Combination therapy for treating cancer expressing tumor antigens

Abstract

The present disclosure relates to methods of treating, ameliorating, preventing, or delaying recurrence or metastasis of cancer in a subject by administering effective amounts of: (a) an antibody-drug conjugate (ADC) comprising (i) an anti-TROP-2 antibody; and / or (ii) a topoisomerase I inhibitor; (b) an anti-PD-(L) 1 antibody; and optionally, (c) an anti-TIGIT antibody.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit under 35 USC §119(e) of U.S. Provisional Application No. 63 / 330,708, filed April 13, 2022, U.S. Provisional Application No. 63 / 359,016, filed July 7, 2022, and U.S. Provisional Application No. 63 / 377,990, filed September 30, 2022, each of which is hereby incorporated by reference in its entirety. Technical Field

[0003] The present disclosure relates to methods for treating, alleviating, preventing or delaying the recurrence or metastasis of a cancer expressing Trop-2 (e.g., metastatic urothelial carcinoma or non-small cell lung cancer) in a subject by administering to the subject an effective amount of: (a) a TROP-2 targeting antibody-drug conjugate (ADC) comprising an anti-TROP-2 antibody; (b) an anti-PD-(L)1 antibody; and optionally, (c) an anti-TIGIT antibody. The present disclosure also relates to methods for treating, alleviating, preventing or delaying the recurrence or metastasis of a tumor antigen (TA)-positive ... + ) A method for preventing recurrence or metastasis of cancer: (a) a tumor antigen-targeting antibody-drug conjugate (ADC) comprising a topoisomerase I inhibitor (TopI ADC); (b) an anti-PD-(L)1 antibody; and optionally, (c) an anti-TIGIT antibody. Background Art

[0004] Antibody drug conjugates, such as sacituzumab govitecan and datopotamab deruxtecan, are under clinical investigation for the treatment of various cancers that express Trop-2 or are tumor antigen-positive. Although evidence of clinical efficacy has been obtained in the monotherapy setting, further therapeutic benefits for patients are still needed.

[0005] Trop-2 has been reported to be expressed in a variety of epithelial cancers, including breast, bladder, lung, colorectal, and prostate cancers. It is estimated that over 430,000 men and women are diagnosed with bladder cancer worldwide. Furthermore, nearly 170,000 people die from bladder cancer worldwide each year. Urothelial carcinoma (UC) is the predominant histological type in the United States and Europe. For over four decades, platinum-based chemotherapy has been the standard of care for bladder cancer. However, recent advances in the genomic characterization of bladder cancer have sparked research into immune checkpoint inhibitors for the treatment of bladder cancer. In fact, from 2016 to 2019, the US Food and Drug Administration approved nine new therapies for the treatment of advanced urothelial cancer, seven of which involved immune checkpoint inhibitors (Patel et al., Treatment of Muscle-Invasive and Advanced Bladder Cancer in 2020, CA Cancer J CLIN, 70:404-423, 2020).

[0006] Despite these advances, there remains a need to develop new therapies and new combinations for the treatment of cancers, such as Trop-2 expressing cancers or tumor antigen positive cancers. Summary of the Invention

[0007] In one aspect, provided herein are methods for treating, alleviating, reducing, preventing, or delaying the recurrence or metastasis of a Trop-2-positive cancer, comprising co-administering to a subject an effective amount of: a) a TROP-2 targeting antibody-drug conjugate (ADC) comprising an anti-TROP-2 antibody (anti-TROP-2 ADC); b) an anti-PD-(L)1 antibody; and optionally, c) an anti-TIGIT antibody.

[0008] In some embodiments, the methods provided herein are for treating a Trop-2-positive cancer, comprising co-administering to a subject an effective amount of: a) a TROP-2 targeting antibody-drug conjugate (ADC) comprising an anti-TROP-2 antibody (anti-TROP-2 ADC); b) an anti-PD-(L)1 antibody; and optionally, c) an anti-TIGIT antibody.

[0009] Also provided herein are methods for treating, alleviating, reducing, preventing, or delaying the recurrence of urothelial carcinoma (UC), comprising co-administering to a subject an effective amount of: a) a TROP-2 targeting antibody-drug conjugate (ADC) comprising an anti-TROP-2 antibody (anti-TROP-2 ADC); b) an anti-PD-(L)1 antibody; and optionally, c) an anti-TIGIT antibody.

[0010] In some embodiments, the methods provided herein are for treating urothelial carcinoma, comprising co-administering to a subject effective amounts of: a) a TROP-2 targeting antibody-drug conjugate (ADC) comprising an anti-TROP-2 antibody (anti-TROP-2 ADC); b) an anti-PD-(L)1 antibody; and optionally, c) an anti-TIGIT antibody.

[0011] Also disclosed herein are methods for treating, alleviating, reducing, preventing, or delaying the recurrence or metastasis of Trop-2-positive cancer, comprising co-administering to a subject an effective amount of: (a) a TROP-2-targeting antibody-drug conjugate (ADC) comprising an anti-TROP-2 antibody (anti-TROP-2 ADC); (b) sepalizumab; and optionally, (c) an anti-TIGIT antibody.

[0012] Also disclosed herein are methods for treating Trop-2-positive cancers, comprising co-administering to a subject effective amounts of: (a) a TROP-2 targeting antibody-drug conjugate (ADC) comprising an anti-TROP-2 antibody (anti-TROP-2 ADC); (b) sepalizumab; and, optionally, (c) an anti-TIGIT antibody.

[0013] Also disclosed herein are methods for treating, alleviating, reducing, preventing, or delaying the recurrence or metastasis of a Trop-2-positive cancer, comprising co-administering to a subject an effective amount of: (a) a TROP-2-targeting antibody-drug conjugate (ADC) comprising an anti-TROP-2 antibody (anti-TROP-2 ADC); (b) sepalimumab; and optionally, (c) dunarizumab.

[0014] Also disclosed herein are methods of treating a TROP-2-positive cancer, comprising co-administering to a subject effective amounts of: (a) a TROP-2-targeting antibody-drug conjugate (ADC) comprising an anti-TROP-2 antibody (anti-TROP-2 ADC); (b) sepalimumab; and optionally, (c) dunarizumab.

[0015] Also disclosed herein are methods for treating, alleviating, reducing, preventing, or delaying the recurrence or metastasis of a Trop-2-positive cancer, comprising co-administering to a subject an effective amount of: (a) a TROP-2-targeting antibody-drug conjugate (ADC) comprising an anti-TROP-2 antibody (anti-TROP-2 ADC); (b) an anti-PD-(L)1 antibody; and optionally, (c) dunalimab.

[0016] Also disclosed herein are methods of treating a TROP-2-positive cancer, comprising co-administering to a subject effective amounts of: (a) a TROP-2-targeting antibody-drug conjugate (ADC) comprising an anti-TROP-2 antibody (anti-TROP-2 ADC); (b) an anti-PD-(L)1 antibody; and optionally, (c) dunalimab.

[0017] Also disclosed herein are methods for treating, alleviating, reducing, preventing, or delaying the recurrence or metastasis of urothelial carcinoma, comprising co-administering to a subject an effective amount of: (a) a TROP-2 targeting antibody-drug conjugate (ADC) comprising an anti-TROP-2 antibody (anti-TROP-2 ADC); (b) sepalizumab; and optionally, (c) an anti-TIGIT antibody.

[0018] Also disclosed herein are methods for treating urothelial carcinoma, comprising co-administering to a subject effective amounts of: (a) a TROP-2 targeting antibody-drug conjugate (ADC) comprising an anti-TROP-2 antibody (anti-TROP-2 ADC); (b) sepalizumab; and optionally, (c) an anti-TIGIT antibody.

[0019] Also disclosed herein are methods for treating, alleviating, reducing, preventing, or delaying the recurrence or metastasis of urothelial carcinoma, comprising co-administering to a subject an effective amount of: (a) a TROP-2 targeting antibody-drug conjugate (ADC) comprising an anti-TROP-2 antibody (anti-TROP-2 ADC); (b) sepalizumab; and optionally, (c) dunarizumab.

[0020] Also disclosed herein are methods of treating urothelial carcinoma, comprising co-administering to a subject effective amounts of: (a) a TROP-2 targeting antibody-drug conjugate (ADC) comprising an anti-TROP-2 antibody (anti-TROP-2 ADC); (b) sepalizumab; and optionally, (c) dunarizumab.

[0021] Also disclosed herein are methods for treating, alleviating, reducing, preventing, or delaying the recurrence or metastasis of urothelial carcinoma, comprising co-administering to a subject an effective amount of: (a) a TROP-2 targeting antibody-drug conjugate (ADC) comprising an anti-TROP-2 antibody (anti-TROP-2 ADC); (b) an anti-PD-(L)1 antibody; and optionally, (c) dunalimab.

[0022] Also disclosed herein are methods of treating urothelial carcinoma, comprising co-administering to a subject effective amounts of: (a) a TROP-2 targeting antibody-drug conjugate (ADC) comprising an anti-TROP-2 antibody (anti-TROP-2 ADC); (b) an anti-PD-(L)1 antibody; and optionally, (c) dunalimab.

[0023] In some embodiments, the anti-TROP-2 ADC comprises an anticancer agent payload.

[0024] In some embodiments, the anticancer agent payload is selected from a microtubule inhibitor, a DNA cleaving agent, and a topoisomerase I inhibitor.

[0025] In some embodiments, the anti-TROP-2 ADC comprises a topoisomerase I inhibitor.

[0026] In some embodiments, the topoisomerase I inhibitor is selected from irinotecan, topotecan, and SN-38.

[0027] In some embodiments, the anti-TROP-2 ADC has the structural formula mAb-CL2A-SN-38, which is represented by the following formula:

[0028]

[0029] (Described, for example, in U.S. Patent No. 7,999,083).

[0030] In some embodiments, the anti-TROP-2 ADC comprises sacilotuzumab (hRS7; described in, e.g., WO2003074566). Figure 3 and Figure 4 middle).

[0031] In some embodiments, the anti-TROP-2 ADC is selected from gosartumomab, dexamethasone delutec (DS-1062), ESG-401, SKB-264, DAC-02, and BAT-8003.

[0032] In some embodiments, the anti-TROP-2 ADC is gosartuzumab.

[0033] In some embodiments, the anti-TROP-2 ADC comprises a microtubule inhibitor.

[0034] In some embodiments, the microtubule inhibitor is selected from the group consisting of an auristatin, a taxane, a vinca alkaloid, an epothilone, and a maytansinoid.

[0035] In some embodiments, the auristatin is selected from monomethyl auristatin E (MMAE) and monomethyl auristatin F (MMAF).

[0036] In some embodiments, the maytansinoid is selected from maytansine (DM1) and raftansine (DM4).

[0037] In some embodiments, the anticancer agent payload is selected from anthracyclines (e.g., doxorubicin, daunorubicin, epirubicin, idarubicin), pyrrolobenzodiazepine (PBD) or dimers thereof, DNA cross-linker SC-DR002 (D6.5), duocarmycin, duocarmycins (A, B1, B2, C1, C2, D, SA, CC-1065), tubulysin B, and analogs thereof.

