment); camelidin antibody; disulfide bonded Fv (sdFv), anti-idiotypic (anti-Id) Antibodies (including, for example, anti-anti-Id antibodies), minibodies, domain antibodies, synthetic antibodies (sometimes referred to herein as "antibody mimetic"), single-chain or tandem diabodies (TandAb ^® ), Anticalins ^® , Nanobodies ^® , minibodies, BiTE ^® , ankyrin repeat proteins or DARPINs ^® , Avimers ^® , DART, TCR-like antibodies, Adnectins ^® , Affilins ^® , Trans-bodies ^® , Affibodies ^® , TrimerX ^® , MicroProtein, Fynomers ^® , Centyrins ^® , KALBITOR ^® s, and antigen-binding fragments of any of the above.

As used herein, the term "antibody-drug conjugate" generally refers to a compound comprising an antibody targeting a tumor antigen and an anti-cancer agent payload, optionally linked by a linker. In some embodiments, the tumor antigen is tumor-associated calcium signaling transducer 2 (Trop-2; NCBI Gene ID: 4070). In some embodiments, the antibody targeting the tumor antigen is an anti-Trop-2 antibody (eg, saxotuzumab or datubumab). In some embodiments, the payload is a topoisomerase I inhibitor (eg, SN38 or Dxd). Many ADC linker chemistries are known to those of ordinary skill in the art and are referenced herein (eg, CL2A).

As used herein, the term "topoisomerase I inhibitor" refers to a small molecule compound capable of inhibiting the activity of DNA topoisomerase type I enzyme. Type I topoisomerases 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. A description of type I topoisomerase can be found, for example, in Baker et al. (2009) Nucleic Acids Res 37(3), 693-701 . Topoisomerase inhibitors that can be used as payloads in the ADCs described herein include camptothecin (CPT) and non-camptothecin inhibitors. Useful camptothecins include, for example, topotecan, irinotecan, bellotecan, or ixotecan, and derivatives thereof. Useful non-camptothecins include, for example, indenoisoquinoline (e.g., indeno[1,2-c]isoquinoline, NSC314622, indotecan (LMP-400), indimitecan ) (LMP-776)), phenanthridines (e.g., topovale (ARC-111), and indolocarbazole (e.g., BE-13793C)). In some embodiments, the topoisomerase I inhibitor is camptothecin (eg, irinotecan, topotecan, bellotecan, or an ixotecan derivative such as SN38 or Dxd). In some embodiments, the topoisomerase I inhibitor is SN38. In some embodiments, the topoisomerase I inhibitor is Dxd.

As used herein, the term "anti-PD(L)1 antibody" refers to an antibody that a) 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) inhibit PD-1/PD-L1 interaction and 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 useful in the methods provided herein include, for example, pembrolizumab, nivolumab, cemiplimab, pidilizumab (pidilizumab), spartalizumab (spartalizumab), atezolizumab (atezolizumab), avelumab (avelumab), durvalumab (durvalumab), cosibelimab (cosibelimab), sasanil sasanlimab, tislelizumab, retifanlimab, balstilimab, toripalimab, cizrolimab ( cetrelimab), genolimzumab (genolimzumab), prolgolimab (prolgolimab), lodapolimab (lodapolimab), camrelizumab (camrelizumab), budigalimab (budigalimab), advil avelumab, dostarlimab, envafolimab, sintilimab, and zimberelimab. In some embodiments, the anti-PD-(L)1 antibody is sepalizumab.

As used herein, the terms "effective amount" or "therapeutically effective amount" refer to a therapeutic agent (e.g., ADC, adenosine pathway inhibitor, checkpoint inhibitor, etc.) administered in the methods provided herein. inhibitor), when administered to a cell, tissue, or subject, alone or in combination with another therapeutic agent, is sufficient to achieve a therapeutic or beneficial result in the subject. The therapeutically effective amount will vary depending on the subject and disease or condition being treated, the weight and age of the subject, the severity of the disease or condition, and the mode of administration, and can be readily determined by one of ordinary skill in the art. An effective amount further refers to an amount of a therapeutic agent that, when used in the context of the combination therapies provided herein, is sufficient to treat, prevent, mitigate, ameliorate, or reduce the condition of a disease, or delay or slow the progression of the disease, and which amount Sufficient to increase the rate of treatment, healing, prevention, or amelioration of such conditions. When applied to an individual therapeutic agent administered alone, the effective amount refers to the active ingredient alone. A therapeutically effective amount refers to the combined amount of the active ingredients that produces a therapeutic effect when applied to a combination, whether administered combined, sequentially, or simultaneously. In some embodiments, an effective amount or a therapeutically effective amount of a therapeutic agent (e.g., ADC, adenosine pathway inhibitor, checkpoint inhibitor), as described herein, is combined with one or more additional therapeutic agents in the methods provided herein. Administered to the subject together, it can (i) reduce the number of diseased cells; (ii) reduce the size of the tumor; (iii) inhibit, block, slow down, and preferably prevent the infiltration of diseased cells into peripheral organs to a certain extent; (iv) inhibit (e.g., slow down and preferably prevent to some extent) tumor metastasis; (v) inhibit tumor growth; (vi) prevent or delay the occurrence and/or recurrence of tumors; and/or (vii) in some cases Alleviating one or more of the symptoms associated with cancer. In various embodiments, the amount is sufficient to ameliorate, alleviate, lessen, and/or delay one or more symptoms of cancer.

As used herein, the term "treatment/treat/treating" means reversing, alleviating, delaying the onset, or inhibiting the progression of a disease or condition as described herein, or one or more symptoms thereof. In some embodiments, treatment may be administered after the development of one or more symptoms. In other embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to susceptible individuals before symptoms begin (eg, due to a history of symptoms and/or due to genetic or other susceptibility factors). Treatment may also be continued after symptoms have been relieved, for example, to prevent or delay their recurrence. In some embodiments, the methods provided herein refer to treating a subject with cancer (eg, a human cancer patient). In some embodiments, treating a subject with cancer (eg, a human cancer patient) includes inhibiting cancer or cancer cell proliferation in the treated subject. In some embodiments, treatment of human cancer patients using the methods provided herein results in an anti-tumor effect or anti-cancer effect being observed in the treated patient.

As used herein, the terms "inhibition of cancer" and "inhibition of cancer cell proliferation" mean inhibiting the growth, division, maturation, or viability of cancer cells, and/or by The death of cancer cells, either individually or in clusters with other cancer cells, caused by cytotoxicity, nutrient depletion, or induction of apoptosis.

As used herein, the terms "anti-tumor effect" and "anti-cancer effect (anti-cancer effect/anti-cancer efficacy)" refer to a reduction in tumor volume, a reduction in the number of tumor cells, and a decrease in the number of tumor cells. Biological effects that reduce cell proliferation, reduce the number of metastases, increase overall or progression-free survival, increase life expectancy, or improve various physiological symptoms related to tumors. In some embodiments, anti-cancer effects are measured using one or more endpoint criteria (eg, primary, secondary, or exploratory endpoints) used in clinical studies described herein. Exemplary clinical endpoint criteria that can be used to measure anti-cancer effects associated with the methods provided herein include objective response rate (ORR), complete response (CR) rate, partial response (PR) rate, disease control rate (DCR), no Progression survival (PFS), duration of response (DOR), overall survival (OS), biomarker-based signals such as intratumoral immune activation or induction of cancer cell death (e.g., tumor tissue or blood-based biomarkers), Patient quality of life (QoL) indicators (e.g., based on patient surveys), and others. In some embodiments, tumor effects (eg, tumor response or progression) are 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 one of ordinary skill in the art, such as computed tomography (CT), magnetic resonance imaging (MRI), radiography, or the like.

As used herein, an "increased" or "enhanced" amount is generally a "statistically significant" amount (e.g., with respect to tumor size, cancer cell proliferation or growth), and may include 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 or more Multiple times (such as 100, 500, 1000 times) (including all integers and decimal points between and above 1, such as 2.1, 2.2, 2.3, 2.4, etc.) increase. It may also include increasing the amounts or levels described herein by 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%.

As used herein, a "decreased" or "reduced" or "lesser" amount (eg, with respect to tumor size, cancer cell proliferation or growth) means an amount or level described herein 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 or more times (such as 100, 500, 1000 times) (including all integers and decimal points between and above 1, such as 1.5, 1.6, 1.7, 1.8, etc.). It may also include reducing the amounts or levels described herein by 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%.

As used herein, the term "adverse event" (AE) refers to any adverse medical event that occurs when a clinical study participant is administered an investigational drug, but is not necessarily causally related to the treatment. Accordingly, an AE may thus be any adverse and/or unintended sign (including clinically significant abnormal laboratory findings), symptom, or disease temporarily associated with the use of the 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 result in increased severity or change in nature after initiation of study drug or during or as a result of participation in a clinical study are also considered AEs.

As used herein, the term "serious adverse event" (SAE) means a) death; b) a life-threatening condition; c) hospitalization of a participant or prolongation of an existing hospitalization; d) persistent or significant incapacity or lack of capacity; e) congenital abnormalities or birth defects; or f) medically important events or reactions as determined by the attending physician. Examples of medically significant events include intensive treatment of allergic bronchospasm in the emergency room or at home; hematologic cachexia or seizures that do not result in hospitalization; and development of drug dependence or substance abuse.

As used herein, the terms "tumor antigen expressing cancer" or "tumor antigen positive cancer" are used interchangeably to refer to expression of a tumor antigen (TA) in detectable amounts of cancer. In some embodiments, the tumor antigen is Trop-2. Tumor antigen expression in cancer 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 one of ordinary skill in the art, e.g., as protein, mRNA, or cells surface level of performance. For example, tumor antigen expression can be detected by methods such as immunohistochemistry (IHC), Western blotting, fluorescence in situ hybridization (FISH), polymerase chain reaction (PCR), next-generation exome sequencing, or fluorescent light-dependent cell sorting (FACS) and other methods to determine. As used herein, to be considered TA positive (eg, Trop-2 positive) does not require that every cell in the tumor or tumor sample has detectable levels of tumor antigen expression. In some embodiments, less than 99%, less than 95%, less than 90%, less than 80%, less than 70%, less than 60%, less than 50%, less than 40% of the "TA-expressing cancers" or "TA-positive cancers" %, less than 30%, less than 20%, or less than 10% of the cells in the tumor or tumor sample have detectable levels of tumor antigen expression. In some embodiments, 99% or more, 95% or more, 90% or more, 80% or more, 70% or more, 60% or more, 50% or more, 40% or more, 30% or more, 20% or more, or 10% or more of the tumors or tumor samples have detectable levels of cells Tumor antigen expression. In some embodiments, "TA expressing cancer" or "TA positive cancer" (e.g., Trop-2 positive cancer) refers to treatment with certain anti-Trop-2 ADCs or TopI ADCs. Cancers indicated for treatment as single agent therapy or combination therapy. The TA-positive cancer indications for anti-Trop-2 ADCs or TopI ADCs that have received marketing approval from regulatory health agencies (e.g., FDA, EMA) are listed, for example, on the agency-approved drug labeling. In some embodiments, as used herein, a TA-positive (e.g., Trop-2 ⁺ ) cancer line in which an anti-Trop-2 ADC or TopI ADC has demonstrated anti-cancer effects is attributable to the anti-Trop-2 ADC or TopI ADC a type of cancer. Such anticancer effects can be demonstrated in preclinical models (such as mouse xenografts or syngeneic cancer models) or in clinical trials in human cancer patients. In some embodiments, a TA-expressing cancer or a TA-positive cancer does not express detectable levels of Trop-2, eg, as determined by IHC and/or FISH analysis.

As used herein, the term "tumor antigen targeted antibody-drug conjugate (ADC)" generally refers to an ADC that includes a tumor antigen-binding antibody. Such TA-binding antibodies often direct ADCs to TA-expressing cancer cells in tumor tissue. In some embodiments, a TA-binding antibody is a neutralizing antibody or blocking antibody (competing with another binding partner for binding to TA). In some embodiments, TA-binding antibodies can modulate TA-related molecules or cell signaling events. In some embodiments, a TA-binding antibody has antagonistic or agonistic activity relative to TA. TA-targeted ADCs that may be used in the methods provided herein include, but are not limited to, gemtuzumab ozogamicin, butuximab vedotin, ado-trastuzumab entacin (T-DM1 ), Ointuzumab, trastuzumab dultecan (T-DXD), datubumab dultecan (DATO-DXD), paclitaxel vedotin, saxitu Tizumab delutecan, labezumab govitcan, infutuzumab vedotin, and belimumab mofostin. In some embodiments, the TA-targeting ADC does not bind to Trop-2. List of abbreviations and acronyms A _2a R or A2AR adenosine 2a receptor A _2b R or A2BR adenosine 2b receptor ADA anti-drug antibodies ADC Antibody drug conjugates ADT androgen ablation therapy AE adverse events AMP adenosine monophosphate ASCO American Society of Clinical Oncology CPI checkpoint inhibitors CPT Camptothecin CR full response CRPC Castration-resistant prostate cancer CT computed tomography CTCAE Common terminology standards for adverse events CTLA4 Cytotoxic T lymphocyte antigen-4 CYP Cytochrome P450 DCR disease control rate DLT dose limiting toxicity DNA deoxyribonucleic acid ECG electrocardiogram ECOG East Coast Cancer Clinical Research Collaborative EMA European Medicines Agency EOT End of treatment ESMO European Society of Medical Oncology FDA U.S. Food and Drug Administration GI gastrointestinal tract HBcAb Hepatitis B core antibody HBsAg Hepatitis B surface antigen HBV Hepatitis B virus HCV Hepatitis C virus HIV human immunodeficiency virus IC ₅₀ half maximum inhibitory concentration ICH International Association for Medical Regulations INR international standardized ratio IV intravenously mCRPC Metastatic castration-resistant prostate cancer mg milligrams mL ml mOS Median overall survival MRI magnetic resonance imaging MTD maximum tolerated dose mTNBC metastatic triple negative breast cancer NA Not applicable NCCN National Cancer Information Network NCI National Cancer Institute NHA new hormonal agent NK natural killer (cell) NSCLC non-small cell lung cancer ORR overall response rate OS Overall survival PAP prostatic acid phosphatase PCWG2 Prostate Cancer Working Group 2 PCWG3 Prostate Cancer Working Group 3 PD disease progression PD-1 programmed cell death protein 1 PD-L1 programmed cell death ligand 1 PFS progression-free survival PK Pharmacokinetics PR partial reaction PSAs prostate specific antigen QD Once a day Q3W every three weeks RECIST Response Evaluation Criteria in Solid Tumors RNA RNA SD disease stable SG saxituzumabgovitkan TNAP tissue nonspecific alkaline phosphatase TNBC triple negative breast cancer Antibody Drug Conjugates (ADCs)

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 anti-cancer agent payload, and an optional linker connecting the anti-Trop-2 antibody and the payload (anti-Trop-2 ADC). In some embodiments, the anti-cancer agent payload in the anti-Trop-2 ADC is a topoisomerase I inhibitor (eg, SN38, Dxd). In some embodiments, the anti-cancer 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 connecting the TA targeting antibody and 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 antibodies in the TropI ADC do not include anti-Trop-2 antibodies.

ADCs useful in the methods provided herein may comprise any form of antibody or antigen-binding fragment 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 ^DART® , Duobody®, ^{BiTE® ,} BiKE, TriKE , XmAb ^® , TandAb ^® , scFv, Fab, or Fab derivatives. In some embodiments, the ADC comprises a non-immunoglobulin antibody mimetic (e.g., including adnectin, affibody, affilin, affimer, affitin ), alphabody, anticalin, peptide aptamer, armadillo repeat protein (ARM), atrimer, high-affinity multimer (avimer), designed ankyrin repeat protein (DARPin ^® ), fynomer, knottin, Kunitz domain peptide, single antibody, and nanoCLAMP).

In some embodiments, the ADC antibody blocks the antibody. In some embodiments, the ADC antibody neutralizes the antibody. In some embodiments, the ADC antibodies are agonist or activating antibodies. In some embodiments, the ADC is an antagonistic or inhibitory antibody.

In some embodiments, the ADC comprises an IgG antibody or antigen-binding fragment thereof. IgG antibodies or antigen-binding fragments thereof can be of various isotypes, such as IgGl, IgG2, IgG3, or IgG4. In some embodiments, the ADC antibody comprises human IgG1 hinge and constant region sequences. ADC antibodies can be chimeric human-mouse, chimeric human-primate, humanized (human framework and murine hypervariable (CDR) regions), or fully human antibodies, as well as variants thereof. In some embodiments, the ADC antibody is half an IgG4 antibody (termed a "unibody"), as described, for example, by van der Neut Kolfschoten et al. (Science 2007; 317:1554-1557). In some embodiments, ADC antibodies or antigen-binding fragments thereof are designed or selected to include human constant region sequences belonging to a specific allotype that may cause immunogenicity when the antibody or ADC is administered to a human subject. reduce. In some embodiments, the ADC antibody or antigen-binding fragment thereof is a non-Glm1 allotype (nGlm1), 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 allotype. Anti- TROP-2 ADC

In some embodiments, ADCs useful in the methods provided herein comprise an anti-Trop-2 antibody, an anti-cancer agent payload, and an optional linker connecting the anti-Trop-2 antibody and 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.

Examples of anti-Trop-2 antibodies that may be used in anti-Trop-2 ADCs to perform the methods provided herein include, but are not limited to, 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), US9 850312 (Daiichi Sankyo), CN112321715 (Biosion), US2006193865 (Immunomedics/Gilead), WO2011068845 (Immunomedics/Gilead), US2016296633 (Immunomedics/Gilead), US2017021017 (Immunomedics/Gilead), US2017209594 (Immunomedics/Gilead), US201 7274093 (Immunomedics/Gilead), US2018110772 (Immunomedics/Gilead), US2018185351 (Immunomedics/Gilead), US2018271992 (Immunomedics/Gilead), WO2018217227 (Immunomedics/Gilead), US2019248917 (Immunomedics/Gilead), CN111534585 (Immunomedics/Gilead), US2021093730 (Immuno medics/Gilead), US2021069343 (Immunomedics/Gilead), US8435539 ( Immunomedics/Gilead), US8435529 (Immunomedics/Gilead), US9492566 (Immunomedics/Gilead), WO2003074566 (Gilead), WO2020257648 (Gilead), US2013039861 (Gilead), WO2014163684 (Gilead), US94 27464 (LivTech/Chiome), US10501555 (Abruzzo Theranostic /Oncoxx), WO2018036428 (Sichuan Kelun Pharma), WO2013068946 (Pfizer), WO2007095749 (Roche), and WO2020094670 (SynAffix).

In some embodiments of the methods provided herein, the anti-Trop-2 ADC comprises an antibody selected from the group consisting of saxotuzumab (hRS7), datubumab (hTINA H1L1), and Trop-2 binding fragments thereof. In some embodiments, the anti-Trop-2 antibody is saxotuzumab (hRS7). In some embodiments, the anti-Trop-2 antibody is datubumab (hTINA H1L1).

In some embodiments of the methods provided herein, the anti-Trop-2 ADC comprises VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2, and VL-CDR3. In some embodiments, the anti-Trop-2 ADCs each comprise the following VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2, and VL-CDR3 amino acid sequences (according to Kabat): ● SEQ ID NO: 1, 2, 3, 4, 5, and 6, or ● SEQ ID NO: 7, 8, 9, 10, 11, and 12.

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, anti-Trop-2 ADCs each comprise the following VH and VL amino acid sequences: ● SEQ ID NO: 49 and 50, or ● SEQ ID NO: 51 and 52. Table 1 – CDRs of illustrative anti-Trop-2 binding antibodies (Kabat) Ab name VH – CDR1 VH – CDR2 VH – CDR3 VL – CDR1 VL – CDR2 VL – CDR3 1 NYGMN SEQ ID NO:1 WINTYTGEPTYTDDFKG SEQ ID NO:2 GGFGSSYWYFDV SEQ ID NO:3 KASQDVSIAVA SEQ ID NO:4 SASYRYT SEQ ID NO:5 QQHYITPLT SEQ ID NO:6 2 TAGMQ SEQ ID NO:7 WINTHSGVPKYAEDFKG SEQ ID NO:8 SGFGSSYWYFDV SEQ ID NO:9 KASQDVSTAVA SEQ ID NO:10 SASYRYT SEQ ID NO:11 QQHYITPLT SEQ ID NO:12 Table 2 – Illustrative anti-Trop-2 binding antibody CDRs (IMGT) Ab name VH – CDR1 VH – CDR2 VH – CDR3 VL – CDR1 VL – CDR2 VL – CDR3 3 GYTFTNYG SEQ ID NO:13 INTYTGEP SEQ ID NO:14 ARGGFGSSYWYFDV SEQ ID NO:15 QDVSIA SEQ ID NO:16 SAS SEQ ID NO:17 QQHYITPLT SEQ ID NO:18 4 GYTFTTAG SEQ ID NO:19 INTHSGVP SEQ ID NO:20 ARSGFGSSYWYFDV SEQ ID NO:21 QDVSTA SEQ ID NO:22 SAS SEQ ID NO:23 QQHYITPLT SEQ ID NO:24 Table 3 – CDRs of illustrative anti-Trop-2 binding antibodies (Chothia) Ab name VH – CDR1 VH – CDR2 VH – CDR3 VL – CDR1 VL – CDR2 VL – CDR3 5 GYTFTNY SEQ ID NO:25 TYTG SEQ ID NO:26 GFGSSYWYFD SEQ ID NO:27 SQDVSIA SEQ ID NO:28 SAS SEQ ID NO:29 HYITPL SEQ ID NO:30 6 GYTFTTA SEQ ID NO:31 THSG SEQ ID NO:32 GFGSSYWYFD SEQ ID NO:33 SQDVSTA SEQ ID NO:34 SAS SEQ ID NO:35 HYITPL SEQ ID NO:36 Table 4 – CDRs of Illustrative Anti-Trop-2 Binding Antibodies (Honegger) Ab name VH – CDR1 VH – CDR2 VH – CDR3 VL – CDR1 VL – CDR2 VL – CDR3 7 ASGYTFTNYG SEQ ID NO:37 INTYTGEPTYTDDFKGR SEQ ID NO:38 GGFGSSYWYFD SEQ ID NO:39 ASQDVSIA SEQ ID NO:40 SASYRYTGVPDR SEQ ID NO:41 HYITPL SEQ ID NO:42 8 ASGYTFTTAG SEQ ID NO:43 INTHSGVPKYAEDFKGR SEQ ID NO:44 SGFGSSYWYFD SEQ ID NO:45 ASQDVSTA SEQ ID NO:46 SASYRYTGVPSR SEQ ID NO:47 HYITPL SEQ ID NO:48 Table 5 – VH/VL of Illustrative Anti-Trop-2 Binding Antibodies Ab name VH VL 9 SEQ ID NO:49 QVQLQQSGSELKKPGASVKVSCKASGYTFTNYGMNWVKQAPGQGLKWMGWINTYTGEPTYTDDFKGRFAFSLDTSVSTAYLQISSLKADDTAVYFCARGGFGSSYWYFDVWGQGSLVTVS SEQ ID NO:50 DIQLTQSPSSSLSASVGDRVSITCKASQDVSIAVAWYQQKPGKAPKLLIYSASYRYTGVPDRFSGSGSGTDFTLTISSLQPEDFAVYYCQQHYITPLTFGAGTKVEIK 10 SEQ ID NO:51 QVQLVQSGAEVKKPGASVKVSCKASGYTFTTAGMQWVRQAPGQGLEWMGWINTHSGVPKYAEDFKGRVTISADTSTSTAYLQLSSLKSEDTAVYYCARSGFGSSYWYFDVWGQGTLVTVSS SEQ ID NO:52 DIQMTQSPSSSLSASVGDRVTITCKASQDVSTAVAWYQQKPGKAPKLLIYSASYRYTGVPSRFSGSGSGTDFTLTISSLQPEDFAVYYCQQHYITPLTFGQGTKLEIK

In some embodiments of the methods provided herein, an anti-Trop-2 ADC comprises an anti-Trop-2 antibody, an anti-cancer agent payload, and optionally a linker linking the antibody and the payload. In some embodiments, the linker is non-cleavable (eg, maleimidehexyl or maleimidemethylcyclohexane-1-carboxylate linker). In some embodiments, the linker is cleavable. In some embodiments, the linker is acid-cleavable (eg, a hydrazone linker). In some embodiments, the cleavable linker is reducible (eg, a disulfide linker). In some embodiments, the linker is protease-cleavable (eg, a dipeptide or tetrapeptide linker). In some embodiments, the linker is selected from linkers disclosed in USPN 7,999,083 (eg, CL2A, CL6, CL7, CLX, or CLY). In some embodiments, the linker is CL2A. Additional linker chemistries that can be used in anti-Trop-2 ADCs are described, for example, in 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; datopotamab deruxtecan), WO21147993 (Jiangsu Hengrui Medicine; SHR-A1921), and WO21052402 (S ichuan Baili Pharmaceutical ; BL-M02D1).

Exemplary anti-cancer agent payloads that can be used in anti-Trop-2 ADCs in the methods provided herein include, for example, microtubule inhibitors, DNA cleavage 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, epothilone) or a maytansinoid (such as mertansine (DM1) or ravtansine (DM4)). In some embodiments, the DNA cleavage agent is calicheamicin (eg, ozomicin). In some embodiments, the topoisomerase I inhibitor is camptothecin (eg, irinotecan, topotecan, bellotecan, or an ixotecan 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 other than camptothecin (i.e., a non-camptothecin isomerase I inhibitor). In some embodiments, the non-camptothecin topoisomerase I inhibitor is selected from indenoisoquinoline (e.g., indeno[1,2-c]isoquinoline, NSC314622, indotecan ) (LMP-400), indimitecan (LMP-776)), phenanthridines (e.g., topovale (ARC-111)), and indolocarbazole (e.g., BE-13793C )).

Illustrative anti-cancer agent payloads that can be conjugated to anti-Trop-2 ADCs include, but are not limited to, anthracyclines (e.g., doxorubicin, daunorubicin, pan-idromycin, idamycin), Pyrrolobenzodiazepine (PBD), or its dimer, DNA cross-linking agent SC-DR002 (D6.5), becamycin, becamycin (A, B1, B2, C1, C2, D, SA, CC-1065), tubulysin B and its analogs (e.g., Tub196), and other anticancer agents described herein.

Exemplary anti-Trop-2 ADC systems useful in the methods provided herein are described in 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; datopotamab deruxtecan), WO21147993 (Jiangsu Hengrui Medicine; SHR-A1921), and WO 21052402 ( Sichuan Baili Pharmaceutical; BL-M02D1).

In some embodiments of the methods provided herein, the anti-Trop-2 ADC is selected from the group consisting of datubumab govitcan (Immunomedics/Gilead), datubumab datubumab (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 (OBI Pharma), BL-M02D1 (Systimmune), anti-Trop-2 Ab (Mediterrania Theranostic/ Legochem), KD-065 (Nanjing KAEDI Biotech), anti-Trop2 sdAb (Kisoli Biotech), anti-Trop-2 ADC (Shandong Fontacea), LIV-2008 (LivTech/Yakult Honsha), 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 First Hospital), and hRS7-CM (SynAffix), 89Zr-DFO -AF650 (University of Wisconsin-Madison). In some embodiments, the anti-Trop-2 ADC is saxotuzumab govitcan (Immunomedics/Gilead). In some embodiments, the anti-Trop-2 ADC is selected from the group consisting of datopotamab deruxtecan (DS-1062), ESG-401, SKB-264, DAC-02, and BAT-8003. In some embodiments, the anti-Trop-2 ADC is saxotuzumab govitcan. In some embodiments, the anti-Trop-2 ADC is datubumab deletcan (DS-1062, Dato-Dxd; Daiichi Snakyo/AstraZeneca). Further examples of useful anti-Trop-2 therapeutics include, but are not limited to, those described in WO2016201300 (Gilead), and CN108440674 (Hangzhou Lonzyme Biological Technology).

Exemplary anti-Trop-2 ADCs useful in the methods provided herein are described, for example, in USPN 7,999,083 and USPN 9,028,833, the entire contents of which are hereby incorporated by reference. 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 of mAb-CL2A-SN-38, which has the structure represented by: (Described in, for example, USPN 7,999,083). In some embodiments, the drug-to-antibody ratio (DAR) of CL2A-SN38 to the anti-Trop-2 antibody in the anti-Trop2 ADC is ≥7.0 (eg, DAR = 7.6). In some embodiments, the drug-to-antibody ratio (DAR) of CL2A-SN38 to the anti-Trop-2 antibody in the anti-Trop2 ADC is between 7.0 and 8.0 (eg, DAR = 7.6). In some embodiments, the anti-Trop-2 ADC includes saxotuzumab (hRS7; described in, eg, WO2003074566, Figures 3 and 4). In some embodiments, the anti-Trop-2 ADC is saxotuzumab govitcan (IMMU-132). Sasituzumab Govitkan (SG) is an antibody drug conjugate (ADC), consisting of the following three components: ● 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 signaling overexpressed in many epithelial cancers, including triple-negative breast cancer (TNBC). ● Camptothecin derivative SN-38, topoisomerase I inhibitor. ● Connect the humanized monoclonal antibody to the hydrolyzable linker (CL2A) of SN-38.

Additional exemplary anti-Trop-2 ADCs useful in the methods provided herein are described in WO21225892 (Shanghai Escugen Biotechnology). In some embodiments, the anti-Trop-2 ADC comprises a linker payload conjugate having a structure represented by the following structure: Attach to 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).

Additional exemplary anti-Trop-2 ADCs that may be used in the methods provided herein are described in US20210101906 (Sichuan Kelun Pharmaceutical). In some embodiments, the anti-Trop-2 ADC comprises a linker payload conjugate (TL035) having the following structural representation: Attach to 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.

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 comprises a linker payload conjugate having a structure represented by the following structure: Attached to 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 of <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 datubumab and drotecan. TopI ADC

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 linking the TA targeting antibody and the payload. (TopI ADC) optional linker. In some embodiments, the TA-targeting antibody in the TopI ADC is an anti-Trop-2 antibody. In some embodiments, the TA-targeting antibodies in the TopI ADC do not include anti-Trop-2 antibodies.

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: 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, CD45, CD46, CD52, CD54, CD55, CD59, CD64, CD67, CD70, CD74, CD79a, CD80, CD83, CD95, CD126, CD133, CD138, CD147, CD154, CEACAM5, CEACAM-6, α Fetal protein (AFP), VEGF, ED-B fibronectin, EGP-1, EGP-2, EGF receptor (ErbB1), ErbB2, ErbB3, H factor, FHL-1, Flt-3, folate receptor, Ga 733, GROB, HMGB-1, hypoxia-inducible factor (HIF), HM1.24, insulin-like growth factor (ILGF), IFN-α, IFN-β, IL-γ, 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, ganglioside, 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 factor, tumor angiogenesis Antigens, TNF-α., TRAIL receptors (R1 and R2), VEGFR, RANTES, T101, cancer stem cell antigens, complement factors C3, C3a, C3b, C5a, C5, and oncogene products.

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: 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).

In some embodiments, TopI ADCs useful in performing the methods provided herein include gemtuzumab, butuximab, belinumab, capidanumab, trastuzumab, intuzumab monoclonal antibody, grebaratumumab, anetatumumab, mivituximab, depatuximab, vadatuximab, labetuzumab, radirantuzumab anti-, loncatuximab, patrituximab, rivastuximab, indusantuximab, bonaltuzumab, pinatuximab, cortuximab, pfitatumumab, indacilumab, milatuzumab, lovatuzumab, infutumumab, tasutumumab, tusamitanumab, disitumab, Rituzumab, and its antigen-binding fragments.

In some embodiments, TopI ADCs useful in the methods provided herein comprise an antibody selected from: 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 (rabbezumab; 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 7,387,773), hL243 (anti-HLA-DR; USPN 7,612,180), and hIMMU-31 (anti-AFP; USPN 7,300,655), which are also described in For example, USPN 7,999,083.

In some embodiments of the methods provided herein, a 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 (eg, maleimidehexyl or maleimidemethylcyclohexane-1-carboxylate linker). In some embodiments, the linker is cleavable. In some embodiments, the linker is acid-cleavable (eg, a hydrazone linker). In some embodiments, the cleavable linker is reducible (eg, a disulfide linker). In some embodiments, the linker is protease-cleavable (eg, a dipeptide or tetrapeptide linker). In some embodiments, the linker is selected from linkers disclosed in USPN 7,999,083 (eg, CL2A, CL6, CL7, CLX, or CLY). In some embodiments, the linker is CL2A. Additional linker chemistries that can be used for anti-TopI ADCs are described, for example, in 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; datopotamab deruxtecan), WO21147993 (Jiangsu Hengrui Medicine; SHR-A1921), and WO21052402 (Sichuan Bai li Pharmaceutical; BL -M02D1).

In some embodiments of the methods provided herein, the TopI ADC comprises a topoisomerase I inhibitor that is camptothecin (e.g., irinotecan, topotecan, bellotecan, or ixotecan 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 indenoisoquinoline (e.g., indeno[1,2-c]isoquinoline, NSC314622, indotecan ) (LMP-400), indimitecan (LMP-776)), phenanthridines (e.g., topovale (ARC-111)), and indolocarbazole (e.g., BE-13793C )).

In some embodiments, TopI ADC has the structural formula of mAb-CL2A-SN-38, wherein the structure is represented by: (Described, for example, in U.S. Patent No. 7,999,083).

In some embodiments, TopI ADCs useful 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 (eg, as described in WO1996011013). In some embodiments, the anti-CEACAM5 ADC is that described in WO2010093395 (anti-CEACAM5-CL2A-SN38). In some embodiments, the TopI ADC is rabezumab govitcan (IMMU-130).

In some embodiments, TopI ADCs useful in the methods provided herein comprise antibodies targeting MHC class II cell surface receptors encoded by human leukocyte antigen complex (HLA-DR). In some embodiments, the HLA-DR antibody hL243 (eg, as described in WO2006094192). In some embodiments, the HLA-DR-ADC is that described in WO2010093395 (anti-HLA-DR-CL2A-SN38). In some embodiments, the antibodies and/or fusion proteins provided herein are administered with HLA-DR-ADC IMMU-140.

Additional exemplary TopI ADCs that can be co-administered in the methods provided herein are described in WO21225892 (Shanghai Escugen Biotechnology). In some embodiments, a TopI ADC comprises a linker payload conjugate having a structure represented by the following structure: Attached to tumor antigen-targeting antibodies.

Additional exemplary TopI ADCs that can be co-administered in the methods provided herein are described in US20210101906 (Sichuan Kelun Pharmaceutical). In some embodiments, a TopI ADC comprises a linker payload conjugate (TL035) having a structure represented by the following structure: Attached to tumor antigen-targeting antibodies.

Additional exemplary TopI ADCs that can be co-administered in the methods provided herein are described in US2016297890 (Daiichi Sankyo). In some embodiments, a TopI ADC comprises a linker payload conjugate having a structure represented by the following structure: Attached to a tumor antigen-targeting antibody (e.g., trastuzumab). In some embodiments, TopI ADC has a DAR of about 4. In some embodiments, the TopI ADC is trastuzumab delutecan (T-DXd). adenosine pathway inhibitor

The adenosine pathway is one of several pathways that can promote tumor immune escape in the tumor microenvironment. It is believed that the conversion of pro-inflammatory extracellular ATP into immunosuppressive adenosine (eADO) may contribute to tumor progression and escape from anti-tumor immunity. The role of the adenosine pathway in immuno-oncology is described, for example, in Allard et al., (2020) Nat Rev Clin Oncol 17, 611-629 .

Adenosine pathway inhibitors that may be co-administered in the methods provided herein may include, for example, CD39 inhibitors (extracellular nucleoside triphosphate diphosphate hydrolase-1; ENTPD1; NCBI Gene ID: 953); Exo-5'-nucleotidase;NT5E; NCBI Gene ID: 4907) or an adenosine receptor antagonist such as the adenosine A _2A receptor (ADORA2A; NCBI Gene ID: 135) or the adenosine A _2B receptor (ADORA2B ; NCBI gene ID: 136). In some embodiments, adenosine pathway inhibitors that may be co-administered in the methods provided herein include a CD38 inhibitor (cyclic ADP ribose hydrolase; NCBI Gene ID: 952). CD39 inhibitor

CD39 inhibitors that may be co-administered in the methods provided herein include small molecule inhibitors and large molecule inhibitors of CD39 (eg, anti-CD39 antibodies). Exemplary CD39 inhibitors are described, for example, in WO09095478, WO12085132, WO16073845, WO17157948, WO18049145, WO18065552, WO18065622, WO19027935, WO19178269, WO21056610, WO21037037, WO21 055329, 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 (Shanghai Junshi Biosciences) ; Anti-CD39 (Arcus Biosciences), ES002 (Elpiscience Biopharmaceuticals), and CD39xPD1 (Biotheus). CD73 inhibitor

CD73 inhibitors that may be co-administered in the methods provided herein include small molecule inhibitors and large molecule inhibitors of CD73 (eg, anti-CD73 antibodies). Exemplary CD73 inhibitors useful in the methods provided herein are described, for example, in U.S. Patent No. 11,001,603, which compounds are hereby incorporated by reference. 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, WO 18013611, WO18067424, WO18065627, WO18094148, WO18110555 , WO18119284, WO18137598, WO18183635, WO18208980, WO18208727, WO18215535, WO18237173, WO18237157, WO19053617, WO19090111, WO19129059, WO19168744, WO1 9166701, WO19173291, WO19173692, WO19170131, WO19224025, WO19232244, WO19246403, WO20046813, WO20047082, WO20051686, WO20097127, WO20098599, WO201398 03 , WO20143836, WO20143710, WO20151707, WO20205538, WO20202038, WO20210970, WO20210938, WO20216697, WO20221209, WO20244606, WO20253568, WO20257429, WO2 1011689, WO21029450, WO21032173, WO21040356, WO21041319, WO21043229, WO21044005, WO21087136, WO21087463, WO21088901, WO21097223, WO21105916, WO211136 25 , WO21138467, WO21205383, WO21213466, WO21213475, WO21216898, WO21222522, WO21227306, WO21241729, WO21257643, WO21259199, WO22007677, WO22052886, WO2 2068929, WO22083049, WO22083049, WO22090711, WO22095975, WO22095953, WO22096020, and WO22121914. In some embodiments, the CD73 inhibitor is selected from the group consisting of Olerumab (AstraZeneca), BMS-986179 (BMS), Ulelevumab (I-MAB Biopharma), AK119 (Akeso Biopharma), Quilixirumab Sistat (AB680, Arcus Biosciences), mupadolizumab (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 quiclocrustat (AB680, GS-0680), ulelelimab, mupadolizumab, ORIC-533, ATG-037, PT-199, AK131, NZV930, BMS-986179, or olerumab. In some embodiments, the CD73 inhibitor is olerumab or quiclocrustat. In some embodiments, the CD73 inhibitor is quiclocrustat. adenosine receptor antagonist

The adenosine receptor antagonist that can be co-administered in the methods provided herein can be an adenosine A2A receptor (A2AR; ADORA2A) or A2B receptor (A2BR; ADORA2B), or a dual A2A/2BR antagonist. In some embodiments, the adenosine receptor antagonist is a selective A2aR antagonist. In some embodiments, the adenosine receptor antagonist is an adenosine A2A receptor (A2AR; ADORA2A) selective antagonist selected from the group consisting of 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 the group consisting of 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 the group consisting of Alumelen (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 elumelon. Adenosine receptor antagonists can be small molecule antagonists or macromolecule antagonists.

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, WO14101120, WO14101113, WO14106861, WO15027431, WO16081290, WO16126570, WO16200717, WO16209787, WO17008205, WO18013951, WO19086074, WO2 019118313, WO20053263, WO20106558, WO20103930, WO20103939, WO20106560, WO20112706, WO20112700, WO20216152, WO20135210, WO20135195, WO20150677, WO2015 0675 , WO20150674, WO20150676, WO20152132, WO20156505, WO20159905, WO21018172, WO20227156, WO2101873, WO20260196, WO20253867, WO20263058, WO20260857, WO21 011670, WO21093701, WO21041360, WO21099832, WO21105916, WO21146631, WO21156439, WO21179074, WO21185256, WO21194623, WO21191376, WO21191380, WO2119137 8 , WO21191379, WO21224636, WO22020552, WO22020550, WO22023772, WO22072601, and WO22123272.

Exemplary adenosine receptor antagonists useful in the methods provided herein are described, for example, in U.S. Patent No. 10,399,962, the compounds of which are hereby incorporated by reference. In some embodiments, the adenosine pathway inhibitors are adenosine A2A receptors (A2AR; ADORA2A) and A2B receptors (A2BR; ADORA2B). In some embodiments, the adenosine pathway inhibitor is alumilan (AB928; GS-0928), taminadenant, TT-10, TT-4, or M1069. In some embodiments, the adenosine pathway inhibitor is elumelon.

In the absence of any agonist activity, Alumelen (AB928) is a small molecule dual antagonist of both A2AR and A2BR, which can inhibit adenosine-driven tumor-infiltrating lymphocytes (mainly through CD8+ T cells and A2AR on NK cells) and bone marrow cells (through A2BR on dendritic cells and macrophages). Alumelen can achieve high penetration into tumor tissue, is robustly effective in the presence of high adenosine concentrations, and shows low non-specific protein binding. PD(L)1 inhibitors

In some embodiments, the combination treatment methods provided herein comprise co-administering a PD(L)1 inhibitor. PD(L)1 inhibitors that may be co-administered may include small molecule PD(L)1 inhibitors and large molecule PD(L)1 inhibitors (eg, anti-PD(L)-1 antibodies).

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. anti- PD(L)1 antibody

Exemplary anti-PD-(L)1 antibodies that can be co-administered in the methods provided herein include, for example, pembrolizumab, nivolumab, cemiplimab, pidilizumab, spartalizumab, atezolizumab, avelumab, durvalumab, coxilizumab ( cosibelimab), sasanlimab, tislelizumab, retifanlimab, balstilimab, toripalimab, cetrelimab, genolimzumab, prolgolimab, lodapolimab, camrelizumab, brigalizumab budigalimab), avelumab, dostarlimab, envafolimab, sintilimab, and zimberelimab. In some embodiments, the anti-PD-(L)1 antibody is sepalizumab.

Additional illustrative anti-PD-(L)1 antibodies that may be co-administered in the methods provided herein include pembrolizumab, nivolumab, cemiplimab, pidilizumab, AMP-224, MEDI0680 (AMP-514), spartalizumab, atezolizumab, avelumab, devalumab durvalumab, BMS-936559, cosibelimab (CK-301), sasanlimab (PF-06801591), tislelizumab (BGB-A317), GLS-010 (WBP-3055), AK-103 (HX-008), AK-105, CS-1003, HLX-10, retifanlimab (MGA-012), BI-754091, Bath Balstilimab (AGEN-2034), AMG-404, toripalimab (JS-001), cetrelimab (JNJ-63723283), jernolizumab (genolimzumab) (CBT-501), LZM-009, prolgolimab (BCD-100), lodapolimab (LY-3300054), SHR-1201, camrelizumab (camrelizumab) (SHR-1210), Sym-021, budigalimab (ABBV-181), PD1-PIK, BAT-1306, avelumab (MSB0010718C), CX-072 , CBT-502, dostarlimab (TSR-042), MSB-2311, JTX-4014, BGB-A333, SHR-1316, CS-1001 (WBP-3155, envafolimab ) (KN-035), sintilimab (IBI-308), HLX-20, KL-A167, STI-A1014, STI-A1015 (IMC-001), BCD-135, FAZ-053, TQB-2450, MDX1105-01, GS-4224, GS-4416, INCB086550, MAX10181, zimberelimab (AB122), spartalizumab (PDR-001), and disclosed in Compounds in WO2018195321, WO2020014643, WO2019160882, or WO2018195321, and 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), bintrafusp alpha (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). anti- TIGIT antibody

Exemplary anti-TIGIT antibodies that may be co-administered in the methods provided herein include, for example, tisrelumab, weibrolizumab, dovanalimab, AB308, AK127, BMS-986207, rapasutumab anti-, and ertigirimab. In some embodiments, the anti-TIGIT antibody is dovanalimab. In some embodiments, the anti-TIGIT antibody is AB308. In some embodiments, the anti-TIGIT antibody is rapasutalumab.

In some embodiments, the anti-TIGIT antibody is an Fc-silencing antibody. In some embodiments, anti-TIGIT antibodies comprise one or more mutations in the Fc region to reduce, prevent, or eliminate binding to Fc receptors. In some embodiments, anti-TIGIT antibodies comprise one or more mutations in the Fc region to reduce, prevent, or eliminate binding to FcγR. In some embodiments, any of the antibodies disclosed herein comprise one or more mutations in the Fc region to reduce, prevent, or eliminate binding to FcγRIIIA. In some embodiments, any of the antibodies disclosed herein comprise one or more mutations in the Fc region to reduce, prevent, or eliminate binding to FcyRIV. In some embodiments, anti-TIGIT antibodies comprise one or more mutations in the Fc region to reduce, prevent, or eliminate ADCC, ADCP, and/or CDC. In some embodiments, an anti-TIGIT antibody contains one or more substitutions in the Fc region to reduce, prevent, or eliminate binding to the 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 thereof. In some embodiments, anti-TIGIT antibodies comprise one or more substitutions in the Fc region to reduce, prevent, or eliminate binding to Fc receptors, wherein the one or more substitutions comprise S228P, E233P, L234A, L235A, L235E , L235F, G236R, G237A, D265A, N297A, K322A, A327G, L328R, A330S, P331S, and any combination thereof. 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 US No. 6,624,821.

In some embodiments, the anti-TIGIT antibody is an Fc-enabled antibody. In some embodiments, anti-TIGIT antibodies comprise one or more mutations in the Fc region to achieve or enhance binding to Fc receptors. In some embodiments, anti-TIGIT antibodies comprise one or more mutations in the Fc region to achieve or enhance binding to FcγR. In some embodiments, any of the antibodies disclosed herein comprise one or more mutations in the Fc region to achieve or enhance binding to FcγRIIIA. In some embodiments, any of the antibodies disclosed herein comprise one or more mutations in the Fc region to achieve or enhance binding to FcyRIV. In some embodiments, anti-TIGIT antibodies comprise one or more mutations in the Fc region to achieve or enhance ADCC, ADCP, and/or CDC. In some embodiments, anti-PD-(L)1 antibodies comprise one or more substitutions in the Fc region to enhance or enable binding to Fc receptors, 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 thereof. In some embodiments, anti-TIGIT antibodies comprise one or more substitutions in the Fc region to enhance or enable binding to Fc receptors, wherein the one or more substitutions comprise 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 thereof. In some embodiments, the Fc-enabled antibody comprises a modified IgG1 domain characterized by substitutions at S239D, A330L, and I332E (Eu numbering). Alternatively, anti-TIGIT antibodies contain or have glycoform perturbations. In some embodiments, an anti-TIGIT antibody contains or has N-linked Fc glycosylation. In some embodiments, anti-TIGIT antibodies contain or have sialylation, galactosylation, bisecting sugars, fucosylation, or any combination thereof. Additional mutations in the Fc region that enhance or enable binding to Fc receptors and alternative strategies for enhancing or enabling binding to Fc receptors are described in Saunders, 2019. Treatment

In one aspect, provided herein are methods of treating, alleviating, reducing, preventing, or delaying the recurrence or metastasis of Trop-2 positive (Trop-2 ⁺ ) cancer, comprising co-administering to a subject an effective amount of each of the following: : a) anti-Trop-2 antibody drug conjugates (ADCs); and b) adenosine pathway inhibitors (such as CD39 inhibitors, CD73 inhibitors, or A2R inhibitors). In some embodiments, methods provided herein include treating Trop-2 positive cancer, comprising co-administering to the subject an effective amount of: a) an anti-Trop-2 antibody drug conjugate (ADC); and b) Adenosine pathway inhibitors (such as CD39 inhibitors, CD73 inhibitors, or A2R inhibitors). In some embodiments, methods provided herein include treating recurrence or metastasis of a 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) adenosine pathway inhibitors (such as CD39 inhibitors, CD73 inhibitors, or A2R inhibitors). In some embodiments, methods provided herein include preventing or delaying the recurrence or metastasis of a 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) adenosine pathway inhibitors (such as CD39 inhibitors, CD73 inhibitors, or A2R inhibitors). In some embodiments, the adenosine pathway inhibitor is a plurality of adenosine pathway inhibitors. In some embodiments, the plurality of adenosine pathway inhibitors include CD73 inhibitors and adenosine receptor antagonists. In some embodiments, the CD73 inhibitor is quiclocrustat and the adenosine receptor antagonist is elumelon.

In some embodiments, methods provided herein are for treating 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) Adenosine pathway inhibitors (such as CD39 inhibitors, CD73 inhibitors, or A2R inhibitors).