[0038] In another aspect, provided herein are methods for treating, alleviating, reducing, preventing or delaying tumor antigen positive (TA + ) a method for preventing the recurrence or metastasis of cancer, comprising co-administering to a subject an effective amount of: a) a tumor antigen-targeting antibody-drug conjugate (ADC) comprising a topoisomerase I inhibitor (TopI ADC); b) an anti-PD-(L)1 antibody; and optionally, c) an anti-TIGIT antibody.

[0039] In some embodiments, the methods provided herein are used to treat tumor antigen positive (TA + ) cancer, comprising co-administering to the subject effective amounts of: a) a tumor antigen-targeting antibody-drug conjugate (ADC) comprising a topoisomerase I inhibitor (TopI ADC); b) an anti-PD-(L)1 antibody; and optionally, c) an anti-TIGIT antibody.

[0040] Also provided herein are methods for treating, alleviating, reducing, preventing, or delaying the recurrence of urothelial carcinoma (UC), comprising co-administering to a subject an effective amount of: a) a tumor antigen-targeting antibody-drug conjugate (ADC) comprising a topoisomerase I inhibitor (TopI ADC); b) an anti-PD-(L)1 antibody; and optionally, c) an anti-TIGIT antibody.

[0041] In some embodiments, the methods provided herein are for treating urothelial carcinoma, comprising co-administering to a subject effective amounts of: a) a tumor antigen-targeting antibody-drug conjugate (ADC) comprising a topoisomerase I inhibitor (TopI ADC); b) an anti-PD-(L)1 antibody; and optionally, c) an anti-TIGIT antibody.

[0042] Also disclosed herein are methods for treating, alleviating, reducing, preventing or delaying tumor antigen positivity (TA + ) a method for preventing the recurrence or metastasis of cancer, comprising co-administering to a subject an effective amount of: (a) a tumor antigen-targeting antibody-drug conjugate (ADC) comprising a topoisomerase I inhibitor (TopI ADC); (b) sepalizumab; and optionally, (c) an anti-TIGIT antibody.

[0043] Also disclosed herein are methods for treating tumor antigen positive (TA+ ) cancer, comprising co-administering to a subject effective amounts of: (a) a tumor antigen-targeting antibody-drug conjugate (ADC) comprising a topoisomerase I inhibitor (TopIADC); (b) sepalizumab; and optionally, (c) an anti-TIGIT antibody.

[0044] Also disclosed herein are methods for treating, alleviating, reducing, preventing or delaying tumor antigen positivity (TA + ) a method for preventing the recurrence or metastasis of cancer, comprising co-administering to a subject an effective amount of: (a) a tumor antigen-targeting antibody-drug conjugate (ADC) comprising a topoisomerase I inhibitor (TopI ADC); (b) sepalizumab; and optionally, (c) dunarizumab.

[0045] Also disclosed herein are methods for treating tumor antigen positive (TA + ) cancer, comprising co-administering to a subject effective amounts of: (a) a tumor antigen-targeting antibody-drug conjugate (ADC) comprising a topoisomerase I inhibitor (TopIADC); (b) sepalizumab; and optionally, (c) dunalizumab.

[0046] Also disclosed herein are methods for treating, alleviating, reducing, preventing or delaying tumor antigen positivity (TA + ) a method for preventing the recurrence or metastasis of cancer, comprising co-administering to a subject an effective amount of: (a) a tumor antigen-targeting antibody-drug conjugate (ADC) comprising a topoisomerase I inhibitor (TopI ADC); (b) an anti-PD-(L)1 antibody; and optionally, (c) dunalimab.

[0047] Also disclosed herein are methods for treating tumor antigen positive (TA + ) cancer, comprising co-administering to a subject effective amounts of: (a) a tumor antigen-targeting antibody-drug conjugate (ADC) comprising a topoisomerase I inhibitor (TopIADC); (b) an anti-PD-(L)1 antibody; and optionally, (c) dunalimumab.

[0048] Also disclosed herein are methods for treating, alleviating, reducing, preventing, or delaying the recurrence or metastasis of urothelial carcinoma, comprising co-administering to a subject an effective amount of: (a) a tumor antigen-targeting antibody-drug conjugate (ADC) comprising a topoisomerase I inhibitor (TopI ADC); (b) sepalizumab; and optionally, (c) an anti-TIGIT antibody.

[0049] Also disclosed herein are methods for treating urothelial carcinoma, comprising co-administering to a subject effective amounts of: (a) a tumor antigen-targeting antibody-drug conjugate (ADC) comprising a topoisomerase I inhibitor (TopI ADC); (b) sepalizumab; and optionally, (c) an anti-TIGIT antibody.

[0050] Also disclosed herein are methods for treating, alleviating, reducing, preventing, or delaying the recurrence or metastasis of urothelial carcinoma, comprising co-administering to a subject an effective amount of: (a) a tumor antigen-targeting antibody-drug conjugate (ADC) comprising a topoisomerase I inhibitor (TopI ADC); (b) sepalizumab; and optionally, (c) dunarizumab.

[0051] Also disclosed herein are methods of treating urothelial carcinoma, comprising co-administering to a subject effective amounts of: (a) a tumor antigen-targeting antibody-drug conjugate (ADC) comprising a topoisomerase I inhibitor (TopI ADC); (b) sepalizumab; and optionally, (c) dunarizumab.

[0052] Also disclosed herein are methods for treating, alleviating, reducing, preventing, or delaying the recurrence or metastasis of urothelial carcinoma, comprising co-administering to a subject an effective amount of: (a) a tumor antigen-targeting antibody-drug conjugate (ADC) comprising a topoisomerase I inhibitor (TopI ADC); (b) an anti-PD-(L)1 antibody; and optionally, (c) dunalimab.

[0053] Also disclosed herein are methods of treating urothelial carcinoma, comprising co-administering to a subject effective amounts of: (a) a tumor antigen-targeting antibody-drug conjugate (ADC) comprising a topoisomerase I inhibitor (TopI ADC); (b) an anti-PD-(L)1 antibody; and optionally, (c) dunalimab.

[0054] In some embodiments, the topoisomerase I inhibitor is camptothecin.

[0055] In some embodiments, the camptothecin is selected from irinotecan, topotecan, belotecan, and an exatecan derivative.

[0056] In some embodiments, the exatecan derivative is selected from Dxd or SN38.

[0057] In some embodiments, the topoisomerase I inhibitor is selected from irinotecan, topotecan, and SN-38.

[0058] In some embodiments, the TopI ADC has the structural formula mAb-CL2A-SN-38, which is represented by the following formula:

[0059]

[0060] (Described, for example, in U.S. Patent No. 7,999,083).

[0061] In some embodiments, the TopI ADC comprises an antibody that binds to a tumor antigen. In some embodiments, the tumor antigen is 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, insulin-like growth factor (ILGF), IFN-a, IFN-b, IL-g, IL-2R, IL-4R, IL-6R, IL-13R, IL-15R, IL-17R, IL-18R, IL-2, IL-6, IL-8, IL-12, IL-15, IL-17, IL-18, IL-25, IP-10, IGF-1R, Ia, HM1.24, gangliosides, HCG, HLA-DR, HLA-G, CD66a-d, MAGE, mCRP, MCP-1, MIP-1A, MIP-1B, macrophage migration inhibitory factor ( MIF), MUC1, MUC2, MUC3, MUC4, MUC5, placental growth factor (P1GF), PSA (prostate-specific antigen), PSMA, PSMA dimer, PAM4 antigen, NCA-95, NCA-90, A3, A33, Ep-CAM, KS-1, Le(y), mesothelin, S100, tenascin, TAC, Tn antigen, Thomas-Friedenreich antigen, tumor necrosis antigen, tumor angiogenesis antigen, TNF-a, TRAIL receptors (R1 and R2), VEGFR, RANTES, T101, cancer stem cell antigens, complement factors C3, C3a, C3b, C5a, C5, and oncogene products.

[0062] In some embodiments, the TopI ADC comprises an antibody selected from the group consisting of gemtuzumab, brentuximab, berantuzumab, camizumab, trastuzumab, inotuzumab, gebatumumab, anetuzumab, milvitutuzumab, dexuzumab, vadatuximab, labetuzumab, laditutuzumab, lantuximab, paltratuzumab, rifatuzumab, indostatuzumab, polotuzumab, pinatuzumab, cotuximab, eupilitutuzumab, indalatuximab, milatuzumab, lovatuzumab, enroku, tesotuzumab, tesituximab, decitumomab, teritutuzumab, and antigen-binding fragments thereof.

[0063] In some embodiments, the TopI ADC comprises an antibody selected from the group consisting of: hLL1 (anti-CD74), hLL2 (anti-CD22), hRFB4 (anti-CD22), hPAM4 (anti-MUC5ac), hMN-3 (anti-NOTCH3), hMN-14 (labetuzumab; anti-CEACAM5); hMN15 (anti-CEACAM6) hA19 (anti-CD19), hA20 (anti-CD22), hMu-9 (anti-CSAp), hL243 (anti-HLA-DR), hImmu-31 (anti-AFP), and antigen-binding fragments thereof.

[0064] In some embodiments, the anti-PD-(L)1 antibody is pembrolizumab, nivolumab, cemiprilimab, pidilizumab, spartalizumab, atezolizumab, avelumab, durvalumab, cocilimab, sazanlimab, tislelizumab, rivalizumab, batilizumab, toripalimab, sitrilimab, genoluzumab, palolizumab, lodalizumab, camrelizumab, budigalimab, avelumab, dotarizumab, envolimab, sintilimab, or sepalizumab.

[0065] In some embodiments, the anti-PD-(L)1 antibody is cepalimumab.

[0066] In some embodiments, the anti-PD-(L)1 antibody is cepalimumab.

[0067] In some embodiments, the anti-PD-(L)1 antibody is an Fc-silent antibody.

[0068] In some embodiments, the anti-PD-(L)1 antibody is an Fc-enabled antibody.

[0069] In some embodiments, any of the methods disclosed herein further comprise administering an anti-TIGIT antibody.

[0070] In some embodiments, the anti-TIGIT antibody is AB308, AGEN-1307 (AGEN-1327), AGEN-1777, AK127, BMS-986207, dunalimab, EOS-448, etilizumab, JS006, M6223, osperlimab, rapasumab, SEA-TGT (SGN-TGT), tisleliumab, or vembryomab.

[0071] In some embodiments, the anti-TIGIT antibody is dunalimab. In some embodiments, the anti-TIGIT antibody is M6223.

[0072] In some embodiments, the anti-PD-(L)1 antibody and the anti-TIGIT antibody are a) sepalizumab and dunalizumab, b) sepalizumab and AB308, c) atezolizumab and tisrelizumab, d) pembrolizumab and vembrolizumab, e) pembrolizumab and dunalizumab, f) pembrolizumab and AB308, g) MK-7684A (pembrolizumab / vembrolizumab co-formulation), h) durvalumab and dunalizumab, i) sepalizumab and rapasumab, or j) pembrolizumab and rapasumab.

[0073] In some embodiments, the anti-PD-(L)1 antibody and the anti-TIGIT antibody are sepalimumab and dunarizumab.

[0074] In some embodiments, the method further comprises co-administering an additional therapeutic agent or treatment modality.