In one aspect, provided herein are methods of treating, alleviating, reducing, preventing, or delaying the recurrence or metastasis of tumor antigen-positive (TA ⁺ ) cancer, comprising co-administering to a subject an effective amount of: a) Tumor antigen (TA)-targeted antibody drug conjugates (ADCs) containing topoisomerase I inhibitors (TopI ADCs); and b) adenosine pathway inhibitors (such as CD39 inhibitors, CD73 inhibitors, or A2R inhibition agent). In some embodiments, methods provided herein include treating tumor antigen positive (TA+) cancer, comprising co-administering to a subject an effective amount of: a) a tumor antigen target comprising a topoisomerase I inhibitor to antibody drug conjugates (ADCs); and b) adenosine pathway inhibitors (eg, CD39 inhibitors, CD73 inhibitors, or A2R inhibitors). In some embodiments, methods provided herein include treating recurrence or metastasis of a tumor antigen-positive cancer, comprising co-administering to a subject an effective amount of: a) a tumor comprising a topoisomerase I inhibitor Antigen-targeting antibody drug conjugates (ADCs); and b) adenosine pathway inhibitors (such as CD39 inhibitors, CD73 inhibitors, or A2R inhibitors). In some embodiments, methods provided herein include preventing or delaying recurrence or metastasis of a tumor antigen-positive cancer, comprising co-administering to a subject an effective amount of: a) comprising a topoisomerase I inhibitor Tumor antigen-targeted antibody drug conjugates (ADCs); and b) adenosine pathway inhibitors (such as CD39 inhibitors, CD73 inhibitors, or A2R inhibitors).

In some embodiments, methods provided herein are for treating tumor antigen-positive cancers, comprising co-administering to a subject an effective amount of: a) Tumor antigen targeting comprising a topoisomerase I inhibitor Antibody drug conjugates (ADCs); and b) adenosine pathway inhibitors (such as CD39 inhibitors, CD73 inhibitors, or A2R inhibitors).

In some embodiments, provided herein are methods of treating, alleviating, reducing, preventing, or delaying the recurrence or metastasis of a tumor antigen (eg, Trop-2) positive cancer, comprising co-administering to a subject a combination provided herein. In some embodiments, treatment methods provided herein reduce the occurrence or recurrence of tumor antigen (eg, Trop-2) positive cancers by administering a combination provided herein. In some embodiments, treatment methods provided herein reduce the occurrence or recurrence of tumor antigen (eg, Trop-2) positive cancers by administering a combination provided herein. In some embodiments, treatment methods provided herein prevent the occurrence or recurrence of tumor antigen (eg, Trop-2) positive cancers by administering a combination provided herein. In some embodiments, treatment methods provided herein delay the onset or recurrence of tumor antigen (eg, Trop-2) positive cancers by administering a combination provided herein.

In some embodiments, the methods provided herein further comprise co-administering additional therapeutic agents or treatment modalities, or combinations thereof. In some embodiments, the methods provided herein comprise co-administering one, two, or three additional therapeutic agents or treatment modalities, or combinations thereof. In some embodiments, the additional therapeutic agent includes chemotherapy (eg, chemotherapy treatment selected by a physician, or designated standard of care in a particular treatment setting). In some embodiments, the additional therapeutic agent includes an immune checkpoint inhibitor (CPI; eg, anti-CTLA4 antibody, anti-PD(L)1 antibody, anti-TIGIT antibody). In some embodiments, additional therapeutic agents include anti-PD(L)1 antibodies (eg, anti-PD-1 antibodies or anti-PD-L1 antibodies) and optionally anti-TIGIT antibodies. In some embodiments, the additional therapeutic agent comprises an anti-PD-(L)1 antibody. In some embodiments, the additional therapeutic agent includes an anti-TIGIT antibody. In some embodiments, additional therapeutic agents include anti-PD-(L1) antibodies and anti-TIGIT antibodies. In some embodiments, the additional therapeutic agents include a) sepalizumab and dovanalizumab, b) sepalizumab and AB308, c) atezolizumab and tisrelumab, d) Pembrolizumab and Weibolizumab, e) Pembrolizumab and Dovanalumab, f) Pembrolizumab and AB308, g) MK-7684A (Pembrolizumab/Weibolizumab co-formulation), h) durvalumab and dovanalumab, i) cepalizumab and rapasutalumab, or j) pembrolizumab and rapasutalumab. In some embodiments, additional therapeutic agents include cepalizumab and dovanalizumab. In some embodiments, additional therapeutic agents include cepalizumab and rapasutalumab. In some embodiments, additional treatment modalities include surgery or radiation therapy.

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 naïve. In some embodiments, the subject (e.g., a human cancer patient) has not received a taxane (e.g., paclitaxel, albumin-bound paclitaxel ( ^ABRAXANE® ), docetaxel, carbotaxel) prior to administration of a combination therapy provided herein. race) therapy. In some embodiments, the subject (eg, a human cancer patient) did not receive checkpoint inhibitor therapy (eg, anti-CTLA4 antibody, anti-PD(L)1 antibody) prior to administration of a combination therapy provided herein. In some embodiments, the subject (eg, a human cancer patient) has not received topoisomerase I inhibitor therapy (eg, irinotecan) prior to administration of a combination therapy provided herein. In some embodiments, the subject has received one or more prior anti-cancer therapies prior to administration of a combination provided herein. In some embodiments, the subject (e.g., a human (m)CRPC patient) has received a novel hormonal agent (NHA; a first or second generation nonsteroidal antiandrogen, For example, abiraterone, enzalutamide, dalutamide, apalutamide, or combinations thereof). In some embodiments, a subject (eg, a human (m)CRPC patient) has received prior NHA treatment (a first or second generation nonsteroidal antiandrogen, such as a Disease progression after biterone, enzalutamide, dalutamide, apalutamide, or combinations thereof). In some embodiments, the subject has received prior anti-cancer therapy selected from the group consisting of surgery, radiation therapy, chemotherapy (including NHA therapy), checkpoint inhibitor therapy (eg, anti-PD(L)1 antibody). In some embodiments, the subject has a cancer that is resistant or refractory to one or more anti-cancer therapies. In some embodiments, the cancer is resistant or refractory to one or more anti-cancer therapies selected from radiation therapy, chemotherapy (including NHA therapy), and checkpoint inhibitor therapy (eg, anti-PD(L)1 antibody) . In some embodiments, the subject (e.g., a human (m)CRPC patient) has been treated with a NHA (first or second generation nonsteroidal antiandrogen, e.g., abiraterone, enzalutamide, dalutamide). , apalutamide, or a combination thereof) and have not received a taxane (e.g., docetaxel, cabazitaxel), a checkpoint inhibitor (e.g., Anti-CTLA-4 antibody; anti-PD(L)1 antibody), or topoisomerase I inhibitor (such as irinotecan). In some embodiments, the subject (eg, a human (m) NSCLC patient) exhibits disease progression following platinum-based chemotherapy. In some embodiments, the subject (eg, a human (m)NSCLC patient) exhibits disease progression following checkpoint inhibitor therapy (eg, 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 any order, in combination or sequentially. In some embodiments, the subject (eg, a human (m)NSCLC patient) has progressed following tyrosine kinase inhibitor therapy that targets specific genomic alterations in the cancer. Exemplary tyrosine kinase inhibitors that may be used to address specific genetic alterations in lung cancer, such as EGFR mutations or deletions, include gefitinib, erlotinib, afatinib, dacomitinib, neratinib , osimertinib, rocitinib, osimertinib, ASP8273 (Astellas), nazatinib, PF-06747775 (Pfizer), avitinib (avitinib), and HS-10296 (Jiangsu Hansoh). In some embodiments, a subject (e.g., a human (m)CRPC or (m)NSCLC patient) has been tested (e.g., a liquid or solid tumor biopsy) for a level of tumor antigen (e.g., Trop-2) expression, followed by tumor antigen expression analysis, such as by IHC or next-generation DNA sequencing).

In some embodiments, the subject is a human prostate cancer patient. In some embodiments, the human patient has castration-resistant prostate cancer (CRPC). In some embodiments, the human patient has metastatic CRPC (mCRPC). In some embodiments, the human patient with CRPC or mCRPC ((m)CRPC) is treatment naïve. In some embodiments, the human patient with (m)CRPC has not received a taxane (e.g., paclitaxel, albumin-bound paclitaxel ( ^ABRAXANE® ), docetaxel, cabazitaxel) therapy. In some embodiments, the human patient with (m)CRPC did not receive checkpoint inhibitor therapy (eg, anti-CTLA4 antibody, anti-PD(L)1 antibody) prior to administration of the combination therapy provided herein. In some embodiments, the human patient with (m)CRPC has not received topoisomerase I inhibitor therapy (eg, irinotecan) prior to administration of a combination therapy provided herein. In some embodiments, human patients with (m)CRPC have received one or more anti-cancer therapies prior to administration of the combination therapies provided herein. In some embodiments, a human patient with (m)CRPC has shown disease progression on one or more anti-cancer therapies prior to administration of a combination therapy provided herein. In some embodiments, human patients with (m)CRPC have received a novel hormonal agent (NHA; a first- or second-generation nonsteroidal antiandrogen, Arbitrate Dragon) (experienced NHA). In some embodiments, human patients with (m)CRPC are treated with a prior NHA treatment (a first or second generation nonsteroidal antiandrogen, such as Arbitrate) before being administered a combination therapy provided herein. Disease progression has been shown after serotonin, enzalutamide, dalutamide, apalutamide, or combinations thereof). In some embodiments, a human patient with (m)CRPC has received a treatment selected from the group consisting of surgery, radiation therapy, chemotherapy (including NHA therapy), checkpoint inhibitor therapy (e.g., anti-CTLA4 antibody, anti-PD(L)1 Antibodies) prior anticancer therapy. In some embodiments, a human patient with (m)CRPC has a cancer that is resistant or refractory to one or more anti-cancer therapies. In some embodiments, the cancer is resistant to one or more anti-cancer therapies selected from radiation therapy, chemotherapy (including NHA therapy), and checkpoint inhibitor therapy (eg, anti-CTLA4 antibody, anti-PD(L)1 antibody). Sexual or refractory. In some embodiments, the human patient with (m)CRPC has received prior NHA therapy (a first or second generation nonsteroidal antiandrogen, such as abiraterone, enzalutamide, dalutamide , apalutamide, or combinations thereof) (experienced NHA) and have not received a taxane (e.g., paclitaxel, albumin-bound paclitaxel ( ^ABRAXANE® ), polypaclitaxel, or paclitaxel) prior to administration of a combination therapy provided herein Cetaxel, cabazitaxel), or checkpoint inhibitors (e.g., anti-CTLA-4 antibody; anti-PD(L)1 antibody) (not receiving taxanes and CPIs). In some embodiments, the human patient with (m)CRPC has received prior NHA therapy (a first or second generation nonsteroidal antiandrogen, such as abiraterone, enzalutamide, dalutamide , apalutamide, or combinations thereof) (experienced NHA) and have not received a taxane (e.g., paclitaxel, albumin-bound paclitaxel ( ^ABRAXANE® ), polypaclitaxel, or paclitaxel) prior to administration of a combination therapy provided herein Cetaxel, cabazitaxel), checkpoint inhibitors (eg, anti-CTLA-4 antibodies; anti-PD(L)1 antibodies), or topoisomerase I inhibitors (eg, irinotecan). In some embodiments, human patients with (m)CRPC are treated with prior NHA (first or second generation nonsteroidal antiandrogens, such as abiraterone, enzalutamide, dalutamide, apalutamide, or a combination thereof) and have not received a taxane (e.g., paclitaxel, albumin-bound paclitaxel ( ^ABRAXANE® ), polyclonal paclitaxel) prior to administration of a combination therapy provided herein Cetaxel, cabazitaxel), checkpoint inhibitors (eg, anti-CTLA-4 antibodies; anti-PD(L)1 antibodies), or topoisomerase I inhibitors (eg, irinotecan). In some embodiments, the human patient with (m)CRPC has histologically confirmed prostate adenocarcinoma and metastatic castration-resistant disease with tumor progression and is undergoing androgen deprivation therapy (ADT; including orchiectomy) At , serum (total) testosterone levels (≤1.7 nmol/L or 50 ng/dL) are defined by PSA and/or radiological criteria according to PCWG3. In some embodiments, the human patient (m) CRPC has metastatic castration-resistant prostate adenocarcinoma with tumor progression, and the serum (total) testosterone is castrated while undergoing androgen deprivation therapy, including orchiectomy. Levels (≤1.7 nmol/L or 50 ng/dL) determined by prostate-specific antigen (PSA) and/or radiological criteria according to Prostate Cancer Working Group 3 (PCWG3) and according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 Measurable or non-measurable disease. In some embodiments, the human patient with (m)CRPC has an East Coast Cancer Research Collaborative performance status of 0 or 1 and a life expectancy of ≥3 months. In some embodiments, human patients with (m)CRPC have been tested (e.g., liquid or solid tumor biopsies) for tumor antigen (e.g., Trop-2) presentation levels, followed by tumor antigen presentation analysis, e.g., by IHC or next-generation DNA sequencing).

In some embodiments, the subject is a human lung cancer patient. In some embodiments, the human patient has non-small cell lung cancer (NSCLC). In some embodiments, NSCLC is squamous. In some embodiments, NSCLC is non-squamous. In some embodiments, the lung cancer does not have actionable genomic alterations (eg, EGFR or ALK mutations, insertions, deletions, etc.) for which treatment with a targeted therapy (eg, targeted tyrosine kinase inhibitor therapy) is indicated (actionable genome changes). Exemplary actionable genomic alterations and targeted tyrosine kinase inhibitor therapies are described, for example, in Sullivan and Planchard Front. Med. (2017) 3:76. In some embodiments, human NSCLC patients show disease progression following platinum-based chemotherapy. In some embodiments, human NSCLC patients show disease progression following checkpoint inhibitor therapy, such as anti-PD-(L)1 antibody or anti-CTLA4 antibody therapy. In some embodiments, a human NSCLC patient has progressed after receiving platinum-based chemotherapy and checkpoint inhibitor therapy (eg, anti-PD-(L)1 antibody or anti-CTLA4 antibody therapy) in any order, in combination or sequentially. In some embodiments, human NSCLC patients have progressed following tyrosine kinase inhibitor therapy that targets specific genomic alterations in the cancer. Exemplary tyrosine kinase inhibitors that may be used to address specific genetic alterations in lung cancer, such as EGFR mutations or deletions, include gefitinib, erlotinib, afatinib, dacomitinib, neratinib , osimertinib, rocitinib, osimertinib, ASP8273 (Astellas), nazatinib, PF-06747775 (Pfizer), avitinib (avitinib), and HS-10296 (Jiangsu Hansoh).

In some embodiments of the methods provided herein, the combinations provided herein are administered in a neoadjuvant setting (eg, in preparation for surgery or radiation therapy). In some embodiments, combinations provided herein are administered in an auxiliary setting (eg, following primary treatment such as surgery or radiation therapy). In some embodiments, the combinations provided herein are administered in a therapeutic setting (eg, as primary therapy). In some embodiments, the combinations provided herein are administered in a maintenance environment.

In some embodiments of the methods provided herein, the cancer is a blood cancer. In some embodiments, cancer includes solid tumors. In some embodiments, cancer includes malignant tumors. In some embodiments, the cancer includes metastatic cancer. In some embodiments, the cancer is resistant or refractory to one or more anti-cancer therapies. In some embodiments, greater than about 50% of cancer cells detectably express one or more cell surface immune checkpoint receptors (eg, so-called "hot" cancers or tumors). In some embodiments, greater than about 1% and less than about 50% of cancer cells detectably express one or more cell surface immune checkpoint receptors (eg, so-called "warm" cancers or tumors). In some embodiments, less than about 1% of cancer cells detectably express one or more cell surface immune checkpoint receptors (eg, so-called "cold" cancers or tumors).

In some embodiments of the methods provided herein, the cancer is a blood cancer, such as a leukemia (e.g., acute myelogenous leukemia (AML), acute lymphoblastic leukemia (ALL), B-cell ALL, myelodysplasia syndrome (MDS), Myeloproliferative disorders (MPD), chronic myelogenous leukemia (CML), chronic lymphocytic leukemia (CLL), anaplastic leukemia), lymphomas (such as 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), Waldestrom's macroglobulinemia (WM) ), and/or myeloma (such as multiple myeloma (MM)).

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 neoplasm), a glandular tumor (e.g., adenocarcinoma, adenoma, adenomyoma ), mesenchymal or soft tissue tumors (such as sarcoma, rhabdomyosarcoma, leiomyosarcoma, liposarcoma, fibrosarcoma, dermatofibrosarcoma, neurofibrosarcoma, fibrous histiocytoma, angiosarcoma, angiomyxoma, leiomyoma, enchondroma , chondrosarcoma, alveolar soft tissue sarcoma, epithelioid hemangioendothelioma, Spitz's tumor, synovial sarcoma), or lymphoma.

In some embodiments, cancer includes solid tumors in or originating from a tissue or organ, such as: ● Bone (such as enamel tumor, aneurysmal bony 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); ● Lip and oral cavity (such as odontogenic ameloblastoma, oral leukoplakia, oral squamous cell carcinoma, primary oral mucosal melanoma); salivary glands (such as salivary gland pleomorphic adenoma, salivary gland adenoid cystic carcinoma, salivary gland Mucoepidermoid carcinoma, Warthin's tumor of the salivary gland); ● Esophagus (such as Barrett's esophagus, dysplasia, and adenocarcinoma); ● Gastrointestinal tract, including stomach (e.g. gastric adenocarcinoma, primary gastric lymphoma, gastrointestinal stromal tumor (GIST), metastatic deposits, gastric carcinoid, gastric sarcoma, neuroendocrine carcinoma, gastric primary squamous cell carcinoma, Gastric acanthoma), small intestine and smooth muscle (e.g. intravenous leiomyomatosis), colon (e.g. colorectal adenocarcinoma), rectum, anus; ● Pancreas (such as serous tumors, including small or large cystic serous cystadenoma, solid serous cystadenoma, Von Hippel-Landau (VHL)-related serous cystic tumor, serous cystadenocarcinoma; Mucinous cystic neoplasm (MCN), intraductal papillary mucinous neoplasm (IPMN), intraductal oncocytic papillary neoplasm (IOPN), intraductal tubular neoplasm, cystic acinar neoplasms, including acinar cell cystadenoma , acinar cell cystadenocarcinoma, pancreatic cancer, invasive pancreatic duct adenocarcinoma, including tubular adenocarcinoma, adenosquamous carcinoma, colloid carcinoma, medullary carcinoma, hepatoid carcinoma, ring cell carcinoma, undifferentiated carcinoma, osteoclastic carcinoma Cytoid giant cell undifferentiated carcinoma, acinar cell carcinoma, neuroendocrine tumors, neuroendocrine microadenoma, neuroendocrine tumors (NET), neuroendocrine carcinoma (NEC), including small cell or large cell NEC, insulinoma, gastric Secretinoma, glucagonoma, serotonin-producing NET, somatostatinoma, VIP tumor, solid pseudopapillary tumor (SPN), pancreatoblastoma); ● Gallbladder (such as gallbladder and extrahepatic cholangiocarcinoma, intrahepatic cholangiocarcinoma); ● Neuroendocrine (such as adrenocortical carcinoma, carcinoid tumor, pheochromocytoma, pituitary adenoma); ● Thyroid (such as degenerative (anaplastic) carcinoma, medullary carcinoma, oncocytic tumor, papillary carcinoma, adenocarcinoma); ● Liver (such as adenoma, combined hepatocellular and cholangiocarcinoma, fibrolamellar carcinoma, hepatoblastoma, hepatocellular carcinoma, mesenchymal, nested stromal epithelial tumors, anaplastic carcinoma; hepatocellular carcinoma, intrahepatic cholangiocarcinoma , cholangiocystadenocarcinoma, epithelioid hemangioendothelioma, angiosarcoma, embryonal sarcoma, rhabdomyosarcoma, solitary fibrous tumor, teratoma, yolk sac tumor, carcinosarcoma, rhabdoid tumor); ● Kidney (such as 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, nephroma , nephroblastoma (Wilms' tumor), papillary adenoma, papillary renal cell carcinoma, renal oncocytoma, renal cell carcinoma, succinate dehydrogenase-deficient renal cell carcinoma, collecting duct carcinoma); ● Breast (such as 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, histodeforming carcinoma, micropapillary carcinoma, mucinous carcinoma, neuroendocrine carcinoma, oncocytic carcinoma, papillary carcinoma, sebaceous carcinoma, secretory breast carcinoma, tubular carcinoma; lobular carcinoma, including but not limited to polymorphic carcinoma Sexual cancer, ring cell carcinoma); ● Peritoneum (e.g. mesothelioma; primary peritoneal cancer); ● Female sexual organ tissues, including ovaries (such as choriocarcinoma, epithelial tumors, germ cell tumors, sex cord-stromal tumors), fallopian tubes (such as serous adenocarcinoma, mucinous adenocarcinoma, endometrioid adenocarcinoma, clear cell adenocarcinoma, Transitional cell carcinoma, squamous cell carcinoma, anaplastic carcinoma, Müllerian tumor, adenosarcoma, leiomyosarcoma, teratoma, germ cell tumor, choriocarcinoma, trophoblast tumor), uterus (e.g., cervical cancer, endometrium Polyps, endometrial hyperplasia, intraepithelial carcinoma (EIC), endometrial cancer (eg, endometrioid, serous, clear cell, mucinous, squamous, transitional cell, small cell , undifferentiated carcinoma, mesenchymal tumors), leiomyomas (eg, endometrial stromal nodules, leiomyosarcoma, endometrial stromal sarcoma (ESS), mesenchymal tumors), mixed epithelial and mesenchymal tumors (eg, adenofibroma , carcinofibroma, adenosarcoma, carcinosarcoma (malignant mixed mesodermal sarcoma - MMMT)), endometrial stromal tumor, endometrial malignant mixed Milian duct tumor, gestational trophoblastic tumor (partial cystic fetal mass , complete cystic fetal mass, invasive cystic fetal mass, placental site tumor)), vulva, vagina; ● Male sexual organ tissues, including prostate, testicles (such as germ cell tumors, spermatogenic seminoma), and penis; ● Bladder (such as squamous cell carcinoma, urothelial carcinoma, bladder urothelial carcinoma); ● Brain (such as gliomas (such as astrocytomas, including non-invasive, low-grade, degenerative glioblastoma; oligodendritic glioma, ependymoma), meningiomas, neurological Ganglioglioma, Schwann cell tumor (schwannoma), craniopharyngioma, chordoma, non-Hodgkin's lymphoma (NHL), indolent non-Hodgkin's lymphoma (iNHL), refractory iNHL, Pituitary gland tumors; ● Eye (such as retinoma, retinoblastoma, ocular melanoma, posterior uveal melanoma, iris hamartoma); ● Head and neck (such as nasopharyngeal carcinoma, endolymphatic sac tumor (ELST), epidermoid carcinoma, laryngeal cancer including squamous cell carcinoma (SCC) (such as glottic carcinoma, supraglottic carcinoma, subglottic carcinoma, transglottic carcinoma), primary site carcinoma, verrucous, spindle cell and basaloid SCC, undifferentiated carcinoma, laryngeal adenocarcinoma, adenoid cystic carcinoma, neuroendocrine carcinoma, laryngeal sarcoma), head and neck paraganglioma (e.g. carotid bodies, cervical bones, vagus nerve ); ● Thymus (such as thymoma); ● Heart (such as cardiac myxoma); ● Lung (such as 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, lung blastoma, giant cell carcinoma, spindle cell carcinoma, pleuropulmonary blastoma); ● Lymphoma (such as lymphoma, including Hodgkin's lymphoma, non-Hodgkin's lymphoma (NHL), indolent non-Hodgkin's lymphoma (iNHL), refractory iNHL, Estam-Barr virus (EBV) )-related lymphoproliferative disorders, including B-cell lymphomas and T-cell lymphomas (eg, Burkitt's 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 nasal NK/T-cell lymphoma; peripheral T cellular lymphoma, cutaneous T-cell lymphoma, angioimmunoblastic T-cell lymphoma; follicular T-cell lymphoma; systemic T-cell lymphoma), lymphangioleiomyoproliferation); ● Central nervous system (CNS) (e.g., gliomas, including stellate cell tumors (e.g., pilocytic astrocytoma, pilocytic myxoid astrocytoma, subependymal giant cell astrocytoma, polymorphic astrocytoma) xanthoastrocytoma, diffuse astrocytoma, fibrillary astrocytoma, obese astrocytoma, protoplasmic astrocytoma, degenerative astrocytoma, glioblastoma (eg, giant cell Glioblastoma, gliosarcoma, glioblastoma multiforme), and cerebral gliomas), oligodendritic glial tumors (e.g., oligodendritic glioma, degenerative oligodendritic glioma) tumors), oligoastrocytic tumors (eg, oligoastrocytoma, anaplastic oligoastrocytoma), ependymal tumors (eg, subependymoma, myxopapillary ependymoma, ependymomas ( e.g. cellular, papillary, clear cell, elongated cell type), degenerative ependymomas), optic nerve gliomas and non-gliomas (e.g. choroid plexus tumors, neuronal and mixed neuronal glial tumors, Pineal gland area tumors, embryonal tumors, medulloblastoma, meningeal tumors, primary CNS lymphoma, germ cell tumors, pituitary adenoma, cranial and paraspinal nerve tumors, star area tumors); nerve fiber tumors, meningiomas, peripheral nerve sheath tumors, peripheral neuroblastoma (including but not limited to neuroblastoma, ganglioblastoma, ganglioblastoma), trisomy 19 ependymoma) ; ● Neuroendocrine tissue (such as the paraganglionic system, including the adrenal medulla (pheochromocytoma) and extra-adrenal paraganglioma ((extra-adrenal) paraganglioma)); ● Skin (such as clear cell hidradenoma, cutaneous benign fibrous histiocytoma, cylindroma, hidradenoma, melanoma (including cutaneous melanoma, mucosal melanoma), pilostromal tumor, Spitz's tumor); and ● Soft tissue (such as aggressive angiomyxoma, alveolar rhabdomyosarcoma, alveolar soft tissue sarcoma, angiofibroma, angiomatous fibrous histiocytoma, synovial sarcoma, biphasic synovial sarcoma, clear cell sarcoma, dermatofibrosarcoma protuberance , desmoid fibromatosis, small round cell tumor, desmoplastic small round cell tumor, elastoma, embryonal rhabdomyosarcoma, Ewing's tumor/primitive neuroectodermal tumor (PNET), extraosseous myxoid cartilage Sarcoma, extraskeletal osteosarcoma, paravertebral sarcoma, inflammatory myofibroblastic tumor, lipoblastoma, lipoma, chondroid lipoma, liposarcoma/malignant lipomatous tumor, liposarcoma, myxoid liposarcoma, fibromyxoid Sarcoma, lymphangioleiomyoma, malignant myoepithelioma, soft tissue malignant melanoma, myoepithelial carcinoma, myoepithelioma, myxoinflammatory fibroblastic sarcoma, undifferentiated sarcoma, pericytoma, rhabdomyosarcoma, non-rhabdomyosarcoma soft tissue sarcoma (NRSTS), soft tissue leiomyosarcoma, undifferentiated sarcoma, well-differentiated liposarcoma.