[0075] In some embodiments, the additional therapeutic agents or treatment modalities include one, two, three, or four additional therapeutic agents and / or treatment modalities.

[0076] In some embodiments, the Trop-2 positive cancer is a solid epithelial cancer.

[0077] In some embodiments, TA + The cancer is a solid epithelial cancer.

[0078] In some embodiments, the solid epithelial cancer is selected from breast cancer (e.g., triple negative breast cancer (TNBC), HR + / Her2 - Breast cancer or HR + / Her2 低 breast), colorectal cancer, lung cancer, stomach cancer, urinary tract cancer, urothelial cancer, bladder cancer, kidney cancer, pancreatic cancer, ovarian cancer, uterine cancer, esophageal cancer, and prostate cancer.

[0079] In some embodiments, the bladder cancer is urothelial carcinoma (UC).

[0080] In some embodiments, the bladder cancer is (i) unresectable locally advanced bladder cancer, (ii) metastatic bladder cancer, or (iii) muscle invasive bladder cancer.

[0081] In some embodiments, the urothelial carcinoma is (i) unresectable locally advanced urothelial carcinoma, (ii) metastatic urothelial carcinoma, or (iii) muscle-invasive urothelial carcinoma.

[0082] In some embodiments, the lung cancer is non-small cell lung cancer (NSCLC).

[0083] In some embodiments, the lung cancer is (i) advanced lung cancer or (ii) metastatic lung cancer.

[0084] In some embodiments, the lung cancer is (i) advanced NSCLC or (ii) metastatic NSCLC.

[0085] In some embodiments, the NSCLC is squamous NSCLC.

[0086] In some embodiments, the NSCLC is non-squamous NSCLC.

[0087] In some embodiments, the metastatic NSCLC is metastatic squamous NSCLC.

[0088] In some embodiments, the metastatic NSCLC is metastatic non-squamous NSCLC.

[0089] In some embodiments, the NSCLC is NSCLC without EGFR, ALK, or other actionable genomic alterations.

[0090] In some embodiments, the cancer is (i) unresectable locally advanced cancer, (ii) metastatic cancer, or (iii) muscle invasive cancer.

[0091] In some embodiments, the cancer is (i) an advanced cancer, or (ii) a metastatic cancer.

[0092] In some embodiments, the Trop-2 positive cancer is (i) an unresectable locally advanced cancer, (ii) a metastatic cancer, or (iii) a muscle invasive cancer.

[0093] In some embodiments, TA + The cancer is (i) unresectable locally advanced cancer, (ii) metastatic cancer, or (iii) muscle-invasive cancer.

[0094] In some embodiments, the cancer has progressed after at least one prior anti-cancer therapy.

[0095] In some embodiments, the subject is treatment naive.

[0096] In some embodiments, the treatment-naive subject has not received prior anticancer therapy for (i) unresectable locally advanced cancer, (ii) metastatic cancer, or (iii) muscle-invasive cancer.

[0097] In some embodiments, the subject has received one or more anti-cancer therapies prior to administration of the combination of an ADC, an anti-PD-(L)1 antibody, and optionally an anti-TIGIT antibody.

[0098] In some embodiments, the subject is not treatment naive.

[0099] In some embodiments, the subject has received one or more prior anticancer therapies for (i) unresectable locally advanced cancer, (ii) metastatic cancer, (iii) muscle-invasive cancer.

[0100] In some embodiments, the subject has received one or more anti-cancer therapies prior to administration of the combination of an ADC, an anti-PD-(L)1 antibody, and optionally an anti-TIGIT antibody.

[0101] In some embodiments, the cancer is resistant to or refractory to one or more anti-cancer therapies.

[0102] In some embodiments, the anti-cancer therapy is selected from surgery, radiation therapy, chemotherapy, and checkpoint inhibitor therapy.

[0103] In some embodiments, the combination of ADC, anti-PD-(L)1 antibody, and optionally anti-TIGIT antibody is administered in a neoadjuvant setting (eg, in preparation for surgery or radiation therapy).

[0104] In some embodiments, the combination of ADC, anti-PD-(L)1 antibody, and optionally anti-TIGIT antibody is administered in an adjuvant therapy setting (eg, after primary treatment such as surgery or radiation therapy).

[0105] In some embodiments, the combination of an ADC, an anti-PD-(L)1 antibody, and optionally an anti-TIGIT antibody is administered in a therapeutic setting (eg, as a primary therapy).

[0106] In some embodiments, the combination of ADC, anti-PD-(L)1 antibody, and optionally anti-TIGIT antibody is administered in a maintenance setting.

[0107] In some embodiments, the subject receives one or more doses of the ADC.

[0108] In some embodiments, the subject receives one or more doses of an anti-PD-(L)1 antibody.

[0109] In some embodiments, the subject receives one or more doses of an anti-TIGIT antibody.

[0110] In some embodiments, the ADC and anti-PD-(L)1 antibody are administered simultaneously.

[0111] In some embodiments, the ADC and anti-PD-(L)1 antibody are administered sequentially.

[0112] In some embodiments, the ADC and anti-TIGIT antibody are administered simultaneously.

[0113] In some embodiments, the ADC and anti-TIGIT antibody are administered sequentially.

[0114] In some embodiments, the anti-PD-(L)1 antibody and the anti-TIGIT antibody are administered simultaneously.

[0115] In some embodiments, the anti-PD-(L)1 antibody and the anti-TIGIT antibody are administered sequentially.

[0116] In some embodiments, the subject is a human.

[0117] In some embodiments, the subject is not cisplatin eligible.

[0118] In some embodiments, the anti-TROP-2 ADC is administered in one or more doses within the range of 8 mg / kg to 10 mg / kg.

[0119] In some embodiments, the anti-TROP-2 ADC is administered in one or more doses of 8 mg / kg or 10 mg / kg.

[0120] In some embodiments, the anti-TROP-2 ADC is administered in one or more doses of 10 mg / kg.

[0121] In some embodiments, the anti-TROP-2 ADC is administered intravenously.

[0122] In some embodiments, the anti-TROP-2 ADC is administered on days 1 and 8 of a 21-day cycle.

[0123] In some embodiments, the anti-PD-(L)1 antibody is administered in one or more doses ranging from 300 mg to 400 mg.

[0124] In some embodiments, the anti-PD-(L)1 antibody is administered at a dose of 360 mg.

[0125] In some embodiments, the anti-PD-(L)1 antibody is administered intravenously.

[0126] In some embodiments, the anti-PD-(L)1 antibody is administered on day 1 of a 21-day cycle.

[0127] In some embodiments, the anti-TIGIT antibody is administered in one or more doses ranging from 800 mg to 1600 mg.

[0128] In some embodiments, the anti-TIGIT antibody is administered at a dose of 1200 mg.

[0129] In some embodiments, the anti-TIGIT antibody is administered intravenously.

[0130] In some embodiments, the anti-TIGIT antibody is administered on day 1 of a 21-day cycle.

[0131] In some embodiments, provided herein are methods of treating, alleviating, reducing, preventing, or delaying recurrence or metastasis of a Trop-2-positive cancer, comprising co-administering to a human patient effective amounts of: a) gosartuzumab; b) sepalizumab; and optionally, c) dunarizumab.

[0132] In some embodiments, provided herein are methods of treating a Trop-2-positive cancer comprising co-administering to a human patient effective amounts of: a) gosartuzumab; b) sepalizumab; and, optionally, c) dunalimab.

[0133] In some embodiments, provided herein are methods for treating, alleviating, reducing, preventing, or delaying tumor antigen positive (TA + ) a method for preventing the recurrence or metastasis of cancer, comprising co-administering to a human patient effective amounts of: a) gosartuzumab; b) sepalizumab; and optionally, c) dunalimumab.

[0134] In some embodiments, provided herein are methods for treating tumor antigen positive (TA + ) cancer, comprising co-administering to a human patient effective amounts of: a) gosartuzumab; b) sepalizumab; and optionally, c) dunalimumab.

[0135] In some embodiments, provided herein are methods of treating, alleviating, reducing, preventing, or delaying recurrence or metastasis of urothelial carcinoma (UC), comprising co-administering to a human patient an effective amount of: a) gosartuzumab; b) sepalizumab; and optionally, c) dunarizumab.

[0136] In some embodiments, provided herein are methods of treating urothelial carcinoma (UC) comprising co-administering to a human patient effective amounts of: a) gosartuzumab; b) sepalizumab; and optionally, c) dunarizumab.

[0137] In some embodiments, provided herein are methods of treating, alleviating, reducing, preventing, or delaying recurrence of metastatic urothelial carcinoma (mUC), comprising co-administering to a human patient effective amounts of: a) gosartuzumab; b) sepalizumab; and optionally, c) dunarizumab.

[0138] In some embodiments, provided herein are methods of treating metastatic urothelial carcinoma (mUC) comprising co-administering to a human patient effective amounts of: a) gosartuzumab; b) sepalizumab; and optionally, c) dunarizumab.

[0139] In some embodiments, gosartuzumab is administered in one or more doses within the range of 8 mg / kg to 10 mg / kg.

[0140] In some embodiments, gosartuzumab is administered in one or more doses of 10 mg / kg.

[0141] In some embodiments, gosartuzumab is administered intravenously.

[0142] In some embodiments, gosartan is administered on days 1 and 8 of a 21-day cycle.

[0143] In some embodiments, sepalimumab is administered in one or more doses ranging from 300 mg to 400 mg.

[0144] In some embodiments, sepalimumab is administered at a dose of 360 mg.

[0145] In some embodiments, cepalimumab is administered intravenously.

[0146] In some embodiments, sepalimumab is administered on day 1 of a 21-day cycle.

[0147] In some embodiments, dunalimab is administered in one or more doses ranging from 800 mg to 1600 mg.

[0148] In some embodiments, dunalimab is administered at a dose of 1200 mg.

[0149] In some embodiments, dunalimab is administered intravenously.

[0150] In some embodiments, dunalimab is administered on day 1 of a 21-day cycle.

[0151] In some embodiments, gosartumumab is administered at a dose of 10 mg / kg on days 1 and 8 of a 21-day cycle; sepalimumab is administered at a dose of 360 mg on day 1 of a 21-day cycle.

[0152] In some embodiments, gosartumumab is administered at a dose of 10 mg / kg on days 1 and 8 of a 21-day cycle; sepalizumab is administered at a dose of 360 mg on day 1 of a 21-day cycle, and dunalimab is administered at a dose of 1200 mg on day 1 of a 21-day cycle.

[0153] In some embodiments, the combination of gosartuzumab, cepalizumab, and optionally dunarizumab is administered in the neoadjuvant setting (eg, in preparation for surgery or radiation therapy).

[0154] In some embodiments, the combination of gosartuzumab, cepalizumab, and optionally dunarizumab is administered in the adjuvant therapy setting (eg, after primary treatment such as surgery or radiation therapy).

[0155] In some embodiments, gosartuzumab, sepalizumab, and optionally dunalimab are administered in a therapeutic setting (eg, as primary therapy).

[0156] In some embodiments, the combination of gosartuzumab, sepalimumab, and optionally dunalimab is administered in a maintenance setting.

[0157] In some embodiments of the methods provided herein, an anti-CD47 antibody is not co-administered to the subject or human patient.