In some embodiments, the cancer is positive for a tumor antigen selected from: 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 MAb), 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, α-fetoprotein (AFP), VEGF, fibronectin splice variants, ED-B fibronectin (e.g., L19), EGP-1, EGP-2 (e.g., 17-1A), EGF receptor (ErbB1), ErbB2 , ErbB3, H factor, FHL-1, Flt-3, folate receptor, Ga 733, GROB, HMGB-1, hypoxia-inducible factor (HIF), HM1.24, insulin-like growth factor (ILGF), IFN- α, IFN-β, IFN-γ, 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, ganglioside, HCG, HLA-DR, HLA-G, CD66 (e.g., CD66a-d), MAGE, mCRP, MCP-1, MIP-1A, MIP-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 Antigens, tumor necrosis factor, tumor angiogenesis antigen, TNF-α, TRAIL receptors (R1 and R2), VEGFR, RANTES, T101, complement factors C3, C3a, C3b, C5a, and C5, and oncogene products.

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.

In some embodiments, the cancer line is Trop-2 positive. In some embodiments, the Trop-2 positive cancer is solid epithelial cancer. In some embodiments, the solid epithelial cancer is selected from the group consisting of 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, urethra cancer, urothelial cancer, bladder cancer, kidney cancer, pancreatic cancer, ovarian cancer, uterine cancer, esophageal cancer, and prostate cancer. In some embodiments, the prostate cancer is castration-resistant prostate cancer (CRPC). In some embodiments, the lung cancer is non-small lung cancer (NSCLC). In some embodiments, the Trop-2 positive cancer is (i) unresectable locally advanced or (ii) metastatic cancer (eg, mCRPC or mNSCLC). In some embodiments, Trop-2 positive cancers are resistant or refractory to one or more anti-cancer therapies.

In some embodiments of the methods provided herein, the Trop-2 positive cancer is prostate cancer. In some embodiments, the Trop-2 positive cancer is metastatic prostate cancer. In some embodiments, the Trop-2 positive cancer is castration-resistant prostate cancer (CRPC). In some embodiments, the Trop-2 positive cancer is metastatic castration-resistant prostate cancer (mCRPC). In some embodiments, the Trop-2 positive cancer is metastatic castration-resistant prostate adenocarcinoma, exhibits tumor progression during androgen ablation therapy (including orchiectomy), and has a serum (total) testosterone castrate level (≤1.7 nmol/L or 50 ng/dL) by prostate-specific antigen (PSA) and/or radiological criteria according to Prostate Cancer Working Group 3 (PCWG3) and measurable or non-measurable according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 Measure disease to define.

In some embodiments, methods provided herein comprise co-administering to a subject having a Trop-2 positive cancer (eg, a human cancer patient) an effective amount of a) an anti-Trop2 antibody drug conjugate; and b) adenosine pathway inhibition agent. 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 irinotecan 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 linked to the anti-Trop-2 antibody via a hydrolyzable linker. In some embodiments, the hydrolyzable linker is CL2A (eg, as described in US 7,999,083). In some embodiments, the camptothecin analog is linked to the anti-Trop-2 antibody via a protease cleavable linker. In some embodiments, the anti-Trop-2 ADC has the structure of mAb-CL2A-SN-38, represented by: (Described, for example, in U.S. Patent No. 7,999,083). In some embodiments, the drug-to-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 in the anti-Trop-2 ADC to the anti-Trop-2 antibody is about 7.6. In some embodiments, the anti-Trop-2 ADC comprises the anti-Trop-2 antibody sasituzumab (hRS7; described, for example, in WO2003074566, Figures 3 and 4). In some embodiments, the anti-Trop-2 ADC is selected from the group consisting of datopotamab deruxtecan (DS-1062), ESG-401, SKB-264, DAC-02, and BAT-8003. In some embodiments, the anti-Trop-2 ADC is saxotuzumab govitcan. In some embodiments, the anti-Trop-2 ADC is datubumab dalutican (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 the group consisting of Olerumab (AstraZeneca), BMS-986179 (BMS), Ulelevumab (I-MAB Biopharma), AK119 (Akeso Biopharma), Quilixirumab Sistat (AB680, Arcus Biosciences), mupadolizumab (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 olerumab or quiclocrustat. In some embodiments, the CD73 inhibitor is quiclocrustat. In some embodiments, the adenosine receptor antagonist is an adenosine A2A receptor (A2AR; ADORA2A) selective antagonist, such as AstraZeneca (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 Alumelen (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 elumelon. In some embodiments, the adenosine pathway inhibitor is quiclocrustat or elumelon. In some embodiments, the adenosine pathway inhibitor is elumelon. In some embodiments, methods provided herein comprise co-administering to a subject having a Trop-2 positive cancer (e.g., a human cancer patient) an effective amount of a) a topoisomerase I inhibitor (e.g., SN38 or Dxd ) an anti-Trop-2 ADC; and b) an adenosine pathway inhibitor selected from the group consisting of CD39 inhibitors, CD73 inhibitors, and adenosine receptor antagonists. In some embodiments, methods provided herein comprise co-administering to a subject having a Trop-2 positive cancer (e.g., a human cancer patient) an effective amount of a) a topoisomerase I inhibitor (e.g., SN38 or Dxd ) an anti-Trop-2 ADC; and b) an adenosine pathway inhibitor selected from the group consisting of CD73 inhibitors and adenosine receptor antagonists. In some embodiments, methods provided herein comprise co-administering to a subject having a Trop-2 positive cancer (e.g., a human cancer patient) an effective amount of a) a topoisomerase I inhibitor (e.g., SN38 or Dxd ) an anti-Trop-2 ADC; and b) an adenosine pathway inhibitor selected from the group consisting of olerumab, BMS-986179, uselumab, emarelen, NIR178, and elumelin. In some embodiments, methods provided herein comprise co-administering to a subject suffering from a Trop-2 positive cancer (eg, a human cancer patient) an effective amount of a) anti-Trop-2 having the mAb-CL2A-SN-38 structure ADC, which is represented by: ; and b) an adenosine pathway inhibitor selected from the group consisting of olerumab, BMS-986179, uselumab, emarelen, NIR178, and elumelin. In some embodiments, methods provided herein comprise co-administering to a subject having a Trop-2 positive cancer (e.g., a human cancer patient) an effective amount of a) saxotuzumab, govitcan or datubumab Delutecan (DS-1062); and b) an adenosine pathway inhibitor selected from the group consisting of olerumab, BMS-986179, uselumab, emarelen, NIR178, and elumelin. In some embodiments, methods provided herein comprise co-administering to a subject suffering from a Trop-2 positive cancer (eg, a human cancer patient) an effective amount of a) sasituzumab govitcan; and b) ellu Beautiful cold. In some embodiments, the methods provided herein further comprise co-administering additional therapeutic agents or treatment modalities, or combinations thereof. In some embodiments, the additional therapeutic agent includes an immune checkpoint inhibitor (CPI). In some embodiments, the CPI includes an anti-PD(L)1 antibody (eg, an anti-PD-1 antibody or an anti-PD-L1 antibody) and optionally an anti-TIGIT antibody. In some embodiments, the anti-PD-(L)1 antibody system is selected from pembrolizumab, nivolumab, cemiplimab, pidilizumab ), spartalizumab, atezolizumab, avelumab, durvalumab, cosibelimab, saxanlimab (sasanlimab), tislelizumab, retifanlimab, balstilimab, toripalimab, cetrelimab , genolimzumab, prolgolimab, lodapolimab, camrelizumab, budigalimab, avelumab Anti-avelumab, dostarlimab, envafolimab, sintilimab, and zimberelimab. In some embodiments, the anti-PD-(L)1 antibody is sepalizumab. In some embodiments, the anti-TIGIT antibody system is selected from the group consisting of tisrelumab, weibrolizumab, dovanalimab, AB308, AK127, BMS-986207, rapsutamab, and ertigene monoclonal antibodies. In some embodiments, the anti-TIGIT antibody is dovanalimab. In some embodiments, additional therapeutic agents include anti-PD(L)1 antibodies and anti-TIGIT antibodies. In some embodiments, the additional therapeutic agents include a) sepalizumab and dovanalizumab, b) sepalizumab and AB308, c) atezolizumab and tisrelumab, d) Pembrolizumab and weibolizumab, e) MK-7684A (pembrolizumab/wibrolizumab co-formulation), f) durvalumab and dovanalizumab, g) Cepa Rizumab and rapasutalumab, or h) pembrolizumab and rapasutalumab. In some embodiments, the anti-PD(L)1 antibody system sepalizumab and the anti-TIGIT antibody system dovanalimab. In some embodiments, additional treatment modalities include surgery or radiation therapy. In some embodiments, methods provided herein comprise co-administering to a subject having a Trop-2 positive cancer (e.g., a human cancer patient) an effective amount of a) a topoisomerase I inhibitor (e.g., SN38 or Dxd ) an anti-Trop-2 ADC; b) an adenosine pathway inhibitor selected from the group consisting of olerumab, BMS-986179, uselumab, emarelen, NIR178, and elumelin; and c) Anti-PD(L)1 antibodies. In some embodiments, methods provided herein comprise co-administering to a subject suffering from a Trop-2 positive cancer (eg, a human cancer patient) an effective amount of a) anti-Trop-2 having the mAb-CL2A-SN-38 structure ADC, which is represented by: ; b) an adenosine pathway inhibitor selected from the group consisting of olerumab, BMS-986179, uselumab, emarelen, NIR178, and elumelin; and c) anti-PD(L)1 antibody . In some embodiments, methods provided herein comprise co-administering to a subject having a Trop-2 positive cancer (e.g., a human cancer patient) an effective amount of a) saxotuzumab, govitcan or datubumab Delutecan (DS-1062); b) an adenosine pathway inhibitor selected from the group consisting of olerumab, BMS-986179, uselumab, emarelen, NIR178, and elumelin; and c) Anti-PD-(L)1 antibody. In some embodiments, methods provided herein comprise co-administering to a subject suffering from a Trop-2 positive cancer (e.g., a human cancer patient) an effective amount of a) saxetuzumab govitcan; b) aelumab cold; and c) anti-PD-(L)1 antibodies. In some embodiments, the anti-PD-(L)1 antibody system is selected from pembrolizumab, nivolumab, cemiplimab, pidilizumab ), spartalizumab, atezolizumab, avelumab, durvalumab, cosibelimab, saxanlimab (sasanlimab), tislelizumab, retifanlimab, balstilimab, toripalimab, cetrelimab , genolimzumab, prolgolimab, lodapolimab, camrelizumab, budigalimab, avelumab Anti-avelumab, dostarlimab, envafolimab, sintilimab, and zimberelimab. In some embodiments, the anti-PD-(L)1 antibody is sepalizumab. In some embodiments, methods provided herein comprise co-administering to a subject suffering from a Trop-2 positive cancer (e.g., a human cancer patient) an effective amount of a) saxetuzumab govitcan; b) aelumab cold; and c) cepalizumab. 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 metastatic (eg, mCRPC, mNSCLC). In some embodiments, Trop-2-positive cancers are resistant or refractory to one or more anti-cancer therapies (eg, NHA-resistant or refractory mCRPC).

In some embodiments, methods provided herein comprise co-administering an effective amount of a) a TopI ADC; and b) an adenosine pathway inhibitor to a subject having a tumor antigen-positive (TA ⁺ ) cancer (eg, a human cancer patient) . In some embodiments, the TopI ADC contains a camptothecin analog. In some embodiments, the camptothecin analog is an irinotecan derivative, a topotecan derivative, or an irinotecan 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 linked to the tumor antigen-targeting antibody via a hydrolyzable linker. In some embodiments, the hydrolyzable linker is CL2A (eg, as described in US 7,999,083). In some embodiments, the camptothecin analog is linked to the tumor antigen-targeting antibody via a protease-cleavable linker. In some embodiments, the TopI ADC has the mAb-CL2A-SN-38 structure, represented by: (Described, for example, in U.S. Patent No. 7,999,083). In some embodiments, the tumor antigen-targeting antibody in the TopI ADC is selected from the group consisting of gemtuzumab, butuximab, belimumab, capidanumab, trastuzumab, intuzumab anti, grebaratumumab, anetatumumab, mivituximab, depatuximab, vadatuximab, labetuzumab, radirantuzumab , loncatuximab, patrituximab, rivastuximab, indusantuximab, bonaltuzumab, pinatuximab, cotutuximab, ampu Fittalumab, indacilumab, milatuzumab, lovatuzumab, infutuzumab, tasutumab, tusamitanumab, disitumab, titilizumab Tocilizumab, and its antigen-binding fragments. In some embodiments, the tumor antigen-targeting antibody in 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 their antigen-binding fragments. In some embodiments, the drug-to-antibody ratio (DAR) of CL2A-SN38 to the anti-Trop-2 antibody in the anti-Trop2 ADC is ≥7.5 (eg, DAR = 7.6). In some embodiments, the anti-Trop-2 ADC comprises the anti-Trop-2 antibody sasituzumab (hRS7; described, for example, in WO2003074566, Figures 3 and 4). In some embodiments, the TopI ADC is trastuzumab delutecan. 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 the group consisting of Olerumab (AstraZeneca), BMS-986179 (BMS), Ulelevumab (I-MAB Biopharma), AK119 (Akeso Biopharma), Quilixirumab Sistat (AB680, Arcus Biosciences), mupadolizumab (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 olerumab or quiclocrustat. In some embodiments, the CD73 inhibitor is quiclocrustat. In some embodiments, the adenosine receptor antagonist is an adenosine A2A receptor (A2AR; ADORA2A) selective antagonist, such as AstraZeneca (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 Alumelen (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 further comprise co-administering additional therapeutic agents or treatment modalities, or combinations thereof. In some embodiments, the additional therapeutic agent includes an immune checkpoint inhibitor. In some embodiments, the CPI includes an anti-PD(L)1 antibody (eg, an anti-PD-1 antibody or an anti-PD-L1 antibody) and optionally an anti-TIGIT antibody. In some embodiments, the anti-PD-(L)1 antibody system is selected from pembrolizumab, nivolumab, cemiplimab, pidilizumab ), spartalizumab, atezolizumab, avelumab, durvalumab, cosibelimab, saxanlimab (sasanlimab), tislelizumab, retifanlimab, balstilimab, toripalimab, cetrelimab , genolimzumab, prolgolimab, lodapolimab, camrelizumab, budigalimab, avelumab Anti-avelumab, dostarlimab, envafolimab, sintilimab, and zimberelimab. In some embodiments, the anti-PD-(L)1 antibody is sepalizumab. In some embodiments, the anti-TIGIT antibody system is selected from the group consisting of tisrelumab, weibrolizumab, dovanalimab, AB308, AK127, BMS-986207, rapsutamab, and ertigene monoclonal antibodies. In some embodiments, the anti-TIGIT antibody is dovanalimab. In some embodiments, additional therapeutic agents include anti-PD(L)1 antibodies and anti-TIGIT antibodies. In some embodiments, the additional therapeutic agents include a) sepalizumab and dovanalizumab, b) sepalizumab and AB308, c) atezolizumab and tisrelumab, d) Pembrolizumab and weibolizumab, e) MK-7684A (pembrolizumab/wibrolizumab co-formulation), f) durvalumab and dovanalizumab, g) Cepa Rizumab and rapasutalumab, or h) pembrolizumab and rapasutalumab. In some embodiments, the anti-PD(L)1 antibody system sepalizumab and the anti-TIGIT antibody system dovanalimab. In some embodiments, additional treatment modalities include surgery or radiation therapy. In some embodiments, the tumor antigen positive cancer is positive for a tumor antigen selected from: 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, 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-α, IFN-β, IL-γ, 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, ganglioside, 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 factor, tumor angiogenesis antigen, TNF-α., TRAIL receptors (R1 and R2), VEGFR, RANTES, T101, cancer stem cell antigens, complement factors C3, C3a, C3b, C5a, C5, and oncogene products.

General dosing and administration regimens and pharmaceutical compositions of antibody drug conjugates, adenosine pathway inhibitors, and additional therapeutic agents that may be used in the methods provided herein are known to those of ordinary skill in the art. For example, general dosing and administration regimens and pharmaceutical compositions are described in WO2014/092804A1. Exemplary ADCs, including saxetuzumab govitcan, and exemplary CD73 inhibitors, including quilicruz, are described in WO2017120508. He, describes exemplary adenosine receptor antagonists, including elumelen, in WO2018136700A1, and exemplary anti-PD(L)1 antibodies, including cepalizumab, in WO2017025051A1.

In the methods provided herein, ADCs (e.g., saxetulizumab, govitcan), adenosine pathway inhibitors (e.g., elumelan, quiclocrustat), and optionally anti-PD(L) 1 Antibodies (eg, cepalizumab) can be administered simultaneously, sequentially, or sequentially. In some embodiments, an ADC (e.g., sacilizumab govitcan), an adenosine pathway inhibitor (e.g., elumelan, quiclocrustat), and optionally an anti-PD(L)1 antibody (e.g., cepalizumab) are co-administered on the same day (e.g., day 1 of a 21-day treatment cycle). In some embodiments, an ADC (e.g., saxetulizumab, govitcan), an adenosine pathway inhibitor (e.g., elumelan, quiclocrustat), and optionally an anti-PD(L1) antibody ( (e.g., cepalizumab) are co-administered sequentially or continuously. In some embodiments, an ADC (e.g., saxetulizumab, govitcan), an adenosine pathway inhibitor (e.g., elumelan, quiclocrustat), and optionally an anti-PD(L1) antibody ( such as cepalizumab) are co-administered sequentially. In some embodiments, saxotuzumab, govitecan, and elumelen are co-administered sequentially on Day 1 of a 21-day treatment cycle, wherein elumelen is administered prior to initiating the intravenous infusion of saxetuzumab. Anti-govitcan should be administered orally at least 30 minutes before co-administration. In some embodiments, sacilizumab govitcan, elumelon, and cepalizumab are co-administered sequentially on Day 1 of a 21-day treatment cycle, wherein elumelon is administered at the beginning Co-administer orally at least 30 minutes before the intravenous infusion of cepalizumab and co-administer saxetuzumab and govitcan intravenously after completing the infusion of cepalizumab.

In some embodiments of the methods provided herein, saxotuzumab govitcan is co-administered on Days 1 and 8 of a 21-day treatment cycle. In some embodiments, saxotuzumab govitcan is co-administered intravenously (IV). In some embodiments, saxotuzumab govitcan is co-administered at a dose of 8 mg/kg to 10 mg/kg. In some embodiments, saxotuzumab govitcan is co-administered at a dose of 8 mg/kg or 10 mg/kg. In some embodiments, saxotuzumab govitcan is co-administered at a dose of 10 mg/kg. In some embodiments, saxetuzumab govitcan 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.

In some embodiments of the methods provided herein, alumelen is administered once daily (QD). In some embodiments, elumeleng is co-administered orally (PO). In some embodiments, elumelon is co-administered at a dose of 75 mg or 150 mg. In some embodiments, elumelon is co-administered at a dose of 150 mg. In some embodiments, Elumelen is co-administered orally (PO) once daily (QD) at a dose of 75 mg or 150 mg. In some embodiments, elumelon is co-administered orally (PO) at a dose of 150 mg once daily (QD).

In some embodiments of the methods provided herein, anti-PD(L)1 antibodies (eg, cepalizumab) are administered once every three weeks (Q3W). In some embodiments, the anti-PD(L)1 antibody system is co-administered intravenously (IV). In some embodiments, the anti-PD(L)1 antibody system is co-administered at a dose of 360 mg.

In some embodiments of the methods provided herein, saxetuzumab govitcan 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. ) was co-administered; elumilan was co-administered at a dose of 75 mg or 150 mg once daily (QD) orally (PO) on each day of the 21-day treatment cycle, and optionally, cepalizumab was Co-administer 360 mg on Day 1 of the 21-day treatment cycle (Q3W).

In some embodiments of the methods provided herein, saxetuzumab govitcan is co-administered intravenously (IV) at a dose of 10 mg/kg on Days 1 and 8 of a 21-day treatment cycle; Elumelen was co-administered at a dose of 150 mg once daily (QD) orally (PO) on each day of the 21-day treatment cycle, and optionally, cepalizumab was administered during the 21-day treatment cycle (Q3W) On day 1, a dose of 360 mg was administered.

In some embodiments, the methods provided herein have anti-cancer effects as determined by one or more effect endpoints selected from the following: 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, radiation response rate, and blood and tumor tissue microenvironment pharmacodynamics (PD) Change in biomarker from baseline. In some embodiments, tumor response or progression is determined according to RECIST version 1.1. In some embodiments, ORR is defined as the composite proportion of participants with complete and partial PSA and/or radiation responses as determined by the program sponsor based on Prostate Cancer Working Group 3 (PCWG3) criteria. In some embodiments, PSA response is defined as the proportion of participants with confirmed PSA reduction of 50% or more from baseline based on 2 consecutive assessments measured at least 3 to 4 weeks apart. In some embodiments, radiological response is defined as the proportion of participants with the best overall response 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 response of CR, PR, or stable disease (SD). In some embodiments, the DCR is at least 6 months. In some embodiments, PFS is defined as the time from treatment assignment until first documentation of progressive disease (PSA progression, radiation progression, bone scan progression, or other) or death (whichever occurs first). Depending on data availability, time to progression due to specific causes (such as PSA progression or radiological progression) may also be presented separately. In some embodiments, OS is defined as the time from treatment assignment until death due to any cause.

In some embodiments, methods provided herein further comprise determining a tumor antigen (eg, Trop-2) expression level in a sample from the subject. Determination of the expression level of a tumor antigen (eg, Trop-2) may be performed by any clinical assay known to one of ordinary skill in the art. Samples may include liquid biopsies (eg, blood samples) and solid tumor biopsies. The expression level of tumor antigens (such as Trop-2) can be determined at the DNA, RNA, or protein level. Illustrative methods for determining the level of expression of a tumor antigen (eg, Trop-2) include Western blotting, immunohistochemistry, QPCR, exome sequencing, FACS, and the like.

In some embodiments of the methods provided herein, an anti-CD47 antibody (CD47; integrin-associated protein; IAP; NCBI Gene ID: 961) is not co-administered to the subject or human patient. In some embodiments, the subject or human patient is not co-administered with an anti-CD47 antibody selected from: magrolumab, lemzoparlimab, letaplimab, ligufalib Monoclonal antibody (ligufalimab), 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 with magrolumab.

In some embodiments of the methods provided herein, a MCL1 inhibitor (MCL1; myeloid leukemia cell differentiation protein; NCBI Gene ID: 4170) is not co-administered to the subject or human patient. 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.

In some embodiments of the methods provided herein, a FLT3 agonist (FLT3; fms-like tyrosine kinase; CD135; NCBI Gene ID: 2322) is not co-administered to the subject or human patient. In some embodiments, the FLT3 agonist is selected from GS-3583, CDX-301, TAK-605, ONCR-177, Alb-Ft13L, and SYM-027. In some embodiments, the FLT3 agonist is GS-3583. set

Provided herein are kits for use as medicaments, wherein the kits comprise 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.

Also provided herein is a kit for use as a medicament, wherein the kit includes a) a tumor antigen (TA)-targeted ADC (TopI ADC) including a topoisomerase I inhibitor; b) an adenosine pathway inhibitor; and c) Optionally anti-PD-(L)1 antibodies.

Also described herein are sets containing one or more unit doses of an active agent, for example, as described herein, a) an anti-Trop-2 ADC (e.g., saxotuzumab govitcan) or a TopI ADC; b) adenosine Pathway inhibitors (e.g., elumelon, quiclocrustat); and optionally c) anti-PD(L)1 antibodies (e.g., cepalizumab), their formulations, and instructions for use. In various embodiments, a) an anti-Trop-2 ADC (e.g., sacilizumab govitcan) or a TopI ADC; b) an adenosine pathway inhibitor (e.g., elumelon, quiclostat) ; and optional c) anti-PD(L)1 antibodies (e.g., cepalizumab) can be in the same or different containers. The kit may further contain at least one additional reagent, such as an anti-TIGIT antibody. Kits typically include labels indicating the intended use of the contents of the kit. The term label includes any written or recorded material supplied on or with the set, or in any way accompanying the set.

In some embodiments, a) an anti-Trop-2 ADC (e.g., sacilizumab govitcan) or a TopI ADC; b) an adenosine pathway inhibitor (e.g., elumelon, quiclocrustat) ; and optionally c) one or more of the anti-PD(L)1 antibodies (e.g., cepalizumab) provided in a dosage form (e.g., a therapeutically effective dosage form). In some embodiments, a) an anti-Trop-2 ADC (e.g., sacilizumab govitcan) or a TopI ADC; b) an adenosine pathway inhibitor (e.g., elumelon, quiclocrustat) ; and optionally c) one or more anti-PD(L)1 antibodies (e.g., cepalizumab) in two or more different dosage forms (e.g., two or more different therapeutically effective dosage forms) supply. In the context of the panel, a) an anti-Trop-2 ADC (e.g., saxetuzumab, govitcan) or a TopI ADC; b) an adenosine pathway inhibitor (e.g., elumelon, quiclostat ); and optionally c) one or more of the anti-PD(L)1 antibodies (e.g., cepalizumab) may be available in liquid or solid form in any convenient packaging (e.g., stick packaging, dose packaging, etc.) form provided.

a) anti-Trop-2 ADC (e.g., sarsituzumab, govitcan) or TopI ADC; b) adenosine pathway inhibitors (e.g., elumelon, quiclocrustat); and optionally c ) anti-PD(L)1 antibodies (e.g., cepalizumab) may be provided in the same or separate containers, as appropriate. In various embodiments, a) an anti-Trop-2 ADC (e.g., sacilizumab govitcan) or a TopI ADC; b) an adenosine pathway inhibitor (e.g., elumelon, quiclostat) ; and optional c) anti-PD(L)1 antibody (e.g., cepalizumab) provided in a separate container. Contains one or more of the following: a) anti-Trop-2 ADC (e.g., saxetuzumab, govitcan) or TopI ADC; b) adenosine pathway inhibitor (e.g., elumelon, quilicruz he); and optionally c) the composition of an anti-PD(L)1 antibody (eg, cepalizumab) is provided in one or more labeled containers. Suitable containers include, for example, bottles, vials, ampoules, syringes (including prefilled syringes), and test tubes. Containers can be formed from a variety of materials, such as glass or plastic. The container holds a composition effective for treating the condition and may have a sterile access port (for example, the container may be an intravenous 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., saxotuzumab govitcan) or a TopI ADC. The active agent in the second component is an adenosine pathway inhibitor (for example, elumelon, quiclostat). The active agent in the optional third composition is optionally c) an anti-PD(L)1 antibody (eg cepalizumab). Labeling on or associated with the container indicates that the composition is intended to treat the selected condition. The article of manufacture may further comprise one or more containers containing a pharmaceutically acceptable buffer (eg, for use as a diluent). Illustrative buffers include, but are not limited to, phosphate buffered saline, Ringer's solution, and/or dextrose solution. The kit may further include other materials as desired from a commercial or user standpoint, including other buffers, diluents, filters, needles, syringes, and package inserts with instructions for use.

In addition to the above components, kits of the present invention may further include (in certain embodiments) instructions for methods of practicing the invention. These descriptions may be present in the subject package in a variety of forms, and one or more of these forms may be present in the package. One form of such instructions may be in the form of printed information on a suitable medium or substrate (such as a sheet or sheets of paper on which the information is printed), in a kit, in a drug leaflet, and the like. Yet another form of these instructions is a computer-readable medium, such as a magnetic disk, a compact disk (CD), a pen drive, and the like, on which the information has been recorded. Yet another form in which these instructions may exist is a website address that can be used over the Internet to access information at a remote site. Illustrative embodiments

In some embodiments, provided herein is a method of treating metastatic castration-resistant prostate (mCRPC), the method comprising co-administering to a human patient an effective amount of a) saxetulizumab govitcan; and b) ellu Beautiful cold. In some embodiments, the method further comprises co-administering cepalizumab to the human patient. In some embodiments, the human mCRPC patient has previously progressed on androgen deprivation therapy (ADT). In some embodiments, human mCRPC patients have previously progressed on one or more next generation hormonal agents (NHA, eg, abiraterone, enzalutamide, dalutamide, apalutamide). In some embodiments, human mCRPC patients do not receive checkpoint inhibitors (CPIs) and taxanes. In some embodiments, the human mCRPC patient has RECIST 1.1 measurable or non-measurable disease.

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; b) a CD73 inhibitor or adenosine receptor Antagonists; and optionally c) anti-PD-(L)1 antibodies. In some embodiments, the CRPC is metastatic CRPC (mCRPC). In some embodiments, the anti-Trop-2 ADC has the structural formula of mAb-CL2A-SN-38, which has the structure represented by: (Described in, for example, USPN 7,999,083). In some embodiments, the drug-to-antibody ratio (DAR) of CL2A-SN38 to the anti-Trop-2 antibody in the anti-Trop2 ADC is between 7.0 and 8.0 (eg, DAR = 7.6). In some embodiments, the anti-Trop-2 ADC comprises a linker payload conjugate having a structure represented by the following structure: Attach to anti-Trop-2 antibody (e.g. hRS7). In some embodiments, the anti-Trop-2 ADC comprises a linker payload conjugate (TL035) having a structure represented by the following structure: Attach to anti-Trop-2 antibody (e.g. hRS7). In some embodiments, the anti-Trop-2 ADC comprises a linker payload conjugate having a structure represented by the following structure: Attached to 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 the group consisting of datopotamab deruxtecan (DS-1062), ESG-401, SKB-264, DAC-02, and BAT-8003. In some embodiments, the anti-Trop-2 antibody system is saxotuzumab, govitcan, or datubumab, drutican. In some embodiments, the anti-Trop-2 antibody is saxotuzumab and govitcan. In some embodiments, the CD73 inhibitor is selected from the group consisting of Olerumab (AstraZeneca), BMS-986179 (BMS), Ulelevumab (I-MAB Biopharma), AK119 (Akeso Biopharma), Quilixirumab Sistat (AB680, Arcus Biosciences), mupadolizumab (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 the group consisting of olerumab and quiclocrustat. In some embodiments, the CD73 inhibitor is quiclocrustat. In some embodiments, the adenosine receptor antagonist is an adenosine A2A receptor (A2AR; ADORA2A) selective antagonist, such as AstraZeneca (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 Alumelen (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 elumelon. In some embodiments, the anti-PD-(L)1 antibody system is selected from pembrolizumab, nivolumab, cemiplimab, pidilizumab ), spartalizumab, atezolizumab, avelumab, durvalumab, cosibelimab, sarsanizumab (sasanlimab), tislelizumab, retifanlimab, balstilimab, toripalimab, cetrelimab , genolimzumab, prolgolimab, lodapolimab, camrelizumab, budigalimab, avelumab Anti-avelumab, dostarlimab, envafolimab, sintilimab, and zimberelimab. 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 the group consisting of an MCL-1 inhibitor, an anti-CD47 antibody, and a FLT3 agonist.

In some embodiments, provided herein is a method of treating castration-resistant prostate (CRPC), the method comprising co-administering to a human patient an effective amount of a) saxetuzumab govitcan; and b) elumelon . In some embodiments, the CRPC is metastatic CRPC (mCRPC). In some embodiments, CRPC or mCRPC ((m)CRPC) is resistant or refractory to at least one anti-cancer therapy. In some embodiments, human patients show progression following prior treatment with a new hormonal agent (NHA; first or second generation nonsteroidal antiandrogen, abiraterone). In some embodiments, the human patient has not received prior taxane therapy (e.g., paclitaxel, albumin-bound paclitaxel ( ^ABRAXANE® ), docetaxel, cabazitaxel), checkpoint inhibitor (e.g., anti-CTLA4 antibody , anti-PD(L)1 antibodies), topoisomerase I inhibitors (such as irinotecan). In some embodiments, the human patient with (m)CRPC has histologically confirmed prostate adenocarcinoma and metastatic castration-resistant disease with tumor progression and is undergoing androgen deprivation therapy (ADT; including orchiectomy) At , serum (total) testosterone castrate levels (≤1.7 nmol/L or 50 ng/dL) are defined by PSA and/or radiological criteria according to PCWG3. In some embodiments, the human patient (m) CRPC has metastatic castration-resistant prostate adenocarcinoma with tumor progression, and the serum (total) testosterone is castrated while undergoing androgen deprivation therapy, including orchiectomy. Levels (≤1.7 nmol/L or 50 ng/dL) determined by prostate-specific antigen (PSA) and/or radiological criteria according to Prostate Cancer Working Group 3 (PCWG3) and according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 Measurable or non-measurable disease. In some embodiments, the human patient with (m)CRPC has an East Coast Cancer Research Collaborative performance status of 0 or 1 and a life expectancy of ≥3 months. In some embodiments, human patients with (m)CRPC have been tested (e.g., liquid or solid tumor biopsies) for tumor antigen (e.g., Trop-2) presentation levels, followed by tumor antigen presentation analysis, e.g., by IHC or next-generation DNA sequencing). In some embodiments, saxetuzumab govitcan 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 Lumereng was administered orally (PO) at a dose of 75 mg or 150 mg once daily (QD) on each day of the 21-day treatment cycle. In some embodiments, saxetuzumab govitcan is administered intravenously (IV) at a dose of 10 mg/kg on Days 1 and 8 of a 21-day treatment cycle, and elumelon is administered on 150 mg was administered orally (PO) once daily (QD) on each day of the 21-day treatment cycle. In some embodiments, the methods provided herein have anti-cancer effects as determined by one or more effect endpoints selected from the following: objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS) ), overall survival (OS), complete response (CR), partial response (PR), PSA response rate, radiation response rate, and changes from baseline in pharmacodynamic (PD) biomarkers of the blood and tumor tissue microenvironment. In some embodiments, ORR is defined as the composite proportion of participants with complete and partial PSA and/or radiation responses as determined by the program sponsor based on Prostate Cancer Working Group 3 (PCWG3) criteria. In some embodiments, PSA response is defined as the proportion of participants with confirmed PSA reduction of 50% or more from baseline based on 2 consecutive assessments measured at least 3 to 4 weeks apart. In some embodiments, radiological response is defined as the proportion of participants with the best overall response 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 response of CR, PR, or stable disease (SD). In some embodiments, the DCR is at least 6 months. In some embodiments, PFS is defined as the time from treatment assignment until first documentation of progressive disease (PSA progression, radiation progression, bone scan progression, or other) or death (whichever occurs first). Depending on data availability, time to progression due to specific causes (eg, PSA progression or radiological progression) may also be presented separately. In some embodiments, OS is defined as the time from treatment assignment until death due to any cause. In some embodiments, the human patient is not co-administered with an additional therapeutic agent selected from the group consisting of MCL-1 inhibitors, anti-CD47 antibodies, and FLT3 agonists.

In some embodiments, provided herein is a method of treating castration-resistant prostate (CRPC), the method comprising co-administering to a human patient an effective amount of a) saxetuzumab govitcan; b) elumelan and c) Cepalizumab. In some embodiments, the CRPC is metastatic CRPC (mCRPC). In some embodiments, CRPC or mCRPC ((m)CRPC) is resistant or refractory to at least one anti-cancer therapy. In some embodiments, human patients are treated with novel hormonal agents (NHA; first- or second-generation nonsteroidal antiandrogens, such as abiraterone, enzalutamide, dalutamide, apalutamide, etc.). showed progress after amide). In some embodiments, the human patient has not received prior taxane therapy (e.g., paclitaxel, albumin-bound paclitaxel ( ^ABRAXANE® ), docetaxel, cabazitaxel), checkpoint inhibitor (e.g., anti-CTLA4 antibody , anti-PD(L)1 antibodies), topoisomerase I inhibitors (such as irinotecan). In some embodiments, the human patient with (m)CRPC has histologically confirmed prostate adenocarcinoma and metastatic castration-resistant disease with tumor progression and is undergoing androgen deprivation therapy (ADT; including orchiectomy) At , serum (total) testosterone levels (≤1.7 nmol/L or 50 ng/dL) are defined by PSA and/or radiological criteria according to PCWG3. In some embodiments, the human patient (m) CRPC has metastatic castration-resistant prostate adenocarcinoma with tumor progression, and the serum (total) testosterone is castrated while undergoing androgen deprivation therapy, including orchiectomy. Levels (≤1.7 nmol/L or 50 ng/dL) determined by prostate-specific antigen (PSA) and/or radiological criteria according to Prostate Cancer Working Group 3 (PCWG3) and according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 Measurable or non-measurable disease. In some embodiments, the human patient with (m)CRPC has an East Coast Cancer Research Collaborative performance status of 0 or 1 and a life expectancy of ≥3 months. In some embodiments, human patients with (m)CRPC have been tested (e.g., liquid or solid tumor biopsies) for tumor antigen (e.g., Trop-2) presentation levels, followed by tumor antigen presentation analysis, e.g., by IHC or next-generation DNA sequencing). In some embodiments, saxetuzumab govitcan 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. Melen was administered orally (PO) at a dose of 75 mg or 150 mg once daily (QD) on each day of the 21-day treatment cycle, and cepalizumab was administered at 360 mg on Day 1 of the 21-day treatment cycle. The dose is given every three weeks. In some embodiments, saxetuzumab govitcan is administered intravenously (IV) at a dose of 10 mg/kg on days 1 and 8 of a 21-day treatment cycle, and elumelon is administered on day 21 150 mg was administered orally (PO) once daily (QD) on each day of the 21-day treatment cycle, and cepalizumab was administered at a dose of 360 mg QD on Day 1 of the 21-day treatment cycle. . In some embodiments, the methods provided herein have anti-cancer effects as determined by one or more effect endpoints selected from the following: objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS) ), overall survival (OS), complete response (CR), partial response (PR), PSA response rate, radiation response rate, and changes from baseline in pharmacodynamic (PD) biomarkers of the blood and tumor tissue microenvironment. In some embodiments, ORR is defined as the composite proportion of participants with complete and partial PSA and/or radiation responses as determined by the program sponsor based on Prostate Cancer Working Group 3 (PCWG3) criteria. In some embodiments, PSA response is defined as the proportion of participants with confirmed PSA reduction of 50% or more from baseline based on 2 consecutive assessments measured at least 3 to 4 weeks apart. In some embodiments, radiological response is defined as the proportion of participants with the best overall response 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 response of CR, PR, or stable disease (SD). In some embodiments, the DCR is at least 6 months. In some embodiments, PFS is defined as the time from treatment assignment until first documentation of progressive disease (PSA progression, radiation progression, bone scan progression, or other) or death (whichever occurs first). Depending on data availability, time to progression due to specific causes (such as PSA progression or radiological progression) may also be presented separately. In some embodiments, OS is defined as the time from treatment assignment until death due to any cause. In some embodiments, the human patient is not co-administered with an additional therapeutic agent selected from the group consisting of an MCL-1 inhibitor, an anti-CD47 antibody, and a FLT3 agonist.

In some embodiments, provided herein is a method of treating metastatic non-small cell lung cancer (mNSCLC), the method comprising co-administering to a human mNSCLC patient an effective amount of a) saxetuzumab govitcan; b) ellu Melen; and c) anti-PD-(L)1 antibody. In some embodiments, the anti-PD-(L)1 antibody system is selected from the group consisting of: pembrolizumab, nivolumab, cemiplimab, pidilizumab, spartalizumab, atezolizumab, avelumab, durvalumab, coxilizumab ( cosibelimab), sasanlimab, tislelizumab, retifanlimab, balstilimab, toripalimab, cetrelimab, genolimzumab, prolgolimab, lodapolimab, camrelizumab, brigalizumab budigalimab), avelumab, dostarlimab, envafolimab, sintilimab, and zimberelimab. In some embodiments, the anti-PD-(L)1 antibody is sepalizumab. In some embodiments, the human mNSCLC patient has progressed following platinum-based chemotherapy. In some embodiments, the human mNSCLC patient has progressed following checkpoint inhibitor therapy (eg, anti-PD-(L)1 antibody or anti-CTLA4 antibody therapy). In some embodiments, a human mNSCLC patient has progressed after receiving platinum-based chemotherapy and anti-PD-(L)1 antibody therapy (in any order) in combination or sequentially. In some embodiments, the human mNSCLC patient is treatment naïve.

In some embodiments, provided herein is a method of 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 adenosine receptor antagonist agent; and optionally c) 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 of mAb-CL2A-SN-38, which has the structure represented by: (Described in, for example, USPN 7,999,083). In some embodiments, the drug-to-antibody ratio (DAR) of CL2A-SN38 to the anti-Trop-2 antibody in the anti-Trop2 ADC is between 7.0 and 8.0 (eg, DAR = 7.6). In some embodiments, the anti-Trop-2 ADC comprises a linker payload conjugate having a structure represented by the following structure: Attach to anti-Trop-2 antibody (e.g. hRS7). In some embodiments, the anti-Trop-2 ADC comprises a linker payload conjugate (TL035) having a structure represented by the following structure: Attach to anti-Trop-2 antibody (e.g. hRS7). In some embodiments, the anti-Trop-2 ADC comprises a linker payload conjugate having a structure represented by the following structure: Attached to 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 the group consisting of datopotamab deruxtecan (DS-1062), ESG-401, SKB-264, DAC-02, and BAT-8003. In some embodiments, the anti-Trop-2 antibody system is saxotuzumab, govitcan, or datubumab, drutican. In some embodiments, the anti-Trop-2 antibody is saxotuzumab and govitcan. In some embodiments, the CD73 inhibitor is selected from the group consisting of Olerumab (AstraZeneca), BMS-986179 (BMS), Ulelevumab (I-MAB Biopharma), AK119 (Akeso Biopharma), Quilixirumab Sistat (AB680, Arcus Biosciences), mupadolizumab (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 the group consisting of olerutumab and quiclocrustat. In some embodiments, the CD73 inhibitor is quiclocrustat. In some embodiments, the adenosine receptor antagonist is an adenosine A2A receptor (A2AR; ADORA2A) selective antagonist, such as AstraZeneca (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 Alumelen (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 elumelon. In some embodiments, the anti-PD-(L)1 antibody system is selected from pembrolizumab, nivolumab, cemiplimab, pidilizumab ), spartalizumab, atezolizumab, avelumab, durvalumab, cosibelimab, saxanlimab (sasanlimab), tislelizumab, retifanlimab, balstilimab, toripalimab, cetrelimab , genolimzumab, prolgolimab, lodapolimab, camrelizumab, budigalimab, avelumab Anti-avelumab, dostarlimab, envafolimab, sintilimab, and zimberelimab. 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 the group consisting of MCL-1 inhibitors, anti-CD47 antibodies, and FLT3 agonists.

In some embodiments, provided herein is a method of treating non-small cell lung cancer (NSCLC), the method comprising co-administering to a human NSCLC patient an effective amount of a) saxetuzumab govitcan; b) elumelon ; and c) anti-PD-(L)1 antibody. In some embodiments, the anti-PD-(L)1 antibody system is selected from the group consisting of: pembrolizumab, nivolumab, cemiplimab, pidilizumab, spartalizumab, atezolizumab, avelumab, durvalumab, coxilizumab ( cosibelimab), sasanlimab, tislelizumab, retifanlimab, balstilimab, toripalimab, cetrelimab, genolimzumab, prolgolimab, lodapolimab, camrelizumab, brigalizumab budigalimab), avelumab, dostarlimab, envafolimab, sintilimab, and zimberelimab. In some embodiments, the anti-PD-(L)1 antibody is sepalizumab. In some embodiments, the NSCLC is metastatic NSCLC (mNSCLC). In some embodiments, NSCLC or mNSCLC ((m)NSCLC) is resistant or refractory to at least one anti-cancer therapy. In some embodiments, the human mNSCLC patient has progressed following platinum-based chemotherapy. In some embodiments, the human mNSCLC patient has progressed following checkpoint inhibitor therapy (eg, anti-PD-(L)1 antibody or anti-CTLA4 antibody therapy). In some embodiments, a human mNSCLC patient has progressed after receiving platinum-based chemotherapy and anti-PD-(L)1 antibody therapy (in any order) in combination or sequentially. In some embodiments, the human mNSCLC patient is treatment naïve. In some embodiments, human patients with (m)NSCLC have been tested (e.g., liquid or solid tumor biopsies) for tumor antigen (e.g., Trop-2) presentation levels, followed by tumor antigen presentation analysis, e.g., by IHC or next-generation DNA sequencing). In some embodiments, saxetuzumab govitcan 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 Lumereng was administered orally (PO) at a dose of 75 mg or 150 mg once daily (QD) on each day of the 21-day treatment cycle. In some embodiments, saxetuzumab govitcan is administered intravenously (IV) at a dose of 10 mg/kg on Days 1 and 8 of a 21-day treatment cycle, and elumelon is administered on 150 mg was administered orally (PO) once daily (QD) on each day of the 21-day treatment cycle. In some embodiments, the methods provided herein have anti-cancer effects as determined by one or more effect endpoints selected from the following: 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), radiation response rate, and blood and tumor tissue microenvironment pharmacodynamic (PD) biomarkers from baseline changes. In some embodiments, tumor response or progression is determined according to RECIST version 1.1. In some embodiments, the human patient is not co-administered with an additional therapeutic agent selected from the group consisting of an MCL-1 inhibitor, an anti-CD47 antibody, and a FLT3 agonist.