[0158] In some embodiments, the anti-CD47 antibody is selected from mololimab, leszolimab, leterlimab, lefalimab, 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.

[0159] In some embodiments, the anti-CD47 antibody is magrolimab.

[0160] In some embodiments of the methods provided herein, an MCL1 inhibitor is not co-administered to the subject or human patient.

[0161] In some embodiments, the MCL1 inhibitor is selected from GS-9716, AMG-176, AMG-397, S-64315, AZD-5991, 483-LM, A-1210477, UMI-77, and JKY-5-037.

[0162] In some embodiments, the MCL1 inhibitor is GS-9716.

[0163] In some embodiments of the methods provided herein, a FLT3 agonist is not administered to the subject or human patient.

[0164] In some embodiments, the FLT3 agonist is selected from GS-3583, CDX-301, TAK-605, ONCR-177, Alb-Ftl3L, and SYM-027.

[0165] In some embodiments, the FLT3 agonist is GS-3583. BRIEF DESCRIPTION OF THE DRAWINGS

[0166] Figure 1 Schematic diagram showing the treatment arms used for the study described in Example 1.

[0167] Figure 2 The assessment schedule / study calendar for the study described in Example 1 is shown.

[0168] Figure 3 Heat maps showing the percentage of tumor-infiltrating immune cell types associated with treatment type (Y-axis, as indicated), per viable cell for CD45+ cells or per CD45+ cell for T cells, CD8 T cells, CD4 T cells, DCs, NK cells, and macrophages; ordinary two-way ANOVA; p < 0.001 for row factor.

[0169] Figure 4 Shown are the survival curves of hTrop-2 transgenic mice bearing orthotopic hTrop-2 EO771 syngeneic mammary carcinoma.

[0170] Figures 5A to 5F Shown are the growth curves of EO771 hTrop-2 in hTrop-2 KI mice 26 days after tumor implantation. Figure 5A Shown are the mean tumor volumes of mice treated with PBS (Group 1), 500 µg control ADC (Group 2), 200 µg control ADC (Group 3), 500 µg murinized SG (Group 4), or 200 µg murinized SG (Group 5). Figure 5B Shown are the growth curves of EO771 hTrop-2 in hTrop-2 KI mice treated with PBS (Group 1). Figure 5C Shown are the growth curves of EO771 hTrop-2 in hTrop-2 KI mice treated with 500 µg of control ADC (Group 2). Figure 5DShown are the growth curves of EO771 hTrop-2 in hTrop-2 KI mice treated with 200 µg of control ADC (Group 3). Figure 5E Shown are the growth curves of EO771 hTrop-2 in hTrop-2 KI mice treated with 500 µg of murinized SG (Group 4). Figure 5F Shown are the growth curves of EO771 hTrop-2 in hTrop-2 KI mice treated with 200 µg of murinized SG (Group 5). DETAILED DESCRIPTION

[0171] Provided herein are combination therapies for treating, alleviating, reducing, preventing, or delaying recurrence or metastasis of a TROP-2 expressing cancer by administering to a subject an effective amount of: (a) an anti-TROP-2 ADC; (b) an anti-PD-(L)1 antibody; and, optionally, (c) an anti-TIGIT antibody.

[0172] Also provided herein is a method for treating, alleviating, reducing, preventing or delaying tumor antigen positive (TA) by administering to a subject an effective amount of + ) Combination therapy for the treatment of recurrence or metastasis of cancer: (a) a tumor antigen-targeting antibody-drug conjugate (ADC) comprising a topoisomerase I inhibitor (TopI ADC); (b) an anti-PD-(L)1 antibody; and optionally, (c) an anti-TIGIT antibody.

[0173] In some embodiments, the treatment methods disclosed herein alleviate cancer (e.g., Trop-2 positive cancer, TA + In some embodiments, the treatment methods disclosed herein reduce the incidence or recurrence of cancer (e.g., Trop-2 positive cancer, TA positive cancer, bladder cancer, urothelial cancer or metastatic urothelial cancer) by administering the combination described herein. + In some embodiments, the treatment methods disclosed herein prevent cancer (e.g., Trop-2 positive cancer, TA positive cancer, bladder cancer, urothelial cancer or metastatic urothelial cancer) by administering the combination described herein. + In some embodiments, the treatment methods disclosed herein delay the development or recurrence of cancer (e.g., Trop-2 positive cancer, TA positive cancer, bladder cancer, urothelial cancer or metastatic urothelial cancer) by administering the combination described herein. + cancer, bladder cancer, urothelial carcinoma, or metastatic urothelial carcinoma).

[0174] In some embodiments, the method further comprises co-administering an additional therapeutic agent or treatment modality.

[0175] In some embodiments, the additional therapeutic agents or treatment modalities include one, two, three, or four additional therapeutic agents and / or treatment modalities.

[0176] In some embodiments, the Trop-2 positive cancer is a solid epithelial cancer.

[0177] In some embodiments, TA + The cancer is a solid epithelial cancer.

[0178] In some embodiments, the solid epithelial cancer is selected from breast cancer (e.g., triple negative breast cancer (TNBC), HR + / Her2 - Breast cancer or HR + / Her2 低 In some embodiments, the bladder cancer is urothelial carcinoma (UC). In some embodiments, the bladder cancer is (i) unresectable locally advanced bladder cancer, (ii) metastatic bladder cancer, or (iii) muscle-invasive bladder cancer. In some embodiments, the urothelial carcinoma is (i) unresectable locally advanced bladder cancer, (ii) metastatic bladder cancer, or (iii) muscle-invasive bladder cancer. In some embodiments, the lung cancer is non-small cell lung cancer (NSCLC). In some embodiments, the lung cancer is (i) advanced lung cancer or (ii) metastatic lung cancer. In some embodiments, the lung cancer is (i) advanced NSCLC or (ii) metastatic NSCLC. In some embodiments, the NSCLC is squamous NSCLC. In some embodiments, the NSCLC is non-squamous NSCLC. In some embodiments, the metastatic NSCLC is metastatic squamous NSCLC. In some embodiments, the metastatic NSCLC is metastatic non-squamous NSCLC. In some embodiments, the NSCLC is NSCLC without EGFR, ALK, or other actionable genomic alterations.

[0179] In some embodiments, the cancer is (i) unresectable locally advanced cancer, (ii) metastatic cancer, or (iii) muscle invasive cancer. In some embodiments, the cancer is (i) advanced cancer, or (ii) metastatic cancer.

[0180] In some embodiments, the Trop-2-positive cancer is (i) an unresectable locally advanced cancer, or (ii) a metastatic cancer (eg, mUC).

[0181] In some embodiments, TA +The cancer is (i) unresectable locally advanced cancer, or (ii) metastatic cancer (eg, mUC).

[0182] In some embodiments, the cancer has progressed after at least one prior anti-cancer therapy.

[0183] In some embodiments, the subject is treatment naive. In some embodiments, the treatment naive subject has not received prior anticancer therapy for (i) unresectable locally advanced cancer, (ii) metastatic cancer, or (iii) muscle invasive cancer.

[0184] In some embodiments, the subject has received one or more anti-cancer therapies prior to administration of the combination of an ADC, an anti-PD-(L)1 antibody, and optionally an anti-TIGIT antibody.

[0185] In some embodiments, the subject is not treatment naive.

[0186] In some embodiments, the subject has received one or more prior anticancer therapies for (i) unresectable locally advanced cancer, (ii) metastatic cancer, or (iii) muscle-invasive cancer.

[0187] In some embodiments, the subject has received one or more anti-cancer therapies prior to administration of the combination of an ADC, an anti-PD-(L)1 antibody, and optionally an anti-TIGIT antibody.

[0188] In some embodiments, the cancer is resistant to or refractory to one or more anti-cancer therapies.

[0189] In some embodiments, the anti-cancer therapy is selected from surgery, radiation therapy, chemotherapy, and checkpoint inhibitor therapy.

[0190] In some embodiments, the combination of ADC, anti-PD-(L)1 antibody, and optionally anti-TIGIT antibody is administered in a neoadjuvant setting (eg, in preparation for surgery or radiation therapy).

[0191] In some embodiments, the combination of ADC, anti-PD-(L)1 antibody, and optionally anti-TIGIT antibody is administered in an adjuvant therapy setting (eg, after primary treatment such as surgery or radiation therapy).

[0192] In some embodiments, the combination of an ADC, an anti-PD-(L)1 antibody, and optionally an anti-TIGIT antibody is administered in a therapeutic setting (eg, as a primary therapy).

[0193] In some embodiments, the combination of ADC, anti-PD-(L)1 antibody, and optionally anti-TIGIT antibody is administered in a maintenance setting.

[0194] In some embodiments, the subject receives one or more doses of the ADC.

[0195] In some embodiments, the subject receives one or more doses of an anti-PD-(L)1 antibody.

[0196] In some embodiments, the subject receives one or more doses of an anti-TIGIT antibody.

[0197] In some embodiments, the anti-TROP-2 ADC, PD-(L)1 antibody, and optionally, anti-TIGIT antibody are administered simultaneously.

[0198] In some embodiments, the anti-TROP-2 ADC, the PD-(L)1 antibody, and optionally the anti-TIGIT antibody are administered sequentially.

[0199] In some embodiments, the TOPI ADC, PD-(L)1 antibody, and optionally, anti-TIGIT antibody are administered simultaneously.

[0200] In some embodiments, the TOPI ADC, PD-(L)1 antibody, and optionally, anti-TIGIT antibody are administered sequentially.

[0201] In some embodiments, the subject is a human.

[0202] In some embodiments, the subject is not cisplatin eligible.

[0203] In some embodiments, the anti-TROP-2 ADC is administered in one or more doses ranging from 8 mg / kg to 10 mg / kg. In some embodiments, the anti-TROP-2 ADC is administered in one or more doses of 8 mg / kg or 10 mg / kg. In some embodiments, the anti-TROP-2 ADC is administered in 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.

[0204] In some embodiments of the methods provided herein, an anti-CD47 antibody is not co-administered to the subject or human patient (CD47; Integrin-Associated Protein; IAP; NCBI Gene ID: 961). In some embodiments, the subject or human patient is not administered an anti-CD47 antibody selected from the group consisting of mololimab, leszolimab, leterlimab, lefalimab, 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 administered mololimab.

[0205] In some embodiments of the methods provided herein, an MCL1 inhibitor is not co-administered to the subject or human patient (MCL1; myeloid leukemia cell differentiation protein; NCBI Gene ID: 4170). In some embodiments, the subject or human patient is not administered 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 administered GS-9716.

[0206] In some embodiments of the methods provided herein, a FLT3 agonist is not administered to a subject or human patient. In some embodiments, a subject or human patient is not administered a FLT3 agonist selected from GS-3583, CDX-301, TAK-605, ONCR-177, Alb-Ftl3L, and SYM-027. In some embodiments, a subject or human patient is not administered GS-3583.