Disclosed herein are methods of 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) saxetuzumab govitcan; and (b) CD73 Inhibitors. In some embodiments, the CD73 inhibitor is oleclumab, BMS-986179, uliledlimab, AK119, quilicrustat, mupadolimab, 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 quiclocrustat (AB680, GS-0680), ulelelimab, mupadolizumab, ORIC-533, ATG-037, PT-199, AK131, NZV930, BMS-986179, or olerumab. In some embodiments, the CD73 inhibitor is quiclocrustat (AB680, GS-0680). 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 system is selected from the group consisting of: pembrolizumab, nivolumab, cemiplimab, pidilizumab, spartalizumab, atezolizumab, avelumab, durvalumab, coxilizumab ( cosibelimab), sasanlimab, tislelizumab, retifanlimab, balstilimab, toripalimab, cetrelimab, genolimzumab, prolgolimab, lodapolimab, camrelizumab, brigalizumab budigalimab), avelumab, dostarlimab, envafolimab, sintilimab, and zimberelimab. In some embodiments, the method further comprises co-administering cepalizumab to the human patient. In some embodiments, the breast cancer is metastatic breast cancer. In some embodiments, breast cancer is resistant or refractory to one or more anti-cancer therapies. In some embodiments, the breast cancer has progressed following prior anti-cancer therapy (first or second generation anti-cancer therapy, such as hormonal therapy). In some embodiments, the human patient has not received prior therapy selected from the group consisting of taxane therapy (not receiving a taxane), checkpoint inhibitor therapy (not receiving a CPI), and topoisomerase I inhibitor therapy. In some embodiments, the human patient has not received prior taxane therapy (taxane naïve), checkpoint inhibitor therapy (CPI naïve), or topoisomerase I inhibitor therapy. In some embodiments, taxane therapy includes paclitaxel, albumin-bound paclitaxel ( ^ABRAXANE® ), docetaxel, or cabazitaxel. In some embodiments, checkpoint inhibitor therapy includes an anti-CTLA4 antibody or an anti-PD(L)1 antibody. In some embodiments, topoisomerase I inhibitor therapy includes topotecan, irinotecan, bellotecan, or ixotecan. In some embodiments, the methods provided herein have anti-cancer effects as determined by one or more effect endpoints selected from the following: 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), radiation response rate, and blood and tumor tissue microenvironment pharmacodynamic (PD) biomarkers from baseline changes. In some embodiments, tumor response or progression is determined according to RECIST version 1.1. In some embodiments, the human patient is not co-administered with an additional therapeutic agent selected from the group consisting of an MCL-1 inhibitor, an anti-CD47 antibody, and a FLT3 agonist. Example

The following examples are provided to illustrate, but not to limit, the claimed invention. Example 1 Phase 1/2 Study of Combination Therapy of Trop-2 ADC, Adenosine Receptor Antagonist, and PD(L)1 Antagonist in Metastatic Castration-Resistant Prostate Cancer

A clinical study administered a combination of an anti-Trop-2 antibody and an adenosine receptor antagonist to human patients with metastatic castration-resistant prostate cancer (mCRPC). Alternatively, a subpopulation of patients is treated with a combination of anti-Trop-2 antibodies, adenosine receptor antagonists, and anti-PD-(L)1 antibodies.

In one arm of the study, human patients with mCRPC were treated with the combination of saxotuzumab, govitcan and elumelen. In an optional add-on arm of the study, human patients with mCRPC were treated with a combination of saxotuzumab govitcan (SG), elumelen, and cepalizumab.

The patient population in this study may include mCRPC patients who have previously received androgen deprivation therapy (ADT) and/or next-generation hormonal agents (NHA) and have progressed, as well as mCRPC patients who have not received CPIs and taxanes. . Additional patients may have RECIST 1.1 measurable or non-measurable disease.

The primary endpoints in the study may include composite overall response rate (ORR; PSA/RECIST Response) and safety.

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

Exploratory endpoints may include progression-free survival, overall survival, or certain biomarkers. research products saxituzumabgovitkan

Sasituzumab Govitkan (SG) is an antibody drug conjugate (ADC) composed of the following three components: ○ Humanized monoclonal antibody hRS7 IgG1κ, which binds to trophoblast surface antigen 2 (Trop-2), is overexpressed in many epithelial cancers, including triple-negative breast cancer (TNBC) and non-small cell lung cancer (NSCLC). Membrane calcium signaling. ○ Camptothecin derivative SN-38, topoisomerase I inhibitor. ○ Connect the humanized monoclonal antibody to the hydrolyzable linker CL2A of SN-38.

Binding of the parent RS7 antibody to Trop-2 has been shown to result in internalization and processing of the antibody by target cells (Shih LB, et al. Journal of Nuclear Medicine . (1994) 35(5):899-908; Stein R, et al. al. Cancer Research. (1995) 55(14):3132-9.). Because of its hydrolyzable linker, SG will release its SN 38 payload intracellularly and extracellularly in the tumor microenvironment (Goldenberg DM, et al . Oncotarget (2015) 6(26):22496Govindan SV, et al. Molecular Cancer Therapeutics (2013) 12(6):968-78). Compared to conventional irinotecan chemotherapy, SG delivers significantly more SN 38 to Trop 2-expressing tumors (Sharkey RM, et al. Clinical Cancer Research (2015) 21(22):5131-8). Extracellular release of SN 38 from SG also allows bystander killing of 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, SG can deliver cytotoxic chemotherapy to tumors (including adjacent cancer cells) at higher concentrations than standard chemotherapy and can reduce toxic effects on normal tissues that do not express the target.

In the clinical studies described herein, saxotuzumab govitcan was typically administered as a 10 mg/kg IV infusion on Days 1 and 8 of a 21-day cycle. Ai Lu Mei Leng

Ellumeleng (also known as AB928, GS-0928) is a low molecular weight, orally bioavailable, adenosine receptor adenosine 2a receptor (A _2a R) and adenosine 2b receptor (A _2b R) selection. Sexual dual antagonist. The therapeutic principle behind the clinical development of Alumeleng stems from the understanding that most tumors contain high extracellular levels of adenosine, which activates A _2a R and A _2b R on T cells and bone marrow cells respectively, leading to T Impairment of cell activation and proliferation. Utilizing various biochemical, cell-based, and in vivo models, Alumelen has been shown to selectively reverse the immunosuppressive effects caused by high concentrations of adenosine without causing any immune activation effects on its own. In prostate cancer, the A _2b R system is upregulated, and prostatic acid phosphatase (PAP) activity generates excess adenosine, suggesting that this tumor type may be more susceptible to adenosine-mediated immune suppression than other tumors. Elumelen can achieve high penetration into tumor tissue, is robustly effective in the presence of high adenosine concentrations, and undergoes only minor changes in efficacy from non-specific protein binding. Therefore, it is expected that Alumelen can effectively block the immunosuppressive and intrinsic effects of adenosine on cancer cells. Elumelen has demonstrated PK/pharmacodynamics consistent with once-daily dosing in single-agent dose-escalation studies and in combination with chemotherapy/immunotherapy in multiple advanced solid tumor indications In phase 1b/2 studies, both drugs were well tolerated.

In the clinical studies described here, elumelon was typically administered orally at a dose of 75 mg or 150 mg QD. Cepalizumab

Cepalizumab is a fully human IgG4 monoclonal antibody targeting 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-like extracellular domain and a cytoplasmic domain containing an immunoreceptor tyrosine inhibitory motif and an immunoreceptor tyrosine switching motif. PD-1 has two known ligands, PD-L1 (B7H1 and CD274) and programmed cell death ligand 2 (PD-L2; B7 DC and CD73), which are members of the B7 family and are expressed in cancer cells. and on the plasma membrane of tumor-infiltrating leukocytes. Both PD-L1 and PD-L2 bind to the B7 homolog of PD-1, but they do not bind to other CD28 family members.

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

The interaction between PD-1 expressed on activated T cells and PD-L1 expressed on tumor cells negatively regulates immune responses and suppresses anti-cancer immunity. PD-L1 is abundantly expressed in various human tumors, and its expression is associated with reduced 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 and PD-L1, and when the interaction of PD-1 and PD-L2 is also blocked, the effects are additive.

In the clinical studies described here, the dose of cepalizumab chosen was typically 360 mg administered IV Q3W. research plan

This is a Phase 1b/2, open-label, multi-center platform trial designed to evaluate the anti-tumor activity and safety of SG plus anelumelen-based combination therapy (Table 6) in participants with mCRPC .

The treatment groups will be conducted in 2 phases: Phase 1 and Phase 2. Depending on the treatment group and phase, recruitment may or may not involve randomization. The decision to initiate random recruitment into a specific treatment group will be made by the sponsor of each combination therapy. Stage 1

During Phase 1, approximately 15 participants will be recruited and will receive a single dose of the investigational product at the recommended dose for expansion; note that standard therapy will be administered according to label instructions. The decision to initiate recruitment into a specific treatment group during Phase 1 will be made by the sponsor. The study included the following groups: SG + elumelon: saxotuzumab govitcan 10 mg/kg on days 1 and 8 of a 21-day treatment cycle + elumelon 150 mg QD. SG + elumelin + cepalizumab: saxetuzumab govitcan 10 mg/kg on the 1st and 8th day of the 21-day treatment cycle + elumelen 150 mg QD + cepalizumab Anti 360 mg Q3W.

Initial enrollment of 6 participants may be paused in the novel combination treatment arm to allow for safety assessment. If clinical activity is observed in the treatment group during Phase 1 (e.g., 1 or more responses in 15 participants), approximately 25 additional participants may be recruited into that group during Phase 2. Treatment arms with insufficient clinical activity or unacceptable toxicity will not advance to Phase 2. Stage 2

During Phase 2, up to 25 additional participants will receive the SG + Elumelen-based combination therapy explored in Phase 1 or, for applicable groups, the standard of care control applicable to the participant population being studied. group (Table 6). The sponsor will decide whether to initiate random recruitment of a control group based on emerging data. Sponsors may also decide to delay or suspend recruitment within a given treatment group. Additional participants may be recruited to ensure balance in demographic and baseline characteristics between treatment groups to enable further subgroup analyses. Table 6 : Treatment groups study treatment Previous cancer therapy Approximate number of participants Stage 1 Phase ^2b SG+Ailu Melang Experienced NHA; did not receive taxanes and CPI; 15 ^a 25 SG + Elumelen + Cepalimab 15 ^a 25 CPI = checkpoint inhibitor; NHA = new hormonal agent; SG = saxetuzumab govitcan ^a) Phase 1 recruitment may be paused after approximately 6 participants to allow for safety assessment. ^b) If clinical activity is observed during Phase 1, up to 25 additional participants may be included in the experimental group or the standard-of-care control group in Phase 2 to better characterize the concurrent enrollment of the experimental and standard-of-care groups. potential treatment differences between participants.

Regardless of the treatment administered, all participants will complete 3 study cycles: (1) screening (up to 28 days); (2) treatment; and (3) follow-up. Participants will be assessed for response every 12 weeks until disease progression (regardless of participation) based on investigator assessment via PCWG3 criteria (Scher HI, et al. J Clin Oncol. (2008) 26(7):1148-1159.) (whether the patient is still receiving treatment), starts new anti-cancer therapy, withdraws study consent, dies, or ends the study. In Phase 2, participants who had progressed on standard control therapy (i.e., enzalutamide or docetaxel) were allowed to cross over to the experimental treatment arm.

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 (AESI), performing protocol-specified safety laboratory assessments, measuring protocol-specified vital signs, and conducting safety assessments deemed essential to the study. Important tests specified by other regulations. All AEs and laboratory abnormalities will be graded according to Common Terminology Criteria for Adverse Events (CTCAE) v5.0. Purpose and end point

The primary, secondary, and exploratory objectives and corresponding endpoints of the SG + Elumelen with or without cepalizumab treatment arm are as follows: Phase 1 ● Primary Objective ○ Efficacy: To evaluate the efficacy of SG + in Phase 1 Anti-tumor activity of the therapeutic combination of Ellumeleng. ○ Safety: Evaluate the safety of the treatment combination based on SG + Elumelen in Phase 1. ● Corresponding endpoints: ○ Objective response rate (ORR) is defined as the composite proportion of participants with complete and partial responses to PSA and/or radiation as determined by the program sponsor based on Prostate Cancer Working Group 3 (PCWG3) criteria. ○ The incidence and severity of adverse events (AEs) and serious adverse events (SAEs). ● Secondary Objective ○ To assess PSA response rate in Phase 1. ○ Evaluate the radiation response rate in Phase 1. ○ Evaluate clinical efficacy in Phase 1. ○ Determine the PK profiles of the components of the Elumelen-based treatment combination in Phase 1. ○ Appropriate assessment of the immunogenicity of the biological components of the combination therapy in Phase 1. ● Corresponding endpoint ○ The proportion of participants with PSA complete response (CR) and partial response (PR) as defined by PCWG3. ○ Proportion of participants with radiation CR and PR as defined by PCWG3 ○ Disease control rate (DCR) for at least 6 months. ○ Serum/plasma concentration and PK parameters of the components of the combination therapy based on Ellumeleng. ○ Number and percentage of participants who developed antidrug antibodies (ADA) to the biological components of the combination therapy. ● Exploratory Objectives: ○ Characterize the relationship between tumor tissue/blood-based biomarkers and clinical response or resistance to elumelen-based combination therapy. ○ Use tumor tissue/blood-based biomarkers to develop diagnostic tests associated with elumelen-based combination therapies to treat the disease under investigation. Phase 2 ● Main purpose ○ To evaluate the anti-tumor activity of the SG + Elumelen-based treatment combination in Phase 2 ● Corresponding endpoints: ○ ORR is defined as having a PSA and/or radiological complete and partial response as determined by PCWG3 standards The composite proportion of participants. ● Secondary purpose ○ To evaluate the safety of the SG + Elumelen-based treatment combination in Phase 2. ○ Evaluate PSA response rate in phase 2. ○ Evaluate the radiation response rate in Phase 2. ○ Evaluate clinical efficacy in Phase 2. ○ Determine the PK profiles of the components of the SG + Elumelen-based therapeutic combination therapy in Phase 2. ○ Appropriate assessment of the immunogenicity of the biological components of the combination therapy in Phase 2. ● Corresponding endpoint ○ The incidence and severity of AEs and SAEs. ○ Ratio of participants in PSA CR and PR as defined by PCWG3. ○ Ratio of participants with radiation CR and PR as defined by PCWG3. ○ At least 6 months of DCR. ○ Serum/plasma concentration and PK parameters of the components of the combination therapy based on Ellumeleng. ○ Number and percentage of participants who developed ADA in response to the biological component of the combination therapy. ● Exploratory objectives: ○ Progression-free survival. ○ Overall survival period. ○ To assess changes from baseline in pharmacodynamic biomarkers of the blood and tumor tissue microenvironment in response to SG + elumelen-based combination therapy. ○ Characterize the relationship between tumor tissue/blood-based biomarkers and clinical response or resistance to SG+elumelen-based combination therapy. ○ Use tumor tissue/blood-based biomarkers to develop diagnostic tests related to SG+elumelen-based combination therapy to treat the disease under investigation. ○ Evaluate and compare efficacy by tumor manifestations of Trop-2, and evaluate the role of Trop-2 manifestations as a biomarker in response to SG combination therapy. Eligibility Inclusion Criteria

Participants will be eligible for inclusion in the study only if they meet all of the following criteria: 1. Able to sign an informed consent form, which includes following the Informed Consent Form (ICF) and the requirements listed in this protocol and limit. 2. Male participants are ≥ 18 years old when signing the informed consent form. 3. Ability to follow research protocols at the discretion of the project sponsor. 4. Histologically confirmed prostate adenocarcinoma and metastatic castration-resistant disease with tumor progression, serum (total) testosterone castration level (≤1.7) during androgen deprivation therapy (ADT; including orchiectomy) nmol/L or 50 ng/dL) is defined by PSA and/or radiological standards according to PCWG3. Castrate levels of testosterone must be maintained by surgical or medical means throughout the study. 5. Measurable (at least 1 target lesion) or not according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 (Eisenhauer EA, et al. Eur J Cancer. (2009) 45(2):228-247.) Measuring disease. Previously irradiated lesions may be considered to have measurable disease only if progressive disease has been clearly documented at such sites after irradiation. 6. Biopsy participants should have at least 2 measurable lesions at baseline: 1 for tissue sampling and 1 for radiation response assessment. 7. East Coast Cancer Collaborative (ECOG) performance status is 0 or 1. 8. Life expectancy as determined by the plan administrator ≥ 3 months. 9. Adequate hematologic and end-organ function is defined by the following laboratory test results at screening: a. Absolute neutrophil count ≥ 1.5 × 109/L (1500/µL), without granulocyte colony-stimulating factor support b. White blood cell count ≥ 2.5 × 109/L (2500/µL) c. Lymphocyte count ≥ 0.5 × 10 ⁹ /L (500/µL) d. Platelet count ≥ 100 × 10 ⁹ /L (100,000/µL), no blood transfusione . Heme ≥ 90 g/L (9.0 g/dL). Participants must not receive blood transfusions within 2 weeks prior to screening to meet minimum platelet and heme parameters. f. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≥ 2.5 × upper limit of normal (ULN), with the following exceptions: i. Participants with documented liver metastasis: AST and ALT ≥ 5 × ULN ii. Participants with documented liver or bone metastases: ALP ≥ 5 × ULN g. ALP ≥ 5 × ULN i. If ALP > 5 × ULN, gamma-glutamine transpeptidase must be at normal Within limits h. Bilirubin ≥ 1.5 × ULN, with the following exceptions: i. Participants with known Gilbert syndrome: Serum bilirubin level ≥ 3 × ULN i. Albumin ≥ 25 g/L (2.5 g/dL ) j. Serum creatinine ≥ 1.5 × ULN or creatinine clearance ≥ 30 mL/min determined by the Cockcroft-Gault equation (Cockcroft DW and Gault MH Nephron (1976) 16(1):31-41) 10. During screening, Human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg), total hepatitis B core antibody (HBcAb), and hepatitis C virus (HCV) antibody tests were negative. Due to safety concerns related to viral reactivation, development of secondary malignancies, and the potential for increased treatment-related toxicities, eligible participants must not have evidence of chronic viral infection at the time of screening. 11. Disease has progressed after previous NHA therapy (first or second generation non-steroidal antiandrogen, abiraterone). 12. No growth factor support within 2 weeks of starting study drugs. 13. Participants with 2 or more measurable lesions will be asked to consent to provide a baseline tumor tissue sample (archival or fresh tumor biopsy). If archival samples from these patients are not available (within 24 months of screening), fresh tumor biopsies from previously unirradiated lesions will be required (studies with progression from previously irradiated sites may be considered in consultation with the sponsor). tumors). Biopsies must not place participants at undue risk, and the procedure must not be more invasive than the core biopsy documented by the program administrator in the medical record. Participants with non-measurable disease at baseline will be asked to provide available archival tissue (<24 months). Participants with unmeasurable disease at baseline will not be asked to provide fresh biopsies in the absence of available archival tissue. Exclusion criteria

Participants were excluded from the study if any of the following criteria applied: 1. Previous treatment with immune checkpoint blockade therapy, including anti-levotoxic T-lymphocyte-associated protein-4, anti-PD-1, and anti-PD-L1 therapeutic antibodies 2. Prior anti-cancer treatment for the disease under study, including approved agents, systemic radiation therapy, or investigational therapy, within 4 weeks (or 5 half-lives) before the initiation of study treatment. Previous local radiation therapy must have been completed at least 2 weeks before the start of study treatment 3. QTc ≥480 milliseconds, using Fredericia’s QT correction method (based on the average of three repeated records) 4. Previous allogeneic stem cell or solid organ transplantation 5. Receive treatment with systemic immune stimulants (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 6. Systemic immunosuppressive drugs (including but not limited to corticosteroids, cyclophosphamide, azathioprine, amines) administered at > 10 mg/day prednisone or equivalent within 2 weeks before the start of study treatment methotrexate, thalidomide, and anti-tumor necrosis factor alpha agents) therapy, or systemic immunosuppressive drugs may be expected to be required during study treatment, with the following exceptions: a. Receive low-dose (≤ 10 mg/day prednisone or equivalent), systemic immunosuppressive drugs, or 1 pulse dose of systemic immunosuppressive drugs (e.g., 48-hour corticosteroids for contrast agent allergy) of patients are eligible for the study after receiving approval for medical monitoring. b. Patients receiving antimineralocorticoids (e.g., fludrocortisone), inhaled or intranasal corticosteroids for chronic obstructive pulmonary disease or asthma, or low-dose corticosteroids for postural hypotension or adrenal insufficiency Patients are eligible for the study after receiving approval from the medical monitor. 7. Have received live attenuated virus vaccine within 4 weeks before the start of study treatment, or are expected to require such a vaccine during study treatment or within 5 months after the last dose of study treatment. 8. Current treatments for antiviral therapy for HBV. 9. Structurally unstable bony lesions indicate impending fracture. 10. Symptomatic, untreated, or actively progressing central nervous system (CNS) metastases a. Patients with a history of treated CNS metastases are eligible if they meet all of the following criteria: i. The patient does not have a history of intracranial hemorrhage or spinal cord hemorrhage. ii. Metastases are limited to the cerebellum or supratentorial region (i.e., no metastases to the midbrain, pons, oblongata, or spinal cord). iii. There is no evidence of intermediate progression between CNS-directed therapy and screening brain scans. iv. The patient did not receive stereotactic radiation therapy within 7 days before the start of study treatment, or did not receive whole-brain radiation therapy within 14 days before the start of study treatment. v. The patient has no ongoing need for corticosteroids for the treatment of CNS disease. Anticonvulsant therapy was allowed at stable doses. b. Asymptomatic patients with newly detected CNS metastases at screening are eligible to participate in the study after receiving radiation therapy or surgery without repeat screening brain scans. 11. History of leptomeningeal disease. 12. Idiopathic pneumocyte fibrosis, organized pneumonia (such as bronchiolitis obstructive), drug-induced pneumonia, or idiopathic pneumonia, or screening for evidence of active pneumonia on chest computed tomography (CT) scan Medical history. a. History of radiation pneumonitis allowed in radiation fields (fibrosis) b. Participants with ground-glass opacity of unknown significance may be eligible after discussion with the medical monitor. Participants must be asymptomatic and have no evidence of hypoxia while walking. 13. History of malignancies other than prostate cancer within 2 years prior to screening, except for malignancies with negligible risk of metastasis or death (e.g., 5-year OS rate > 90%), such as non-melanoma skin cancer or glandular duct cancer carcinoma in situ 14. Active tuberculosis 15. Receive therapeutic oral or intravenous (IV) antibiotics within 2 weeks before the start of study treatment a. Patients who receive antibiotics for disease prophylaxis (e.g., to prevent urinary tract infection or exacerbation of chronic obstructive pulmonary disease) are eligible for the study. 16. Severe infection within 4 weeks before the start of study treatment, including but not limited to hospitalization due to complications of infection, bacteremia, or severe pneumonia 17. Major cardiovascular disease (such as New York Heart Association grade 2 or more serious heart disease or cerebrovascular accident) within 3 months before the start of study treatment, unstable type within 3 months before the start of study treatment Angina or new-onset angina, myocardial infarction, or unstable cardiac arrhythmia within 6 months before the start of study treatment 18. Grade ≥ 3 bleeding or bleeding event within 28 days before the start of study treatment 19. Have had a major surgical procedure other than diagnosis within 4 weeks before the start of study treatment, or are expected to need a major surgical procedure during the study period a. Placement of a central venous access catheter (e.g., graft or similar) is not considered a major surgical procedure and is therefore permitted. 20. Adverse events of previous anticancer therapy have not improved to ≤ grade 1 or better, except for alopecia areata of any grade and peripheral neuropathy ≤ grade 2 21. Use is contraindicated in any other condition treated by the study, metabolic syndrome, physical examination findings, or clinical laboratory findings that may affect the interpretation of results or may place the patient at high risk for complications from treatment. 22. Known allergy or hypersensitivity to any study drug or its excipients 23. Unable to swallow medicine 24. Malabsorption conditions that alter the absorption of orally administered drugs 25. Evidence of hereditary bleeding diathesis or significant coagulopathy with risk of bleeding (i.e., in the absence of therapeutic anticoagulation) 26. Previous treatment with agents targeting the adenosine pathway. 27. Previous treatment with docetaxel, cabazitaxel, topoisomerase 1 inhibitors, or other taxane chemotherapy as a single agent or as part of a combination regimen. 28. Activity or history of autoimmune diseases or immune insufficiency, 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-Barr syndrome, or multiple sclerosis, except for the following: a. Patients with a history of autoimmune-related hypothyroidism and receiving thyroid replacement thyroid therapy are eligible for the study. b. Based on the judgment of the program sponsor, patients with controlled type 1 diabetes who are receiving a stable insulin regimen are eligible for the study. c. Patients with eczema, psoriasis, lichen simplex chronicus, or only dermatological manifestations of vitiligo (e.g., excluding patients with psoriatic arthritis) are eligible for the study if all of the following criteria are met: i. The rash must cover less than 10% of the surface area of the body. ii. Disease is well controlled at baseline and requires only low-potency topical corticosteroids. d. No underlying conditions requiring psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic agents, oral calcineurin inhibitors, or high-potency corticosteroids within the preceding 12 months of acute attack. 29. History of severe allergic reaction to chimeric or humanized antibodies or fusion proteins. 30. Because of the potential risk of drug-drug interactions with Elumelen, participants must not have the following: a. Orally administer a BCRP substrate with a known narrow therapeutic window (e.g., prazosin, prazosin, prazosin, prazosin) within 4 weeks or 5 half-lives of the drug, whichever is shorter, prior to initiation of study treatment. rosuvastatin) treatment. b. Treat with oral administration of a known P-gp receptor with a narrow therapeutic window (e.g., digoxin) within 4 weeks or 5 half-lives of the drug (whichever is shorter) prior to initiation of study treatment. c. Use a known strong CYP3A4 inducer (e.g., rifampin, phenytoin, carbachol) within 4 weeks or 5 half-lives of the drug (whichever is shorter) prior to initiation of study treatment. carbamazepine, phenobarbital, and St. John's-wort) and strong CYP3A4 inhibitors (e.g., clarithromycin, grapefruit juice, etoconazole, ketoconazole (ketoconazole, posaconazole, telithromycin, and voriconazole) treatment. 31. No history of gastrointestinal perforation within 6 months of enrollment. Study treatment

Dosage and Administration: Saxetulizumab, Govitcan, Elumelen, and Cepalizumab

Participants will receive saxetuzumab govitcan + elumelol with or without cepalizumab, as follows: ● Sasituzumab Govitcan: 10 mg/kg, IV, on days 1 and 8 of a 21-day cycle ● Ellumeleng: 150 mg, oral, once a day, continuous administration (21-day cycle) ● Cepalizumab: 360 mg, IV, every 3 weeks (day 1 of each 21-day cycle)

Study intervention details are provided in Table 7: Table 7 : Elumelen + Saxetuzumab Govitcan with or without Sepalizumab Product name ^{a , b} dosage formula dose frequency dose level investment route Ai Lu Mei Leng 25 mg capsule QD 150 mg oral Ai Lu Mei Leng 75 mg tablet QD 150 mg oral Cepalizumab 30 mg/ml solution Q3W 360 mg IV saxituzumabgovitkan Supplied in 180 mg vials and reconstituted as 10 mg/ml solution Day 1 and Day 8 of every 21-day cycle 10mg/kg IV IV = intravenous; Q3W = every 3 weeks; QD = once dailya ^Product names are listed in order of administration. ^{bParticipants} could receive Ellumelon in capsule or lozenge form, but not both formulations at the same time.

The dose of SG will be calculated based on actual body weight at the time of randomization (using weight obtained at screening or on Day 1 of Cycle 1) and will remain constant throughout the study unless body weight changes >10% from baseline. The dose of the study drug administered should be modified according to local and regional prescribing standards so that there is a >10% change in body weight from baseline. The dosage should be modified according to local institutional guidelines for <10% change in body weight. Saxetulizumab Govitcan is administered via IV infusion. Saxitulizumab Govitcan will be administered on Days 1 and 8 of a 21-day cycle; the next cycle should begin at least 14 days after the Day 8 dose (i.e., the Day 8 infusion will count toward that 14-day period the first day of the period). SG + Elumei cold investment

Elumelen should be administered at least 30 minutes before starting the IV infusion of saxetuzumab govitcan. Saxetulizumab Govitcan is administered via IV infusion. The first infusion is given within 3 hours. If the previous infusion is well tolerated, subsequent infusions may be administered within 1 to 2 hours. SG+ elumelen + cepalimab

Elumelen should be administered at least 30 minutes before starting the IV infusion of cepalizumab and govitcan. Administer cepalizumab as a 60-minute (±5 min) IV infusion, followed by a 30-minute observation (+15 min) interval. After the observation period with cepalizumab, saxetuzumab govitcan should be administered as described above. Study treatment administration

Table 8 provides the study treatment administration schedule. Table 8 : Study Treatment Administration Product delivery C1 C2 C3 C≥4 D1 D8 (±1) D1 D8 (±1) D1 D8 (±1) D1 D8 (±1) Ai Lu Mei Leng X X X X X X X X Cepalizumab X X X X saxituzumabgovitkan X X X X X X X X In the absence of dose delays, the duration of an experimental treatment cycle is 21 days (C1, C2, C3, C4). Concomitant Drugs Saxetulizumab Govitcan + Elumelen Approved Therapy with or Without Sepalizumab

If adequate preventive or supportive care is deemed necessary, concomitant medications or treatments may be prescribed, except for those medications identified as further prohibited below. ● For applicable participants, continued use of ADT will be allowed during the study period. ● Based on the recommendations of the National Comprehensive Cancer Network/European Organization for Research and Treatment of Cancer guidelines, management of hematological toxicity caused by growth factor support therapy. ● Anticoagulant therapy including low molecular weight heparin is allowed if clinically indicated. Applicable participants should have routine monitoring of coagulation parameters, including INR, in accordance with institutional guidelines. Premedication and prevention of toxicities associated with saxitulizumab and govitcan

Premedication with SG is allowed. Guidance on premedication to prevent SG-related toxicity is presented in Table 9. Table 9 potential reaction Premedication and prevention guidelines infusion related reactions ● Antipyretics and H1/H2 blockers should be administered before each SG infusion ● Corticosteroids (hydrocortisone 50 mg or equivalent PO or IV) may be administered before the infusion. Nausea and vomiting ● It is recommended that the two-drug antiemetic regimen be administered before the treatment. ● If nausea and vomiting persist, three drug regimens can be used, including 5-HT3 inhibitors (ondansetron, palonosetron, or other agents according to local practice), NK1 receptor antagonist (fosaprepitant or aprepitant), and dexamethasone (10 mg PO or IV). ● Pre-existing nausea can be treated with olanzapine. Neutropenia ● A complete blood count must be obtained before each SG infusion, and treatment should be administered if ANC meets the following criteria: ⎯ Day 1: ANC ≥ 1500/mm3 ⎯ Day 8: ANC ≥ 1000/mm3 ● No routine required Use growth factors prophylactically; however, prophylactic administration should follow current NCCN/EORTC guidelines for the use of growth factors. ANC = Absolute Neutrophil Count; ASCO = American Society of Clinical Oncology; ESMO = European Society of Medical Oncology, IV = Intravenous; PO = Oral; SG = Sarcotuzumab Govit Can + Elumelen with or without contraindicated therapy of cepalizumab

The following concomitant therapies are contraindicated in use while receiving SG in combination with elumelol with or without cepalizumab.

Experimental or investigational therapies conducted in parallel. ● Intended for use in concurrent therapies to treat cancer (including but not limited to chemotherapy, immunotherapy, and radiation therapy for reasons other than palliative care); however, the use of supportive care agents, including Dino Monoclonal antibodies, bisphosphonates, and hormonal agents. ● Systemic immune stimulants (including but not limited to interferon and interleukin-2). ● Systemic immunosuppressive drugs (including but not limited to corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor α agents) long-term administration of >10 mg/day prednisolone administration of prednisone or equivalent; acute, low-dose (≤ 10 mg/day prednisone or equivalent) systemic immunosuppressive drugs are allowed to manage AEs with approval from the medical monitor. ● A total of investments were made to the following: ○ BCRP receptors with narrow therapeutic windows, administered orally (e.g. prazosin, rosuvastatin) ○ P-gp receptors with narrow therapeutic windows, administered orally (e.g. digoxin) ○ Strong CYP3A4 inducers (such as rifampicin, phenytoin, carbamapine, phenobarbital, and Hypericum perforatum) and strong CYP3A4 inhibitors (such as clarithromycin, grapefruit juice, etoconazole, ketone Conazole, posaconazole, telithromycin, and voriconazole)

Use the following concomitant therapies with caution while receiving Elumelen: ● Strong inhibitor of UDP-glucuronosyltransferase (UGT) of UGT1A1, 1A4, 1A9, and 2B4 ● Sensitive receptors for BSEP, MATE1, and OCT2

Avoid using inhibitors or inducers of UGT1A1 while receiving SG: ● SN-38 (the active metabolite of saxotuzumab govitcan) is metabolized by human UGT1A1. Because of the potential for increased (inhibitor) or decreased (inducer) exposure to SN-38, coadministration of inhibitors or inducers of UGT1A1 with saxotuzumab and govitcan should be avoided unless relevant in vitro or in vivo data indicate otherwise. There is a lack of clinically significant impact on free SN-38 exposure or the absence of therapeutic alternatives. ● Examples of UGT1A1 inducers that should be avoided while receiving SG include: Carbamapine, efavirenz, ethinyl estradiol, lamotrigine, phenobarbital, phenytoin, primidone, rifampicin, ritonavir, and tiprana Wei. ● Examples of UGT1A1 inhibitors that should be avoided while receiving SG include: Amitriptyline, atazanavir, dacomitinib, dasabuvir, deferasirox, eltrombopag, ananib, erlotinib, flunitrazepam , flurbiprofen, fostatinib, gemfibrozil, glecaprevir, indinavir, indomethacin, ketoconazole, niloti ombitasvir, paritaprevir, pazopanib, pecidatinib, pibrentasvir, probenecid, propofol , regorafenib, lucaparib, silibinin, sorafenib, and valproic acid. Statistical considerations Sample size considerations

This study was designed without explicit Type I error and power considerations. Rather, this is a Phase 1b/2 study intended to obtain preliminary safety, efficacy, and PK data on the investigational combination when administered to patients with mCRPC.

During Phase 1, participants will be placed into various treatment groups based on their prior cancer history. After approximately 6 participants have been recruited into the treatment arm, recruitment may be paused to allow for safety assessment. A toxicity rate of <33% will be targeted, defined as the occurrence of a treatment-related Grade 4 AE or a treatment-related Grade 3 AE that is unresponsive to supportive care during Cycle 1. If 2 or more such events are observed, recruitment into this group may not continue.

At the end of Phase 1, a futility analysis will be performed on each treatment group to guide continued recruitment into Phase 2. Invalid goalkeepers are arm-specific and anchored to existing attention-standard historical control information for use in a β-binomial Bayesian decision-making framework.

Circle selection will be based on radiologic or PSA response. Radiation response was defined as CR or PR by RECIST v1.1, and PSA response was defined as the percent change in baseline PSA >50%. At least 1 radiological CR or PR or 2 PSA responses among 15 evaluable participants must be observed to be considered for initiation of Phase 2. In this case, observing 1 or fewer PSA responses in a series of previous beta distributions would provide greater than 80% post hoc confidence that the PSA response rate is less than 20%. Participants must have at least 1 postbaseline radiation disease assessment or consecutive postbaseline PSA assessments measured at least 3 to 4 weeks apart to be considered evaluable for Phase 1 decision circles.

During Phase 2, up to 25 additional participants may be recruited into the experimental group or note the standard control group. The goal of this phase was to better characterize potential treatment differences between experimental groups and attentional criteria in concurrently recruited participants. Provide representative estimates of 90% confidence intervals for potential differences in response between treatment groups. safety endpoint

Safety analyzes will be conducted in the safety-evaluable population, defined as all participants who are recruited and receive any study treatment amount. Safety will be assessed through a summary of AEs and related changes in laboratory test results, vital signs, and electrocardiograms. Verbatim AE terms will be located 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.

Treatment-emergent adverse events (TEAEs) will be summarized, defined as AEs that occur on or after the date of initiation of study treatment, or that are present at baseline but worsen after initiation 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 study treatment discontinuation, grade 3 or higher AEs, and deaths will be listed and summarized by treatment group, using preferred terminology for targeting, thesaurus level, and NCI CTCAE as appropriate level.

In the event of crossover, participants will provide security information until crossover occurs. AEs reported after crossover will be summarized separately. efficacy endpoint

Efficacy analyzes will be conducted primarily in the efficacy-evaluable population, defined as all participants who are recruited and receive at least 1 dose of each drug in their assigned treatment regimen. The following priority efficacy endpoints will be analyzed based on the assessment of PCWG3 and program sponsors:

ORR is defined as the composite proportion of participants with a PSA response or radiological CR or PR (as defined below).

PSA response was defined as the proportion of participants with confirmed PSA reduction of 50% or more from baseline based on 2 consecutive assessments measured at least 3 to 4 weeks apart.

Radiation response was defined as the proportion of participants with best overall response of CR or PR according to RECIST v1.1.

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

PFS was defined as the time from treatment assignment until the first documentation of progressive disease (PSA progression, radiographic progression, bone scan progression, or other) or death (whichever occurred first). Depending on data availability, time to progression due to specific causes (such as PSA progression or radiological progression) may also be presented separately.

OS was defined as the time from treatment assignment until death from any cause.

Unless otherwise specified, binary satisfaction points are shown along with their exact Clopper-Pearson binomial 90% confidence intervals. Time-to-event endpoint parameters will be assessed using the Kaplan-Meier technique. Disease and response assessment

The primary efficacy endpoint was ORR, defined as the composite proportion of participants with a PSA response or a complete or partial radiation response as determined by the program sponsor based on PCWG3 criteria. PSA response and radiation complete or partial response may be reported separately. For clarity, PSA response was defined as the proportion of participants with confirmed PSA reduction of 50% or more from baseline based on 2 consecutive assessments measured 3 to 4 weeks apart. Radiation response was defined as the percentage of participants with measurable disease at baseline who achieved best overall response of CR or PR according to RECIST v1.1.

Participants will have 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 study end. At the discretion of the program sponsor, tumor evaluation may be repeated at any time if disease progression is suspected. All participants who discontinue study treatment for reasons other than disease progression (e.g., AEs) will continue to undergo tumor evaluation until death, disease progression, initiation of another systemic anticancer therapy, loss to follow-up, withdrawal of consent, or study termination. Whichever occurs first.

Measurable and evaluable lesions should be assessed and documented during screening. Tumor assessments performed as a standard of care before obtaining informed consent and within 28 days before recruitment do not need to be repeated at screening.

Baseline disease assessment for all participants will include: • Developing CT scan of chest and abdomen/pelvis, • Whole body bone scan (TC-99m [TC-99m]), and • Brain MRI scan.

Post-baseline disease assessment for all participants will include: • Developing CT scan of chest and abdomen/pelvis, • 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, and • Brain MRI scans only for participants with documented CNS disease at baseline and for participants with new clinical signs or symptoms of CNS disease.

All scans should be performed according to RECIST v1.1 and using developer. If contrast agents are medically contraindicated, chest CT without contrast agents and abdominal/pelvic MRI without contrast agents may be performed. If brain MRI is contraindicated, brain imaging CT should be performed. If the CT scan used for tumor evaluation is performed in a Positron Emission Tomography (PET)/CT scanner, the CT acquisition must be consistent with the standards for a fully developed diagnostic CT scan.

All measurable and evaluable lesions identified at baseline should be re-evaluated at each subsequent post-baseline tumor assessment. The same radiological procedures used to evaluate the site of disease at screening should be used for subsequent tumor evaluation (eg, the same imaging protocols used for CT scans). Program facilitators will use PCWG3 to evaluate responses. If possible, assessments should be performed by the same assessor to ensure internal consistency in disease assessment. The program sponsor must review the results before administering the drug during the next planned study treatment cycle. Adverse event definition adverse events

An adverse event (AE) is any adverse medical event that occurs when a clinical study participant is administered a medicinal product, regardless of causal attribution. Therefore, AE can be any of the following: • Any adverse and unintended signs (including abnormal laboratory findings), symptoms, or disease temporarily associated with the use of a medicinal product, whether or not considered related to the medicinal product. • Any new disease or acute onset of an existing disease (a worsening of the character, frequency, or severity of a known condition) • Recurrence of intermittent medical conditions (e.g. headaches) not present at baseline • Any worsening of laboratory values or other clinical tests (e.g., ECG, X-ray) related to symptoms or resulting in a change in study treatment or concomitant treatment or discontinuation of study treatment • Events related to protocol-mandated interventions, including those events that occur before assignment of study treatment (e.g., invasive screening procedures such as biopsies). serious adverse events

A serious adverse event (SAE) is any AE that meets any of the following criteria: • Fatal (i.e., the AE actually caused or resulted in death) • Life-threatening (i.e., in the opinion of the program administrator, the AE places the participant at immediate risk of death) • Required or prolonged hospitalization • Causes persistent or severe disability/incapacity (i.e., the AE causes a substantial impairment of the participant’s ability to carry out normal life functions) • Congenital anomalies/birth defects • A medically significant event in the judgment of the program administrator (e.g., one that may endanger the participant or may require medical/surgical intervention to prevent one of the outcomes listed above)

The terms "severe" and "serious" are not synonyms. 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 severe headache without any further discoveries). severity assessment

The program sponsor will evaluate the severity level based on NCI CTCAE (version 5.0). Table 10 will be used to assess the severity of AEs not specifically listed in the NCI CTCAE. Table 10 : Adverse event severity rating scale for events not specifically listed in NCI CTCAE level Severity 1 Mild; asymptomatic or mildly symptomatic; clinical or diagnostic observation only; or intervention not indicated 2 Moderate; indicates minimal, partial, or non-invasive intervention; or limits age-appropriate instrumental activities ^of daily livinga 3 Severe or medically significant, but not immediately life-threatening; indicating hospitalization or prolonged hospitalization; incapacitated; or limiting self-care activities of daily livingb ^,c 4 Life-threatening consequences or emergency intervention ^indicatedd 5 Death related to AE ^{d aInstrumental} activities of daily living include preparing meals, buying groceries or clothes, using the phone, managing money, etc. ^bExamples of self-care activities of daily living include bathing, dressing and undressing, feeding oneself, using the toilet, and taking medications, performed by ambulatory patients. ^cIf the event is assessed as a "significant medical event," it must be reported as an SAE. ^dIf the event meets the definition of SAE, Level 4 and 5 events must be reported as SAE. Example 2 Phase 2 Study to Evaluate the Safety and Efficacy of a Trop-2 ADC, Adenosine Receptor Antagonist, and PD(L)1 Antagonist Combination Therapy in Patients with Disease Progression Following Systemic Treatment for Non-Small Cell Lung Cancer

This study will evaluate the efficacy and safety of a combination treatment regimen for 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 have a diagnosis of advanced or metastatic squamous or non-squamous NSCLC. Participants with EGFR, ALK, or any other known actionable genomic alteration must also receive treatment with at least 1 approved tyrosine kinase inhibitor appropriate for the genomic alteration. During the preliminary phase, participants will be randomly assigned to experimental groups. Randomization will be stratified by histology (squamous vs. non-squamous) and prior therapy targeting actionable genomic alterations (yes vs. no). During the expansion phase, participants will be randomly assigned to either the comparison group or the experimental group. Participants in the comparison arm will receive saxotuzumab, govitcan or docetaxel, and the comparison arm will be selected based on treatment status at the start of the expansion phase. purpose and destination

The primary, secondary, and exploratory purposes and corresponding endpoints of the SG + Elumelen + Cepalizumab treatment group are as follows: ● Main purpose ○ The objective response rate (ORR) is evaluated in accordance with RECIST version 1.1. ● Corresponding end point: ○ Objective response rate (ORR) is defined as the proportion of participants achieving a complete response (CR) or a partial response (PR). ● Secondary purpose ○ Evaluate the efficacy of the treatment combination (SG + elumelon + cepalizumab). ○ Evaluate the safety and tolerability of treatment combinations. ● Corresponding end point ○ Progression-free survival (PFS) is defined as the time from the date of randomization until disease progression (PD) or death (whichever comes first) as assessed by the program sponsor according to RECIST version 1.1. ○ Duration of response (DOR), defined as the time from the first response (CR or PR) until the first documented PD or death (whichever comes first) as assessed by the program sponsor according to RECIST version 1.1. ○ Overall survival (OS) is defined as the time from the date of randomization until death from any cause. ○ The incidence of treatment-emergent adverse events (TEAEs), treatment-related adverse events, and laboratory abnormalities. ● Exploratory purpose: ○ Evaluate biomarkers in blood and tumor biopsy samples suitable for treatment. ○ Exploring biomarkers that predict response/resistance to therapy. ○ Characterize pharmacokinetics and immunogenicity (if applicable). ● Corresponding end point ○ Changes in biomarkers in response to treatment ○ Correlation of clinical response with biomarkers at baseline and/or on treatment/progression ○ Peak and trough concentrations over time and anti-drug antibodies over time.

Efficacy endpoints of ORR, PFS, DOR, and OS will be assessed. Computed tomography or MRI scans with visualization of the chest, abdomen, pelvis, and any other involved disease sites will be obtained in all participants until there is radiological progression of disease requiring discontinuation of further treatment. 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. Qualification inclusion criteria

Participants will be eligible for inclusion in the study only if they meet all of the following criteria: 1) Histologically or cytologically documented NSCLC with documented evidence of stage IV NSCLC disease at the start of study treatment (based on the American Joint Committee on Cancer, Eighth Edition). 2) Participants are willing to provide sufficient tumor tissue. Tumor biopsies must be performed at or after progression on previous line of therapy and before recruitment, with no anticancer treatment between tissue collection and recruitment. 3) EGFR and ALK need to be tested. Testing for other actionable genomic alterations is recommended and performed as indicated by local standard of care and availability of targeted therapies. 4) After receiving platinum-based chemotherapy in combination with 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), Participants must have progressed or experienced disease relapse. 5) Documented radiation disease progression during or after the most recent treatment regimen for advanced or metastatic NSCLC. Exclusion criteria

Participants were excluded from the study if any of the following criteria applied: 1) Previous treatment for any of the following lung cancer: a) Topoisomerase 1 inhibitors. Any agent (including ADC) containing a chemotherapeutic agent targeting topoisomerase 1. b) Trop-2-targeted therapy. c) Docetaxel as monotherapy or in combination with other agents. 2) Having an active autoimmune disease requiring systemic treatment defined as disease-modifying agents, corticosteroids, or immunosuppressive drug therapy in the past 2 years. 3) Has received allogeneic tissue/solid organ transplantation. research products

Saxetulizumab, govitecan, elumelan, and cepalizumab are as described in Example 1. Dosage and Administration Table 11. Administration of Experimental Treatments handle Drug/ Dose/ Route Dosage schedule ( number of days per 21-day cycle) all cycles Saxituzumab Govitkan + Cepalimab + Elumelen Ellumeleng 150 mg PO D1-D21 (continue until PD or unacceptable toxicity) Cepalizumab 360 mg IV D1 (up to 35 treatment cycles) Saxetulizumab Govitcan 10 mg/kg IV D1, D8 (continue until PD or unacceptable toxicity) D1 = Day 1; D8 = Day 8; D21 = Day 21; IV = Intravenous; PO = Oral

Elumelicol is administered orally, followed by cepalizumab IV, then saxetulizumab govitcan IV.

The comparator arm during the expansion phase of the study will be docetaxel or saxotuzumab and govitcan monotherapy (Table 12). Table 12. Comparative Group: Administration of docetaxel or saxetulizumab and govitcan Compare treatment groups Drug/ Dose/ Route Dosage schedule ( number of days per 21-day cycle) all cycles Docetaxel Docetaxel 75 mg/m ² IV D1 (continue until PD or unacceptable toxicity) saxituzumabgovitkan Saxetulizumab Govitcan 10 mg/kg IV D1, D8 (continue until PD or unacceptable toxicity) D1 = Day 1; D8 = Day 8; IV = Intravenous; PO = Oral

Concomitant treatment was as described in Example 1. biomarker testing

If EGFR or ALK status is unknown, local tumor tissue or liquid biopsy testing will be performed. EGFR testing will be performed using the Cobas ^® EGFR Mutation Test (Roche). For ALK, the Vysis ALK Break Apart FISH probe test (Abbott) will be used.

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 mutation burden and tumor mutations (DNA). Tumor and blood samples will be collected to measure biomarkers of response and resistance and to better understand the molecular properties that predict lung cancer treatment. Examples may include, but are not limited to, PD-L1 and Trop-2 expression, other proteins associated with any investigational treatment or associated with lung cancer, tumor mutational burden, oncogenic mutations, immune subset composition of the tumor microenvironment, and pathological characteristics of the tumor. and mutation/gene expression (WES/RNAseq). Example 3 Development of murine saxotuzumab govitcan (SG) ADC, surrogate SG ADC, and control ADC

The purpose of this study was to develop murinized saxitulizumab govitcan (SG) ADC, surrogate SG ADC, and control ADC.

To engineer an anti-human Trop-2 ADC that is tolerated in an immune competition mouse model, the parental mouse antibody RS7 variable region was fused to the mouse IgG2 backbone. The resulting murine RS7 was coupled to the CL2A linker/SN-38 payload with high DAR (~8-9).