[0207] definition

[0208] As used herein, the term "antibody" refers to a polypeptide that includes canonical immunoglobulin sequence elements sufficient to confer specific binding to a specific target antigen (e.g., a heavy chain variable domain, a light chain variable domain, and / or one or more CDRs sufficient to confer specific binding to a specific target antigen). Thus, the term "antibody" includes, for example, but is not limited to, human antibodies, non-human antibodies, antibody fragments, and antigen-binding agents comprising antibody fragments, including synthetic, engineered, and modified forms thereof. For example, the term "antibody" encompasses both naturally occurring and non-naturally occurring antibodies. Generally speaking, an antibody may comprise at least two heavy (H) chains and two light (L) chains interconnected by disulfide bonds, or an antigen-binding molecule thereof. Each H chain comprises a heavy chain variable region (abbreviated herein as VH) and a heavy chain constant region. The heavy chain constant region comprises three constant domains, CH1, CH2, and CH3. Each light chain comprises a light chain variable region (abbreviated herein as VL) and a light chain constant region. The light chain constant region comprises one constant domain, CL. The VH and VL regions can be further subdivided into hypervariable regions, termed complementarity-determining regions (CDRs), interspersed with more conserved regions, termed framework regions (FRs). Each VH and VL contains three CDRs and four FRs, arranged from amino-terminus to carboxyl-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4. The variable regions of the heavy and light chains contain the binding domain that interacts with the antigen. The constant region of an Ab mediates the binding of the immunoglobulin to host tissues or factors, including various cells of the immune system (e.g., effector cells) and the first component (C1q) of the classical complement system. Naturally produced antibodies are glycosylated, 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 comprising two heavy chain molecules and two light chain molecules, antibody light chain monomers, antibody heavy chain monomers, antibody light chain dimers, antibody heavy chain dimers, antibody light chain-antibody heavy chain pairs, intrabodies, antibody fusions (sometimes referred to herein as "antibody conjugates"), heteroconjugate antibodies, single domain antibodies, monovalent antibodies, single chain antibodies, or single chain F antibodies. v (scFv), camelized antibody, affibody, Fab fragment, Fab' fragment, F(ab')2 fragment, Fd' fragment, Fd fragment, isolated CDR, single chain Fv, polypeptide-Fc fusion, single domain antibody (e.g., shark single domain antibody (such as IgNAR) or fragment thereof); camel antibody; disulfide-linked Fv (sdFv), anti-idiotypic (anti-Id) antibody (including, for example, anti-anti-Id antibody), minibody, domain antibody, synthetic antibody (sometimes referred to herein as "antibody mimics"), single chain or tandem diabody (TandAb ®)、Anticalins ® 、Nanobodies ® , miniantibodies, BiTEs ® , ankyrin repeat proteins or DARPINs ® 、Avimers ® , DART, TCR-like antibodies, Adnectins ® 、Affilins ® 、Trans-bodies ® 、Affibodies ® 、TrimerX ® 、MicroProteins、m Fynomers ® 、Centyrins ® 、KALBITOR ® , and antigen-binding fragments of any of the above.

[0209] As used herein, the term "Fc-silent antibody" refers to an antibody comprising one or more mutations in the Fc domain that reduce, prevent or eliminate the binding of the Fc region of the antibody to an Fc receptor (such as FcγR or FcR), which can result in reduced antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP) and / or complement-dependent cytotoxicity (CDC). Exemplary mutations that can reduce, prevent, or eliminate antibody binding to Fc receptors include, but are not limited to, S228P, E233P, L234A, L235A, L235E, L235F, G236R, G237A, D265A, N297A, L328R, P331S, and any combination of these mutations (Saunders, Conceptual Approaches to Modulate Antibody Effector Functions and Circulation Half-Life, Front. Immunol., 2019, doi.org / 10.3389 / fimmu.2019.01296). In some embodiments, substitutions at any or all of positions 234, 235, 236, and / or 237 reduce affinity for Fcγ receptors, particularly FcγRI receptors (see, e.g., U.S. Patent No. 6,624,821). In some embodiments, alanine is a preferred residue for substitution, and L234A / L235A is a preferred double mutation for reducing effector function. In some embodiments, other combinations of mutations that reduce effector function include, but are not limited to, L234A / L235A / G237A, E233P / L234V / L235A / G236, A327G / A330S / P331S, K322A, L234A and L235A, L234F / L235E / P331S. Optionally, positions 234, 236, and / or 237 in human IgG2 are substituted with alanine, and position 235 is substituted with glutamine. (See, e.g., U.S. Patent No. 5,624,821.) Two amino acid substitutions in the complement C1q binding site at EU index positions 330 and 331 reduce complement fixation (see Tao et al., J. Exp. Med. 178:661 (1993), and Canfield and Morrison, J. Exp. Med. 173:1483 (1991)).Substitution of IgG2 residues at positions 233 to 236 and IgG4 residues at positions 327, 330, and 331 into human IgG1 significantly reduces ADCC and CDC (see, e.g., Armour K L. et al., 1999 Eur J Immunol. 29(8):2613-24; and Shields R L. et al., 2001. J Biol Chem. 276(9):6591-604). Mutations N297A, N297Q, or N297G (Eu numbering) reduce glycosylation and, therefore, effector function. 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 an Fc receptor. 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 an 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 an 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 FcγRIV. In some embodiments, any of the antibodies disclosed herein comprise one or more mutations in the Fc region to reduce, eliminate, or prevent ADCC, ADCP, and / or CDC. In some embodiments, the mutations in the Fc region that reduce, prevent, or eliminate binding to Fc receptors occur at EU index positions 228, 233, 234, 235, 235, 235, 236, 237, 265, 297, 322, 327, 328, 330, 331, and any combination of these positions. In some embodiments, mutations in the Fc region that reduce, prevent, or eliminate binding to an Fc receptor include, but are not limited to, S228P, E233P, L234A, L235A, L235E, L235F, G236R, G237A, D265A, N297A, K322A, A327G, L328R, A330S, P331S, and any combination of these mutations. Additional mutations in the Fc region that reduce, prevent, or eliminate binding to an Fc receptor, as well as alternative strategies for reducing, preventing, or eliminating binding to an Fc receptor, are described, for example, in Saunders, 2019; Tao, 1993; Canfield and Morrison, 1991; Armour, 1999; Shields, 2001; and U.S. Patent No. 6,624,821.

[0210] As used herein, the terms "Fc-enabled antibody," "Fc-enhanced antibody," and "Fc-competent antibody" are used interchangeably and refer to antibodies comprising an Fc domain capable of binding to an Fc receptor (such as an FcγR or FcR). These antibodies may also comprise one or more mutations to enhance or increase binding to an Fc receptor, which may result in enhanced antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), and / or complement-dependent cytotoxicity (CDC). Exemplary mutations that may enhance ADCC include, but are not limited to, S298A, E333A, K334A, S239D, I332E, P247I, A339Q, and any combination of these mutations (van der Horst et al., Fc-Engineered Antibodies with Enhanced Fc-Effector Function for the Treatment of B-Cell Malignancies, Cancers (Basel), 12(10):3041, 2020). Exemplary mutations that can enhance ADCP include, but are not limited to, F234L, R292P, Y300L, V305I, P396L, A330L, G236A, and any combination of these mutations (van der Horst et al., 2020). Exemplary mutations that can enhance CDC include, but are not limited to, E345G, E430G, K326W, E333S, S267E, H268E, S324T, and any combination of these mutations (van der Horst et al., 2020). In some embodiments, any of the antibodies disclosed herein comprise one or more mutations in the Fc region that enhance or enable binding to an Fc receptor. In some embodiments, any of the antibodies disclosed herein comprise one or more mutations in the Fc region that enhance or enable binding to an FcγR. In some embodiments, any of the antibodies disclosed herein comprise one or more mutations in the Fc region that enhance or enable binding to an FcγRIIIA. In some embodiments, any of the antibodies disclosed herein comprise one or more mutations in the Fc region to enhance binding to or enable binding to FcγRIV. In some embodiments, any of the antibodies disclosed herein comprise one or more mutations in the Fc region to enable or enhance ADCC, ADCP, and / or CDC.In some embodiments, one or more substitutions in the Fc region that enhance or enable binding to an Fc receptor occur at EU index position 234, 235, 236, 239, 243, 247, 267, 268, 292, 298, 300, 305, 324, 326, 330, 332, 333, 334, 339, 345, 396, 430, and any combination of these positions. In some embodiments, mutations in the Fc region that enhance or enable binding to Fc receptors include, but are not limited to, F234L, L235V, G236A, S239D, F243L, P247I, S267E, H268E, R292P, S298A, Y300L, V305I, S324T, K326W, A330L, I332E, E333A, E333S, K334A, A339Q, E345G, P396L, E430G, and any combination of these mutations. In some embodiments, the Fc-enabled antibody comprises a modified IgG1 domain characterized by substitutions at S239D, A330L, and I332E (Eu numbering). Alternatively, glycoform perturbations can be used to enhance Fc-mediated therapeutic antibody function. N-linked Fc glycosylation on IgG1 antibodies is important for effector function. Sialylation, galactosylation, bisecting sugars, and fucosylation can all affect the binding and activity of IgG molecules. Controlling the glycosylation pattern on therapeutic antibodies can be achieved in a variety of ways. The cell type used to produce the recombinant antibody and its culture conditions can influence the glycosylation and activity of the therapeutic antibody. In addition, bioreactor conditions and downstream processing can also affect glycan microheterogeneity. Low-fucosylated or afucosylated antibodies have been shown to enhance Fc-mediated properties. Various approaches to achieve this reduction in fucose levels through glycoengineering are well known in the art. One approach involves manipulating enzymes involved in post-translational modification of antibodies. This can involve overexpression of glucosidases (such as β-1-4-N-acetylglucosaminyltransferase III), knocking out fucosyltransferases, or using cell lines that are naturally fucose-deficient or mutated to express low fucosylation levels. In addition, inhibitors of N-linked glucosidases (such as castanospermine) can also be used to obtain IgG molecules with low fucose content. In some embodiments, amino acid engineered variants can have a broader affinity for multiple FcγRs, while glycoform-engineered antibodies can generally have a more specific affinity for enhanced FcγRIIIa binding. Glycoforms interact with proximal amino acids on the Fc portion, and substitutions of amino acids that contact Ig oligosaccharides can generate different glycoform structures.Additional mutations in the Fc region that enhance or enable binding to Fc receptors, as well as alternative strategies for enhancing or enabling binding to Fc receptors, are described in Saunders, 2019.

[0211] As used herein, the term "antibody-drug conjugate" generally refers to a compound comprising an antibody targeting a tumor antigen and an anticancer agent payload, optionally connected via a linker. In some embodiments, the tumor antigen is tumor-associated calcium signal transducer 2 (Trop-2; NCBI Gene ID: 4070). In some embodiments, the tumor antigen-targeting antibody is an anti-Trop-2 antibody (e.g., saccitrezumab or dedabrafenib). In some embodiments, the payload is a topoisomerase I inhibitor (e.g., SN38 or Dxd). Many ADC linker chemistries are known to those skilled in the art and are referenced herein (e.g., CL2A).