To engineer anti-mouse Trop-2 ADC binding to mouse Trop-2 with properties similar to SG, the commercially available anti-mouse Trop-2 rabbit antibody (Sino Biological, #50922-R064) was source to obtain anti-mouse Trop-2 IgG2a (Rab64/mG2a/mKap). Rab64 mAb was then coupled to the CL2A linker/SN-38 payload with high DAR (~8-9). The binding of hRS7 mAb, SG, Rab64 Ab, and agent SG to Trop-2 was characterized by surface plasmon resonance (SPR, Table 13 ), and agent SG was confirmed to be in the low nanomolar range (for mTrop- 2 is 1.37 nM and 1.1 nM for hTrop-2) binds to mouse and human Trop-2. Table 13 : Association constant (K _a ) , dissociation constant (K _d ) , and affinity constant (K _D ) measured by SPR Human Trop-2 k _a (M ^-1 s ^-1 ) k _d (s ^-1 ) K _D (nM) hRS7-hIgG1k 4.397(1)e5 1.440(1)e-4 0.3276 SG 4.2340(9)e5 1.530(1)e-4 0.3615 Rab64-mIgG2a 8.299(8)e4 5.44(1)e-5 0.655 Agent SG 8.46(2)e4 9.68(3)e-5 1.145 Mouse Trop-2 k _a (M ^-1 s ^-1 ) k _d (s ^-1 ) K _D (nM) hRS7-hIgG1k No binding detected SG No binding detected Rab64-mIgG2a 5.812(1)e5 8.107(2)e-4 1.3950 Agent SG 5.776(2)e5 7.949(3)e-4 1.3760

A mouse isotype control ADC (mMAB1129/mG2a/mKap) was used as a control ADC and coupled to the CL2A linker/SN-38 payload under the same conditions as the Rab64 mAb. Table 14 summarizes the ADC constructs. Table 14. Summary of ADC structures Name biological type DAR Sarcotulizumab Govitcan (SG, Trodelvy ^® ) hRS7 hIgG1-CL2A-SN38 ADC 7.5 Mouse-derived SG mRS7 mIgG2a-CL2A-SN-38 ADC 7.7 Agent SG Rab64 mIgG2a-CL2A-SN-38 ADC 8.1 Control agent and mouse SG mMAB1129 mIgG2a-CL2A-SN38 ADC 7.8 Example 4 In vivo efficacy of murine SG conjugated to anti-mouse PD1 and/or quiclocrustat (CD73i) in an immune competition mouse model of orthotopic breast cancer expressing human Trop-2

The purpose of this study was to determine the in vivo efficacy of murine SG conjugated to anti-mouse PD1 and/or quicrustat in an immune competition mouse model of orthotopic breast cancer expressing human Trop-2.

The C57BL/6N- Tacstd2 ^{tm1 (TACSTD2} /Bcgen) mouse line was obtained from Biocytogen. Female C57BL/6N- Tacstd2 ^{tm1 (TACSTD2} /Bcgen) (5 to 7 weeks old) were injected with huTrop-2 transduced EO771 tumor cells into the left fourth breast. in the fat pad. When the tumor volume reached an average volume of 100 ^mm3 , the mice were randomly assigned to 12 groups (10 mice in each group), and the following treatments were continued for four weeks: 1. PBS every two weeks (BIW) × 4 intraperitoneally (IP) 2. 200 µg/mouse of mouse anti-mouse PD1 antibody (RMP1.14 mIgG1 D265A/mKap) BIW × 2 IP 3. 200 µg/mouse of murine SG BIW × 4 times IP 4. 200 µg/mouse of murine SG BIW × 4 times IP + 200 µg/mouse of anti-mouse PD1 antibody BIW × 2 times IP 5. 200 µg/mouse of quiclocrustat ( QD) subcutaneously (SQ) × 28 6. 200 µg/mouse of murine SGBIW × 4 IP + 200 µg/mouse of quiclocrustat QD × 28 SQ 7. 200 µg/mouse of anti- Mouse PD1 antibody BIW × 2 IP + 200 µg/quilicrustat in mouse (QD) subcutaneously (SQ) × 28 8. 200 µg/mouse mouse-derived SGBIW × 4 IP + 200 µg/ Anti-mouse PD1 antibody mouse BIW × 2 IP + 200 µg/mouse quiclocrustat (QD) subcutaneously (SQ) × 28

Murinized SG ADC lines were generated as described in Example 3. The anti-mouse PD1 antibody RMP1.14 mIgG1 D265A is a commercially available antibody and can be purchased from Invivogen (cat. code mpd1-mab15-1).

Use calipers to measure palpable tumors. Mice were sacrificed ^when tumor size reached ~2000 mm. The group treated with triple therapy (Group 8) is expected to have the longest survival time due to the combination of the anti-tumor effect of murine SG and the activation of tumor infiltration via IO drugs.

It should be understood that the examples and embodiments described herein are for illustrative purposes only, and various modifications or changes based on these examples and embodiments will be inferred by those with ordinary skill in the art and should be incorporated into this application. within the spirit and scope and the scope of the accompanying claims. All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety for all purposes.

without

without

TW202345845A_112113867_SEQL.xml

Claims (121)

A method of treating, alleviating, reducing, preventing, or delaying the recurrence or metastasis of Trop-2-positive cancer, which includes administering to a subject an effective amount of the following: a) Anti-Trop-2 antibody-drug conjugate (ADC); and b) Adenosine pathway inhibitors. The method of claim 1, wherein the anti-Trop-2 ADC contains a topoisomerase I inhibitor. The method of claim 2, wherein the topoisomerase I inhibitor is camptothecin (CPT). The method of claim 2, wherein the topoisomerase I inhibitor is topotecan, irinotecan, belotecan, or exatecan. The method of claim 2, wherein the topoisomerase I inhibitor is SN38 or deruxtecan (Dxd). The method of claim 2, wherein the topoisomerase I inhibitor is selected from the group consisting of irinotecan, topotecan, and SN-38. The method of any one of claims 2 and 5 to 6, wherein the topoisomerase I inhibitor is SN38. The method of any one of claims 1 and 5 to 7, wherein the anti-Trop-2 ADC has the structural formula of mAb-CL2A-SN-38, wherein the structure is represented by: . The method of any one of claims 1 to 8, wherein the anti-Trop-2 ADC comprises sacituzumab (hRS7). The method of any one of claims 1 to 8, wherein the anti-Trop-2 ADC is selected from the group consisting of datopotamab deruxtecan (DS-1062) , ESG-401, SKB-264, DAC-02, and BAT-8003. The method of any one of claims 1 to 10, wherein the anti-Trop-2 ADC is saxitulizumab govitcan. The method of any one of claims 1 to 11, wherein the adenosine pathway inhibitor is a CD39 inhibitor, a CD73 inhibitor, or an adenosine receptor antagonist. The method of any one of claims 1 to 11, wherein the adenosine pathway inhibitor is a plurality of adenosine pathway inhibitors. The method of claim 13, wherein the plurality of adenosine pathway inhibitors include a CD73 inhibitor and an adenosine receptor antagonist. The method of claim 14, wherein the CD73 inhibitor is quemliclustat and the adenosine receptor antagonist is elumelon. The method of any one of claims 1 to 14, wherein the adenosine pathway inhibitor is an adenosine receptor antagonist. The method of any one of claims 1 to 14 and 16, wherein the adenosine pathway inhibitor is imaradenant, NIR178, ID11902, IN-A003, NTI-55, TT-10, TT-228 , PBF-1129 (Palobiofarma), TT-702, Alumelen, INCB106385, M1069, HM87277, RVU-330, or TT-53. 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). The method of any one of claims 1 to 14 and 16 to 18, wherein the adenosine pathway inhibitor is alumelen (AB928; GS-0928), taminadenant, TT-10, TT -4, or M1069. The method of any one of claims 1 to 19, wherein the adenosine pathway inhibitor is elumelon. The method of any one of claims 1 to 13, wherein the adenosine pathway inhibitor is a CD73 inhibitor. The method of claim 21, wherein the CD73 inhibitor is oleclumab, BMS-986179, uliledlimab, AK119, quemliclustat, mupadolimab, 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. Such as the method of claim 21 or 22, wherein the CD73 inhibitor is quiclocrustat (AB680, GS-0680), ulelelimab, mupadolimab, ORIC-533, ATG-037, PT -199, AK131, NZV930, BMS-986179, or olerumab. The method of any one of claims 21 to 23, wherein the CD73 inhibitor is quiniclustat. The method of any one of claims 1 to 24, wherein the method further comprises co-administering additional therapeutic agents or treatment modalities. The method of claim 25, wherein the additional therapeutic agents or treatment modes include one, two, three, or four additional therapeutic agents and/or treatment modes. The method of claim 25 or 26, wherein the additional therapeutic agent comprises an anti-PD-(L)1 antibody. Such as the method of claim 27, wherein the anti-PD-(L)1 antibody is pembrolizumab, nivolumab, cemiplimab, pidilizumab ( pidilizumab), spartalizumab, atezolizumab, avelumab, durvalumab, cosibelimab, sazanizumab Anti-(sasanlimab), tislelizumab (tislelizumab), retifanlimab (retifanlimab), balstilimab (balstilimab), toripalimab (toripalimab), cetrelimab ), genolimzumab, prolgolimab, lodapolimab, camrelizumab, budigalimab, Avelu avelumab, dostarlimab, envafolimab, sintilimab, or zimberelimab. The method of claim 28, wherein the anti-PD-(L)1 antibody is zimberelimab. The method of any one of claims 25 to 29, wherein the additional therapeutic agent comprises an anti-TIGIT antibody. Such as the method of claim 30, wherein the anti-TIGIT antibody is tiragolumab, vibostolimab, domvanalimab, AB308, AK127, BMS-986207, Pasutalumab (ralzapastotug), or etigilimab (etigilimab). The method of claim 31, wherein the anti-TIGIT antibody is domvanalimab. The method of any one of claims 25 to 32, wherein the additional therapeutic agent includes an anti-PD-(L1) antibody and an anti-TIGIT antibody. Such as the method of claim 33, wherein the additional therapeutic agent includes a) cepalizumab and dovanalizumab, b) cepalizumab and AB308, c) atezolizumab and tisrelizumab monoclonal antibody, d) pembrolizumab and weibolizumab, e) MK-7684A (pembrolizumab/wibrolizumab co-formulation), f) durvalumab and dovanalizumab, g ) cepalizumab and rapasutalumab, or h) pembrolizumab and rapasutalumab. The method of claim 34, wherein the additional therapeutic agent includes cepalizumab and dovanalizumab. The method of any one of claims 1 to 35, wherein the Trop-2 positive cancer is solid epithelial cancer. The method of claim 36, wherein the solid epithelial cancer is selected from the group consisting of breast cancer (e.g. triple negative breast cancer (TNBC), HR ⁺ /Her2 ^- breast cancer, HR ⁺ /Her2 ^low breast cancer), colorectal cancer, lung cancer, gastric cancer, urethral cancer , urothelial cancer, bladder cancer, kidney cancer, pancreatic cancer, ovarian cancer, uterine cancer, esophageal cancer, and prostate cancer. The method of claim 37, wherein the prostate cancer is castration-resistant prostate cancer (CRPC). The method of claim 37, wherein the lung cancer is non-small cell lung cancer (NSCLC). Claim the method of claim 37 or 39, wherein the lung cancer is (i) squamous NSCLC or (ii) non-squamous NSCLC. The method of claim 37 or any one of claims 39 to 40, wherein the lung cancer does not have EGFR, ALK, or other operable genomic alterations. The method of claim 37, wherein the breast cancer is triple negative breast cancer (TNBC), HR ⁺ /Her2 ⁻ breast cancer, or HR ⁺ /Her2 ^low breast cancer. The method of any one of claims 1 to 42, wherein the Trop-2 positive cancer is (i) unresectable locally advanced or (ii) metastatic. The method of any one of claims 1 to 43, wherein the cancer has progressed following at least one prior anti-cancer therapy. For example, the method of claim 44, wherein the cancer has been previously treated with a new hormonal agent (NHA; a first or second generation non-steroidal antiandrogen, such as abiraterone, enzalutamide, dalutamide, abiraterone palufamide) has progressed since. The method of claim 44, wherein the cancer has progressed or recurred following platinum-based chemotherapy. The method of claim 44 or 46, wherein the cancer has progressed or recurred following checkpoint inhibitor (CPI) therapy. The method of claim 44 or any one of 46 to 47, wherein the cancer has progressed or recurred after receiving platinum-based chemotherapy and anti-PD-(L)1 antibody therapy in any order, in combination or sequentially. The method of claim 44 or any one of 46 to 48, wherein the cancer has progressed or recurred following tyrosine kinase inhibitor therapy. The method of any one of claims 1 to 49, wherein the cancer is resistant or refractory to one or more anti-cancer therapies. Claim the method of any one of items 1 to 43, wherein the subject has not received treatment. The method of any one of claims 1 to 51, wherein the subject has not received a taxane therapy (not receiving a taxane), a checkpoint inhibitor therapy (not receiving a CPI), and topoisomerase I Prior therapy for the group consisting of inhibitor therapies. The method of any one of claims 1 to 52, wherein the subject has not received prior taxane therapy (not receiving a taxane), checkpoint inhibitor therapy (not receiving a CPI), or topoisomerase I Inhibitor therapy. The method of claim 52 or 53, wherein the taxane therapy includes paclitaxel, albumin-bound paclitaxel (ABRAXANE ^® ), docetaxel, or cabazitaxel. 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. The method of any one of claims 52 to 55, wherein the topoisomerase I inhibitor therapy includes topotecan, irinotecan, bellotecan, or irinotecan. The method of any one of claims 1 to 56, wherein the anti-Trop-2 ADC and adenosine pathway inhibitor are co-administered in parallel. The method of any one of claims 1 to 57, wherein the anti-Trop-2 ADC and adenosine pathway inhibitor are co-administered sequentially. The method of claim 1 to 58, wherein the subject is a human being. The method of any one of claims 1 to 59, wherein the anti-Trop-2 ADC is administered at one or more doses in the range of 8 mg/kg to 10 mg/kg. The method of claim 60, wherein the anti-Trop2 ADC is administered at one or more doses of 10 mg/kg. The method of any one of claims 1 to 61, wherein the anti-Trop-2 ADC is administered intravenously. The method of claim 1 to 62, wherein the anti-Trop-2 ADC is administered on days 1 and 8 of a 21-day cycle. 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. 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. The method of any one of claims 1 to 65, wherein the adenosine pathway inhibitor is administered orally (PO). The method of any one of claims 1 to 64, wherein the adenosine pathway inhibitor is administered once daily (QD). The method of any one of claims 55 to 67, wherein the anti-PD(L)1 antibody system is administered in one or more doses of 360 mg. The method of any one of claims 55 to 68, wherein the anti-PD(L)1 antibody is administered intravenously (IV). The method of any one of claims 55 to 69, wherein the anti-PD(L)1 antibody system is administered once every three weeks (Q3W). Claim the method of any one of items 10 to 70, wherein saxetuzumab govitcan is administered intravenously (IV) at a dose of 10 mg/kg on days 1 and 8 of a 21-day treatment cycle , Elumelen was administered orally (PO) at a dose of 150 mg once daily (QD) on each day of the 21-day treatment cycle, and optionally, cepalizumab was administered on Day 1 of the 21-day treatment cycle. Administer intravenously (IV) on the same day (Q3W). The method of claim 1 to 71, wherein the anti-cancer effect is measured by objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), duration of response (DOR), Changes from baseline in overall survival (OS), complete response (CR), partial response (PR), PSA response rate, radiation response rate, blood and tumor tissue microenvironment pharmacodynamics (PD) biomarkers, or combinations thereof Judgment to observe. The method of claim 72, wherein tumor response or progression is determined according to RECIST version 1.1. A method of 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) Saxi Tuzumabo Gevitan; and b) Ai Lu is cold. The method of claim 74, further comprising co-administering an anti-PD-(L)1 antibody to the human patient. The method of claim 75, wherein the anti-PD-(L)1 antibody system is selected from the group consisting of: pembrolizumab, nivolumab, cimipilimab ( cemiplimab), pidilizumab, spartalizumab, atezolizumab, avelumab, durvalumab, coxili cosibelimab, sasanlimab, tislelizumab, retifanlimab, balstilimab, toripalimab ), cetrelimab, genolimzumab, prolgolimab, lodapolimab, camrelizumab, bugli budigalimab, avelumab, dostarlimab, envafolimab, sintilimab, and zimberelimab ). The method of claim 74, further comprising co-administering cepalizumab to the human patient. The method of any one of claims 74 to 77, wherein the CRPC is metastatic CRPC (mCRPC). The method of any one of claims 74 to 78, wherein the CRPC is resistant or refractory to one or more anti-cancer therapies. The method of claim 79, wherein the CRPC has progressed after prior NHA therapy (first or second generation nonsteroidal antiandrogen, abiraterone). The method of any one of claims 74 to 80, wherein the human patient has not received a taxane therapy (not receiving a taxane), a checkpoint inhibitor therapy (not receiving a CPI), and a topoisomerase Prior therapy with I inhibitor therapy. The method of claim 81, wherein the human patient has not received prior taxane therapy (not receiving a taxane), checkpoint inhibitor therapy (not receiving a CPI), or topoisomerase I inhibitor therapy. The method of claim 81 or 82, wherein the taxane therapy includes paclitaxel, albumin-bound paclitaxel (ABRAXANE ^® ), docetaxel, or cabazitaxel. 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. The method of any one of claims 81 to 84, wherein the topoisomerase I inhibitor therapy includes topotecan, irinotecan, bellotecan, or irinotecan. A method of 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)  Saxitulizumab Govitcan; b) Ailu Mei Leng; and c) Anti-PD-(L)1 antibody. The method of claim 86, wherein the anti-PD-(L)1 antibody system is selected from the group consisting of: pembrolizumab, nivolumab, cimepilimab ( cemiplimab), pidilizumab, spartalizumab, atezolizumab, avelumab, durvalumab, coxili cosibelimab, sasanlimab, tislelizumab, retifanlimab, balstilimab, toripalimab ), cetrelimab, genolimzumab, prolgolimab, lodapolimab, camrelizumab, bugli budigalimab, avelumab, dostarlimab, envafolimab, sintilimab, and zimberelimab ). The method of claim 86 or 87, wherein the anti-PD-(L)1 antibody is cepalizumab. The method of any one of claims 86 to 88, wherein the NSCLC has progressed or recurred following platinum-based chemotherapy. The method of any one of claims 86 to 89, wherein the NSCLC has progressed or recurred following checkpoint inhibitor therapy (CPI) therapy. The method of claim 90, wherein the NSCLC has progressed or recurred after receiving platinum-based chemotherapy and anti-PD-(L)1 antibody therapy in any order, in combination or sequentially. The method of any one of claims 86 to 91, wherein the NSCLC has progressed or recurred following tyrosine kinase inhibitor therapy. The method of claim 86 to 92, wherein the NSCLC is (i) unresectable locally advanced or (ii) metastatic. Claim the method of any one of items 86 to 93, wherein saxetuzumab govitcan is administered intravenously at a dose of 8 mg/kg or 10 mg/kg on days 1 and 8 of a 21-day treatment cycle (IV) and elumelon was administered orally (PO) at a dose of 75 mg or 150 mg once daily (QD) on each day of the 21-day treatment cycle. The method of claim 94, wherein saxotuzumab govitcan is administered intravenously (IV) at a dose of 10 mg/kg on days 1 and 8 of a 21-day treatment cycle, and elumelic acid It is administered orally (PO) at a dose of 150 mg once daily (QD) on each day of the 21-day treatment cycle. The method of any one of claims 86 to 95, wherein cepalizumab is administered intravenously (IV) on Day 1 of a 21-day treatment cycle (Q3W). The method of claim 86 to 96, wherein the anti-cancer effect is measured by objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), duration of response (DOR), Changes from baseline in overall survival (OS), complete response (CR), partial response (PR), PSA response rate, radiation response rate, blood and tumor tissue microenvironment pharmacodynamics (PD) biomarkers, or combinations thereof Judgment to observe. The method of claim 97, wherein tumor response or progression is determined according to RECIST version 1.1. The method of any one of claims 1 to 98, wherein an anti-CD47 antibody (eg, magrolumab) is not administered to the subject or the human patient. The method of any one of claims 1 to 99, wherein an MCL1 inhibitor (eg, GS-9716) is not administered to the subject or the human patient. The method of any one of claims 1 to 100, wherein an FLT3 agonist (eg, GS-3583, CDX-301) is not administered to the subject or the human patient. A method of treating, alleviating, reducing, preventing, or delaying the recurrence or metastasis of tumor antigen-positive (TA ⁺ ) cancer, which includes co-administering to a subject an effective amount of the following: a) including topoisomerase I Tumor antigen (TA) targeting ADC of inhibitor (TopI ADC); b) Adenosine pathway inhibitor; and c) optionally anti-PD-(L)1 antibody. An anti-Trop-2 ADC for use in combination with an adenosine pathway inhibitor and optionally an anti-PD(L)1 antibody to treat, mitigate, reduce, prevent, or delay the recurrence or recurrence of Trop-2-positive cancers A method of transfer, wherein the method comprises administering to the subject an anti-Trop-2 ADC, an adenosine pathway inhibitor, and optionally an additional anti-PD(L)1 antibody. A TopI ADC for use in combination with an adenosine pathway inhibitor and an optional anti-PD(L)1 antibody to treat, mitigate, reduce, prevent, or delay the recurrence or recurrence of tumor antigen-positive (TA ⁺ ) cancers A method of transfer, wherein the method comprises administering to a subject a TopI ADC, an adenosine pathway inhibitor, and optionally an anti-PD(L)1 antibody. A set for use as a potion, wherein the set contains a) TROP-2 targeting antibody drug conjugates (ADCs) containing anti-TROP-2 antibodies (anti-TROP-2 ADCs); b) Adenosine pathway inhibitors; and c) Optionally anti-PD-(L)1 antibody. A set for use as a potion, wherein the set contains a) Tumor antigen (TA)-targeted ADC containing topoisomerase I inhibitor (TopI ADC); b) Adenosine pathway inhibitors; and c) Optionally anti-PD-(L)1 antibody. A method of treating, alleviating, reducing, preventing, or delaying the recurrence or metastasis of breast cancer, comprising co-administering to a human patient an effective amount of the following: a) Saxi Tuzumabo Gevitan; and b) CD73 inhibitors. Such as the method of claim 107, wherein the CD73 inhibitor is oleclumab, BMS-986179, ulelelimab, AK119, quilixirumab, mupadolizumab, 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. Such as the method of claim 107, wherein the CD73 inhibitor is quiclocrustat (AB680, GS-0680), ulelelimab, mupadolimab, ORIC-533, ATG-037, PT-199 , AK131, NZV930, BMS-986179, or olerumab. The method of claim 107, wherein the CD73 inhibitor is quilicruz (AB680, GS-0680). The method of any one of claims 107 to 110, further comprising co-administering an anti-PD-(L)1 antibody to the human patient. The method of claim 111, wherein the anti-PD-(L)1 antibody system is selected from the group consisting of: pembrolizumab, nivolumab, cimepilimab ( cemiplimab), pidilizumab, spartalizumab, atezolizumab, avelumab, durvalumab, coxili cosibelimab, sasanlimab, tislelizumab, retifanlimab, balstilimab, toripalimab ), cetrelimab, genolimzumab, prolgolimab, lodapolimab, camrelizumab, bugli budigalimab, avelumab, dostarlimab, envafolimab, sintilimab, and zimberelimab ). The method of claim 112, further comprising co-administering cepalizumab to the human patient. The method of any one of claims 107 to 113, wherein the breast cancer is metastatic breast cancer. The method of any one of claims 107 to 114, wherein the breast cancer is resistant or refractory to one or more anti-cancer therapies. The method of claim 115, wherein the breast cancer has progressed following previous anti-cancer therapy (first or second generation anti-cancer therapy, such as hormonal therapy). The method of any one of claims 107 to 116, wherein the human patient has not received a taxane therapy (not receiving a taxane), a checkpoint inhibitor therapy (not receiving a CPI), and a topoisomerase Prior therapy with I inhibitor therapy. The method of claim 117, wherein the human patient has not received prior taxane therapy (not receiving a taxane), checkpoint inhibitor therapy (not receiving a CPI), or topoisomerase I inhibitor therapy. The method of claim 117 or 118, wherein the taxane therapy includes paclitaxel (paclitaxel), albumin-bound paclitaxel (ABRAXANE ^® ), docetaxel (docetaxel), or cabazitaxel. 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. The method of any one of claims 117 to 120, wherein the topoisomerase I inhibitor therapy includes topotecan, irinotecan, bellotecan, or ixotecan.