[0212] As used herein, the term "effective amount" or "therapeutically effective amount" refers to the amount of a therapeutic agent (e.g., ADC, adenosine pathway inhibitor, checkpoint inhibitor) administered in the methods provided herein that is sufficient to achieve a therapeutic or beneficial outcome in the subject when administered alone or in combination with another therapeutic agent to a cell, tissue, or subject. The therapeutically effective amount can vary depending on the subject, the disease or condition being treated, the subject's weight and age, the severity of the disease or condition, and the mode of administration, which can be readily determined by one of ordinary skill in the art. An effective amount also refers to an amount of a therapeutic agent sufficient to treat, prevent, alleviate, ameliorate, or alleviate the disease condition, or to delay or slow the progression of the disease, when used in the context of the combination therapies provided herein, as well as an amount sufficient to achieve an increase in the rate of treatment, cure, prevention, or improvement of such conditions. When applied to separate therapeutic agents administered independently, an effective amount refers to the active ingredient alone. When applied to a combination, a therapeutically effective amount refers to the combined amounts of the active ingredients that produce a therapeutic effect, whether administered in combination, sequentially, or simultaneously. In some embodiments, as described herein, an effective amount or therapeutically effective amount of a therapeutic agent (e.g., ADC, adenosine pathway inhibitor, checkpoint inhibitor) administered to a subject in conjunction with one or more additional therapeutic agents in the methods provided herein can (i) reduce the number of diseased cells; (ii) reduce tumor size; (iii) inhibit, block, slow down, and preferably prevent to some extent the infiltration of diseased cells into peripheral organs; (iv) inhibit (e.g., slow down to some extent and preferably prevent) tumor metastasis; (v) inhibit tumor growth; (vi) prevent or delay tumor development and / or recurrence; and / or (vii) alleviate to some extent one or more symptoms associated with cancer. In various embodiments, this amount is sufficient to improve, alleviate, reduce, and / or delay one or more of the symptoms of cancer.

[0213] As used herein, the term "treatment" refers to reversing, alleviating a disease or disorder as described herein, or one or more symptoms thereof, delaying its onset, or inhibiting its progression. In some embodiments, treatment may be administered after the onset of one or more symptoms. In other embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual before the onset of symptoms (e.g., based on a history of symptoms and / or based on genetic factors or other susceptibility factors). Treatment may also be continued after the symptoms subside, for example to prevent or delay their recurrence. In some embodiments, the methods provided herein refer to treating a subject (e.g., a human cancer patient) having cancer. In some embodiments, treating a subject (e.g., a human cancer patient) having cancer includes inhibiting the proliferation of cancer or cancer cells in the treated subject. In some embodiments, treating a human cancer patient using the methods provided herein results in an anti-tumor effect or anti-cancer effect being observed in the treated patient.

[0214] As used herein, the terms "inhibit cancer" and "inhibit cancer cell proliferation" refer to inhibiting the growth, division, maturation or vitality of cancer cells, and / or causing the death of cancer cells alone or in aggregate with other cancer cells through cytotoxicity, nutrient depletion or apoptosis induction.

[0215] As used herein, "anti-tumor effect" or "anti-cancer effect" refers to a biological effect that can be manifested as a reduction in tumor volume, a reduction in the number of tumor cells, a reduction in tumor cell proliferation, a reduction in the number of metastases, an extension of overall survival or progression-free survival, an extension of life expectancy, or an improvement in various physiological symptoms associated with the tumor. In some embodiments, the anti-cancer effect is measured using one or more endpoint criteria (e.g., primary endpoint, secondary endpoint, or exploratory endpoint) used in the clinical studies described herein. Exemplary clinical endpoint criteria that can be used to measure the anti-cancer effect associated with the methods provided herein include objective response rate (ORR), complete response (CR) rate, partial response (PR) rate, disease control rate (DCR), progression-free survival (PFS), overall survival (OS), (e.g., intratumoral immune activation or induction of cancer cell death) based on biomarker (e.g., tumor tissue or blood-based biomarker) signals, patient quality of life (QoL) indicators (e.g., based on patient surveys), and others.

[0216] As used herein, an "increase" or "enhancement" amount is generally a "statistically significant" amount (e.g., with respect to tumor size, cancer cell proliferation or growth) and can include an increase of 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 9, 10, 15, 20, 30, 40, or 50 times or more (e.g., 100, 500, 1000 times) the amounts or levels recited herein, including all integers and decimal points between these multiples and greater than 1, e.g., 2.1, 2.2, 2.3, 2.4, etc. It may also include an increase of at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 100%, at least 150%, at least 200%, at least 500%, or at least 1000% of the amounts or levels described herein.

[0217] As used herein, "lower" or "decrease" or a "smaller" amount (e.g., with respect to tumor size, cancer cell proliferation or growth) refers to a decrease of about 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 9, 10, 15, 20, 30, 40, or 50 times or more (e.g., 100, 500, 1000 times) (including all integers and decimal points between these multiples and greater than 1, e.g., 1.5, 1.6, 1.7, 1.8, etc.) the amount or level described herein. It may also include at least a 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% reduction in the amounts or levels described herein.

[0218] As used herein, the term "adverse event" (AE) refers to any undesirable medical occurrence in a clinical study participant administered an investigational drug that is not necessarily causally related to the treatment. Thus, an AE can be any unfavorable and / or unexpected sign (including clinically significant abnormal laboratory test results), symptom, or illness that is temporally associated with the use of an investigational drug, regardless of whether the AE is considered related to the investigational drug. Adverse events can also include pre- or post-treatment complications that arise due to protocol-mandated procedures or special circumstances. In some embodiments, pre-existing events that increase in severity or change in nature after the initiation of the investigational drug or during or as a result of participation in a clinical study are also considered AEs.

[0219] As used herein, the term "serious adverse event" (SAE) means a) death; b) life-threatening condition; c) hospitalization of a participant, or prolongation of an existing hospitalization; d) persistent or severe disability or incapacitation; e) congenital anomaly or birth defect; or f) a medically significant event or reaction as determined by the treating physician. Examples of medically significant events include intensive treatment of allergic bronchospasm in the emergency room or at home; blood dyscrasias or seizures that do not result in hospitalization; and progression of drug dependence or drug abuse.

[0220] As used herein, the terms "tumor antigen-expressing cancer" or "tumor antigen-positive cancer" are used interchangeably and refer to cancers that express detectable levels of a tumor antigen (TA). In some embodiments, the tumor antigen is Trop-2. Tumor antigen expression in cancerous tissue or cancer cells can be detected in a sample from a subject with cancer (e.g., a human cancer patient) by any method known to a skilled artisan, for example, as protein, mRNA, or cell surface expression levels. For example, tumor antigen expression can be determined by methods such as immunohistochemistry (IHC), Western blot, fluorescence in situ hybridization (FISH), polymerase chain reaction (PCR), next-generation exome sequencing, or fluorescence-associated cell sorting (FACS). As used herein, in order to be considered TA-positive (e.g., Trop-2-positive), it is not required that every cell in a tumor or tumor sample have a detectable level of tumor antigen expression. In some embodiments, a "TA-expressing cancer" or "TA-positive cancer" (e.g., Trop-2-positive cancer) refers to a cancer for which treatment with an anti-Trop-2 ADC or TopI ADC is indicated as a monotherapy or combination therapy. For example, the TA-positive cancer indications of anti-Trop-2 ADCs or TopI ADCs that have received marketing authorization from health regulatory agencies (e.g., FDA, EMA) are listed on the agency-approved drug label. In some embodiments, as used herein, TA-positive (e.g., Trop-2 + ) cancer is a cancer in which an anti-Trop-2 ADC or TopI ADC has demonstrated an anti-cancer effect attributable to the anti-Trop-2 ADC or TopI ADC. Such anti-cancer effect can be demonstrated in preclinical models (e.g., mouse xenograft or syngeneic cancer models) or in clinical trials conducted in human cancer patients.

[0221] Antibody-drug conjugates (ADCs)

[0222] The therapeutic methods provided herein include administering an antibody-drug conjugate (ADC) to a subject, such as a human cancer patient. In some embodiments, the ADC comprises an anti-Trop-2 antibody, an anticancer agent payload, and an optional linker connecting the anti-Trop-2 antibody to the payload (anti-Trop-2 ADC). In some embodiments, the ADC comprises a tumor antigen (TA)-targeting antibody, a topoisomerase I inhibitor payload, and an optional linker connecting the TA-targeting antibody to the payload (TopI ADC).

[0223] ADCs that can be used in the methods provided herein can include any form of antibody or antigen-binding fragment thereof. For example, without limitation, ADCs can include any form of monospecific or multispecific (e.g., bispecific, trispecific) antibodies or antigen-binding fragments thereof, such as DARTs. ® 、Duobody ® 、BiTE ® 、BiKE、TriKE、XmAb ® 、TandAb ® In some embodiments, the ADC comprises a non-immunoglobulin antibody mimetic (e.g., adnectin, affimer, affilin, affimer, affitin, alphabody, anticalin, peptide aptamer, armadillo repeat protein (ARM), atrimer, avimer, designed ankyrin repeat protein (DARPin), ® ), fynomer, knottin, Kunitz domain peptide, monomer, and nanoCLAMP).

[0224] In some embodiments, the ADC antibody is a blocking antibody. In some embodiments, the ADC antibody is a neutralizing antibody. In some embodiments, the ADC antibody is an agonist or activating antibody. In some embodiments, the ADC antibody is an antagonist or inhibitory antibody.

[0225] 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 IgG1, IgG2, IgG3, or IgG4. In some embodiments, the ADC antibody comprises a human IgG1 hinge sequence and constant region sequence. The ADC antibody can be chimeric human-mouse, chimeric human-primate, humanized (human framework regions and murine hypervariable (CDR) regions), or fully human, as well as variants thereof. In some embodiments, the ADC antibody is a half-IgG4 antibody (referred to as a "monoantibody"), as described, for example, by van der Neut Kolfschoten et al. (Science 2007;317:1554-1557). In some embodiments, the ADC antibody or antigen-binding fragment thereof is designed or selected to comprise a human constant region sequence of a specific allotype, which can result in reduced immunogenicity when the antibody or ADC is administered to a human subject. In some embodiments, the ADC antibody or antigen-binding fragment thereof is a non-Glml allotype (nGlml), such as Glm3, Glm3,1, Glm3,2, or Glm3,1,2. In some embodiments, the allotype is selected from the group consisting of nGlml, Glm3, nGlml,2, and Km3 allotypes.

[0226] anti-TROP-2 ADC

[0227] In some embodiments, an ADC that can be used in the methods provided herein comprises an anti-Trop-2 antibody, an anti-cancer agent payload, and optionally a linker connecting the anti-Trop-2 antibody to the payload (anti-Trop-2 ADC).

[0228] Examples of anti-TROP-2 antibodies that can be used in anti-TROP-2 ADCs to perform the methods provided herein include, but are not limited to, those described in the following patents: WO2020016662 (Abmart), WO2020249063 (Bio-TheraSolutions), US20190048095 (Bio-Thera Solutions), WO2013077458 (LivTech / Chiome), EP20110783675 (Chiome), WO2015098099 (Daiichi Sankyo), WO2017002776 (Daiichi Sankyo), WO2020130125 (Daiichi Sankyo), WO2020240467 (Daiichi Sankyo), US2021093730 (Daiichi Sankyo), US9850312 (Daiichi Sankyo), and US9850312 (Daiichi Sankyo).Sankyo), CN112321715 (Biosion), US2006193865 (Immunomedics / Gilead), WO2011068845 (Immunomedics / Gilead), US2016296633 (Immunomedics / Gilead), US2017021017 (Immunomedics / Gilead), US2017209594 (Immunomedics / Gilead), US2017274093 (Immunomedics / Gilead), US2018110772 (Immunomedics / Gilead), US2018185351 (Immunomedics / Gilead), US2018271992 (Immunomedics / Gilead), WO2018217227 (Immunomedics / Gilead), US2019248917 (Immunomedics / Gilead), CN111534585 (Immunomedics / Gilead), US2021093730 (Immunomedics / Gilead), US2021069343 (Immunomedics / Gilead), US8435539 (Immunomedics / Gilead), US8435529 (Immunomedics / Gilead), US9492566 (Immunomedics / Gilead), WO2003074566 (Gilead), WO2020257648 (Gilead), US2013039861 (Gilead), WO2014163684 (Gilead), US9427464 (LivTech / Chiome), US10501555 (AbruzzoTheranostic / Oncoxx), WO2018036428 (Sichuan Kelun Pharma), WO2013068946 (Pfizer), WO2007095749 (Roche) and WO2020094670 (SynAffix).

[0229] In some embodiments of the methods provided herein, the anti-Trop-2 ADC comprises an antibody selected from saccitretin (hRS7), dedabrocitin (hTINA H1L1), Trop-2-XPAT, and BAT-8003. In some embodiments, the anti-Trop-2 ADC comprises saccitretin (hRS7). In some embodiments, the anti-Trop-2 antibody comprises dedabrocitin (hTINA H1L1).

[0230] In some embodiments of the methods provided herein, the anti-Trop-2 ADC comprises a VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2, and VL-CDR3 selected from one of Tables 1 to 4. In some embodiments, the anti-Trop-2 ADC comprises the following VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2, and VL-CDR3 amino acid sequences (according to Kabat), respectively:

[0231] SEQ ID NO: 1, 2, 3, 4, 5 and 6, or

[0232] ●SEQ ID NO: 7, 8, 9, 10, 11 and 12.

[0233] In some embodiments of the methods provided herein, the anti-Trop-2 ADC comprises a variable domain (VH and VL) selected from Table 5. In some embodiments, the anti-Trop-2 ADC comprises the following VH amino acid sequence and VL amino acid sequence, respectively:

[0234] SEQ ID NOs: 49 and 50, or

[0235] ●SEQ ID NO: 51 and 52.

[0236] Table 1 - CDRs of illustrative anti-Trop-2 binding antibodies (Kabat)

[0237] Antibody name VH – CDR1 VH – CDR2 VH – CDR3 VL – CDR1 VL – CDR2 VL – CDR3 1 NYGMNSEQ ID NO: 1 WINTYTGEPTYTDDFKGSEQ ID NO:2 GGFGSSYWYFDVSEQ ID NO: 3 KASQDVSIAVASEQ ID NO:4 SASYRYT SEQ ID NO: 5 QQHYITPLTSEQ ID NO:6 2 TAGMQSEQ ID NO:7 WINTHSGVPKYAEDFKGSEQ ID NO:8 SGFGSSYWYFDVSEQ ID NO:9 KASQDVSTAVASEQ ID NO:10 SASYRYT SEQ ID NO: 11 QQHYITPLTSEQ ID NO:12

[0238] Table 2 – CDRs of illustrative anti-Trop-2 binding antibodies (IMGT)

[0239] Antibody name VH – CDR1 VH – CDR2 VH – CDR3 VL – CDR1 VL – CDR2 VL – CDR3 3 GYTFTNYGSEQ ID NO:13 INTYTGEPSEQ ID NO:14 ARGGFGSSYWYFDVSEQ ID NO:15 QDVSIASEQ ID NO:16 SASSEQ ID NO:17 QQHYITPLTSEQ ID NO:18 4 GYTFTTAG SEQ ID NO: 19 INTHSGVP SEQ ID NO: 20 ARSGFGSSYWYFDVSEQ ID NO:21 QDVSTASEQ ID NO:22 SASSEQ ID NO:23 QQHYITPLTSEQ ID NO:24

[0240] Table 3 - CDRs of illustrative anti-Trop-2 binding antibodies (Chothia)

[0241] Antibody name VH – CDR1 VH – CDR2 VH – CDR3 VL – CDR1 VL – CDR2 VL – CDR3 5 GYTFTNYSEQ ID NO:25 TYTGSEQ ID NO:26 GFGSSYWYFDSEQ ID NO:27 SQDVSIA SEQ ID NO:28 SASSEQ ID NO:29 HYITPLSEQ ID NO:30 6 GYTFTTASEQ ID NO:31 THSGSEQ ID NO:32 GFGSSYWYFDSEQ ID NO:33 SQDVSTASEQ ID NO:34 SASSEQ ID NO:35 HYITPLSEQ ID NO:36

[0242] Table 4 - CDRs of illustrative anti-Trop-2 binding antibodies (Honegger)

[0243] Antibody name VH – CDR1 VH – CDR2 VH – CDR3 VL – CDR1 VL – CDR2 VL – CDR3 7 ASGYTFTNYGSEQ ID NO:37 INTYTGEPTYTDDFKGRSEQ ID NO:38 GGFGSSYWYFDSEQ ID NO:39 ASQDVSIA SEQ ID NO:40 SASYRYTGVPDRSEQ ID NO:41 HYITPLSEQ ID NO:42 8 ASGYTFTTAG SEQ ID NO:43 INTHSGVPKYAEDFKGRSEQ ID NO:44 SGFGSSYWYFDSEQ ID NO:45 ASQDVSTASEQ ID NO:46 SASYRYTGVPSR SEQ ID NO:47 HYITPLSEQ ID NO:48

[0244] Table 5 - VH / VL of illustrative anti-Trop-2 binding antibodies

[0245] Antibody name VH VL 9 SEQ ID NO:49QVQLQQSGSELKKPGASVKVSCKASGYTFTNYGMNWVKQAPGQGLKWMGWINTYTGEPTYTDDFKGRFAFSLDTSVSTAYLQISSLKADDTAVYFCARGGFGSSYWYFDVWGQGSLVTVS SEQ ID NO:50DIQLTQSPSSSLSASVGDRVSITCKASQDVSIAVAWYQQKPGKAPKLLIYSASYRYTGVPDRFSGSGSGTTDFTLTISSLQPEDFAVYYCQQHYITPLTFGAGTKVEIK 10 SEQ ID NO:51QVQLVQSGAEVKKPGASVKVSCKASGYTFTTAGMQWVRQAPGQGLEWMGWINTHSGVPKYAEDFKGRVTISADTSTSTAYLQLSSLKSEDTAVYYCARSGFGSSYWYFDVWGQGTLVTVSS SEQ ID NO:52DIQMTQSPSSSLSASVGDRVTITCKASQDVSTAVAWYQQKPGKAPKLLIYSASYRYTGVPSRFSGSGSGTDFTLTISSLQPEDFAVYYCQQHYITPLTFGQGTKLEIK

[0246] In some embodiments of the methods provided herein, the anti-Trop-2 ADC comprises an anti-Trop-2 antibody, an anticancer agent payload, and optionally a linker connecting the antibody to the payload. In some embodiments, the linker is non-cleavable (e.g., a maleimidocaproyl or maleimidomethylcyclohexane-1-carboxylate linker). In some embodiments, the linker is cleavable. In some embodiments, the linker is acid-cleavable (e.g., a hydrazone linker). In some embodiments, the cleavable linker is reducible (e.g., a disulfide linker). In some embodiments, the linker is protease-cleavable (e.g., a dipeptide or tetrapeptide linker). In some embodiments, the linker is selected from the linkers disclosed in USPN 7,999,083 (e.g., CL2A, CL6, CL7, CLX, or CLY). In some embodiments, the linker is CL2A. Additional linker chemistries that can be used for anti-Trop-2 ADCs are described, for example, in the following patents: WO21225892 (Shanghai Escugen Biotechnology; ESG-401, STI-3258), WO22010797 (BiOneCure Therapeutics; BIO-106), CN112237634 (Shanghai Fudan-Zhangjiang Biopharmaceutical; FDA018-ADC), WO19114666 (Sichuan Kelun Pharmaceutical; KLA264), WO22078524 (Hangzhou DACBiotech; DAC-002), WO15098099 (Daiichi Sankyo; dexamethasone depot), WO21147993 (Jiangsu Hengrui Medicine; SHR-A1921), and WO21052402 (Sichuan Kelun Pharmaceutical; KLA264). Baili Pharmaceutical; BL-M02D1) dual antagonist.

[0247] Exemplary anticancer agent payloads that can be used in the anti-Trop-2 ADCs in the methods provided herein include, for example, microtubule inhibitors, DNA 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, an epothilone) or a maytansine alkaloid (e.g., maytansine (DM1) or raftansine (DM4)). In some embodiments, the DNA cleavage agent is a calicheamicin (e.g., ozogamicin). In some embodiments, the topoisomerase I inhibitor is a camptothecin (e.g., irinotecan, topotecan, belotecan, or an exatecan derivative, such as SN38 or Dxd). In some embodiments, the anticancer agent payload is SN38. In some embodiments, the anticancer agent payload is Dxd.

[0248] Additional illustrative anticancer agents that can be conjugated to an anti-Trop-2 ADC include, but are not limited to, anthracyclines (e.g., doxorubicin, daunorubicin, epirubicin, idarubicin), pyrrolobenzodiazepine (PBD) or dimers thereof, the DNA cross-linker SC-DR002 (D6.5), duocarmycin, duocarmycins (A, B1, B2, C1, C2, D, SA, CC-1065), tubulysin B and its analogs (e.g., Tub196), and other anticancer agents described herein.

[0249] Exemplary anti-Trop-2 ADCs that can be used in the methods provided herein are described in the following patents: WO21225892 (Shanghai Escugen Biotechnology; ESG-401, STI-3258), WO22010797 (BiOneCure Therapeutics; BIO-106), CN112237634 (Shanghai Fudan-Zhangjiang Biopharmaceutical; FDA018-ADC), WO19114666 (Sichuan Kelun Pharmaceutical; KLA264), WO22078524 (Hangzhou DAC Biotech; DAC-002), WO15098099 (Daiichi Sankyo; dexamethasone depot), WO21147993 (Jiangsu Hengrui Medicine; SHR-A1921), and WO21052402 (Sichuan Baili Pharmaceutical; daptomycin). Pharmaceutical; BL-M02D1).

[0250] In some embodiments of the methods provided herein, the anti-Trop-2 ADC is selected from gosartuzumab (Immunomedics / Gilead), dedabrafenib (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-Trop2sdAb (Kisoli Biotech), anti-Trop-2 ADC (Shandong Fontacea), LIV-2008 (LivTech / YakultHonsha), TROP2-TRACTr (BiTE;Janux), TROP-2-IR700 (Chiome, photosensitizer), TROP2-XPAT (Amunix), BAT-8003 (Bio-Thera Solutions), GQ-1003 (Genequantum Healthcare, Samsung BioLogics), DAC-002 (Hangzhou DAC Biotech, Shanghai Junshi Biosciences), E1-3s (Immunomedics / Gilead, IBC Pharmaceuticals, s BioTech), humanized anti-Trop2-SN38 antibody conjugate (Shanghai Escugen Biotechnology, TOT Biopharma), anti-Trop2 antibody-CLB-SN-38 conjugate (Shanghai Fudan-Zhangjiang Bio-Pharmaceutical), TROP2-Ab8 (Abmart), Trop2-IgG (Nanjing Medical University (NMU)), 90Y-DTPA-AF650 (Peking University First Hospital) and hRS7-CM (SynAffix), 89Zr-DFO-AF650 (University of Wisconsin-Madison). In some embodiments, the anti-Trop-2 ADC is goxatuzumab (Immunomedics / Gilead). In some embodiments, the anti-Trop-2 ADC is selected from goxatuzumab, dedabruzumab drutilecan (DS-1062), ESG-401, SKB-264, DAC-02, and BAT-8003. In some embodiments, the anti-Trop-2 ADC is goxatuzumab. In some embodiments, the anti-Trop-2 ADC is dedabruzumab drutilecan (DS-1062, Dato-Dxd; Daiichi Snakyo / AstraZeneca). Other examples of anti-TROP-2 therapeutic agents include, but are not limited to, those described in WO2016201300 (Gilead) and CN108440674 (Hangzhou Rongze Biotechnology Co., Ltd.);

[0251] Exemplary anti-Trop-2 ADCs that can be used in the methods provided herein are described, for example, in U.S. Patent Nos. 7,999,083 and 9,028,833, which are hereby incorporated by reference in their entireties. In some embodiments, the anti-Trop-2 ADC comprises a topoisomerase I inhibitor. In some embodiments, the topoisomerase I inhibitor is selected from irinotecan, topotecan, and SN-38. In some embodiments, the anti-Trop-2 ADC has the structural formula mAb-CL2A-SN-38, which is represented by the following formula:

[0252]

[0253] (described, e.g., in U.S. Patent No. 7,999,083). In some embodiments, the anti-Trop2 ADC has a drug-antibody ratio (DAR) of CL2A-SN38 to anti-Trop-2 antibody of ≥ 7.0 (e.g., DAR = 7.6). In some embodiments, the anti-Trop-2 ADC comprises sacilotuzumab (hRS7; described, e.g., in WO2003074566). Figure 3 and Figure 4 In some embodiments, the anti-Trop-2 ADC is gosatuzumab (IMMU-132). Gosatuzumab (SG) is an antibody-drug conjugate (ADC) composed of the following three components:

[0254] ●Humanized monoclonal antibody hRS7 IgG1κ, which binds to trophoblast cell surface antigen 2 (Trop-2; TACSTD2; EGP-1; NCBI Gene ID: 4070), a transmembrane calcium signal transducer overexpressed in many epithelial cancers, including triple-negative breast cancer (TNBC).

[0255] The camptothecin-derived agent SN-38 is a topoisomerase I inhibitor.

[0256] A hydrolyzable linker (CL2A) that connects the humanized monoclonal antibody to SN-38.

[0257] Additional exemplary anti-Trop-2 ADCs that can be used in the methods provided herein are described in WO21225892 (Shanghai Escugen Biotechnology). In some embodiments, the anti-Trop-2 ADC comprises a linker-payload conjugate having the structure:

[0258]

[0259] Attached to an anti-Trop-2 antibody (e.g., hRS7). In some embodiments, the anti-Trop-2 ADC has a DAR of 1 to 8. In some embodiments, the anti-Trop-2 ADC has a DAR > 7.0. In some embodiments, the anti-Trop-2 ADC is ESG-401 (STI-3258).

[0260] Additional exemplary anti-Trop-2 ADCs that can be used in the methods provided herein are described in US20210101906 (Sichuan Kelun Pharmaceutical). In some embodiments, the anti-Trop-2 ADC comprises a linker-payload conjugate (TL035) having the structure:

[0261]

[0262] Attached to an anti-Trop-2 antibody (e.g., hRS7). In some embodiments, the anti-Trop-2 ADC has a DAR of 1 to 8. 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.

[0263] 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 the structure:

[0264]

[0265] Attached to an anti-Trop-2 antibody (e.g., hTINA1-H1L1). In some embodiments, the anti-Trop-2 ADC has a DAR of about 4. In some embodiments, the anti-Trop-2 ADC is dexamethasone.

[0266] TopI ADC

[0267] In some embodiments, an ADC that can be used in the methods provided herein comprises a tumor antigen (TA)-targeting antibody, a topoisomerase I inhibitor payload, and optionally a linker connecting the TA-targeting antibody to the payload (TopIADC).

[0268] In some embodiments, a TopI ADC that can be used in the methods provided herein comprises an antibody that binds a tumor antigen selected from the group consisting of carbonic anhydrase IX, B7, CCCL19, CCCL21, CSAp, HER-2 / neu, BrE3, CD1, CD1a, CD2, CD3, CD4, CD5, CD8, CD11A, CD14, CD15, CD16, CD18, CD19, CD20, CD21, CD22, CD23, CD25, CD29, CD30, CD32b, CD33, CD37, CD38, CD40, CD40L, CD44, CD46, and CD47. 5. CD46, CD52, CD54, CD55, CD59, CD64, CD67, CD70, CD74, CD79a, CD80, CD83, CD95, CD126, CD133, CD138, CD147, CD154, CEACAM5, CEACAM-6, alpha-fetoprotein (AFP), VEGF, ED-B fibronectin, EGP-1, EGP-2, EGF receptor (ErbB1), ErbB2, ErbB3, factor H, FHL-1, Flt-3, folate receptor, Ga 733, GROB, HMGB-1, hypoxia-inducible factor (HIF), HM1.24, insulin-like growth factor (ILGF), IFN-a, IFN-b, IL-g, IL-2R, IL-4R, IL-6R, IL-13R, IL-15R, IL-17R, IL-18R, IL-2, IL-6, IL-8, IL-12, IL-15, IL-17, IL-18, IL-25, IP-10, IGF-1R, Ia, HM1.24, gangliosides, HCG, HLA-DR, HLA-G, CD66a-d, MAGE, mCRP, MCP-1, MIP-1A, MIP-1B, macrophage migration inhibitory factor ( MIF), MUC1, MUC2, MUC3, MUC4, MUC5, placental growth factor (P1GF), PSA (prostate-specific antigen), PSMA, PSMA dimer, PAM4 antigen, NCA-95, NCA-90, A3, A33, Ep-CAM, KS-1, Le(y), mesothelin, S100, tenascin, TAC, Tn antigen, Thomas-Friedenreich antigen, tumor necrosis antigen, tumor angiogenesis antigen, TNF-a, TRAIL receptors (R1 and R2), VEGFR, RANTES, T101, cancer stem cell antigens, complement factors C3, C3a, C3b, C5a, C5, and oncogene products.

[0269] In some embodiments, a TopI ADC useful in the methods provided herein comprises an antibody that binds a tumor antigen selected from the group consisting of: CEACAM5, CEACAM6, CD74, CD19, CD20, CD22, CSAp, HLA-DR, HLA-G, MUC5ac, and AFP.

[0270] In some embodiments, a TopI ADC that can be used to perform the methods provided herein comprises an antibody selected from the group consisting of gemtuzumab, brentuximab, berantuzumab, camizumab, trastuzumab, inotuzumab, gebatumumab, anetuzumab, milvitutuzumab, dexuzumab, vadatuximab, labetuzumab, laditutuzumab, lantuximab, paltratuzumab, rifatuzumab, indostatuzumab, polotuzumab, pinatuzumab, cotuximab, eupilitutuzumab, indalatuximab, milatuzumab, lovatuzumab, enroku, tesotuzumab, tesituximab, decitumomab, teritutuzumab, and antigen-binding fragments thereof.

[0271] In some embodiments, a TopI ADC that can be used in the methods provided herein comprises an antibody selected from the group consisting of: hLL1 (anti-CD74), hLL2 (anti-CD22), hRFB4 (anti-CD22), hPAM4 (anti-MUC5ac), hMN-3 (anti-NOTCH3), hMN-14 (labetuzumab; anti-CEACAM5); hMN15 (anti-CEACAM6), hA19 (anti-CD19), hA20 (anti-CD22), hMu-9 (anti-CSAp), hL243 (anti-HLA-DR), and hImmu-31 (anti-AFP) (e.g., each further described in US 7,999,083).

[0272] In some embodiments of the methods provided herein, the TopI ADC comprises a linker connecting the topoisomerase I inhibitor payload to the tumor antigen-targeting antibody. In some embodiments, the linker is non-cleavable (e.g., a maleimidocaproyl or maleimidomethylcyclohexane-1-carboxylate linker). In some embodiments, the linker is cleavable. In some embodiments, the linker is acid-cleavable (e.g., a hydrazone linker). In some embodiments, the cleavable linker is reducible (e.g., a disulfide linker). In some embodiments, the linker is protease-cleavable (e.g., a dipeptide or tetrapeptide linker). In some embodiments, the linker is selected from the linkers disclosed in USPN 7,999,083 (e.g., CL2A, CL6, CL7, CLX, or CLY). In some embodiments, the linker is CL2A. Additional linker chemistries that can be used for anti-TopI ADCs are described, for example, in the following patents: WO21225892 (Shanghai Escugen Biotechnology; ESG-401, STI-3258), WO22010797 (BiOneCure Therapeutics; BIO-106), CN112237634 (Shanghai Fudan-Zhangjiang Biopharmaceutical; FDA018-ADC), WO19114666 (Sichuan Kelun Pharmaceutical; KLA264), WO22078524 (Hangzhou DAC Biotech; DAC-002), WO15098099 (Daiichi Sankyo; dexamethasone depot), WO21147993 (Jiangsu Hengrui Medicine; SHR-A1921), and WO21052402 (Sichuan Baili Pharmaceutical; DAC-002). Pharmaceutical; BL-M02D1).

[0273] In some embodiments of the methods provided herein, the topoisomerase I inhibitor comprised by the TopI ADC is a camptothecin (e.g., irinotecan, topotecan, belotecan, or an exatecan derivative, 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.

[0274] In some embodiments, the TopI ADC has the structural formula mAb-CL2A-SN-38, which is represented by the following formula:

[0275]

[0276] (Described, for example, in U.S. Patent No. 7,999,083).

[0277] In some embodiments, a TopI ADC that can be used in the methods provided herein comprises an antibody that targets carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5; CD66e; NCBI Gene ID: 1048). In some embodiments, the CEACAM5 antibody is hMN-14 (e.g., as described in WO1996011013). In some embodiments, the anti-CEACAM5 ADC is as described in WO2010093395 (anti-CEACAM5-CL2A-SN38). In some embodiments, the TopI ADC is labetuzumab govetecan (IMMU-130).

[0278] In some embodiments, the TopI ADC that can be used in the methods provided herein comprises an antibody that targets the MHC class II cell surface receptor encoded by the human leukocyte antigen complex (HLA-DR). In some embodiments, the HLA-DR antibody is hL243 (e.g., as described in WO2006094192). In some embodiments, the HLA-DR-ADC is as described in WO2010093395 (anti-HLA-DR-CL2A-SN38). In some embodiments, the antibodies and / or fusion proteins provided herein are administered together with the HLA-DR-ADC IMMU-140.

[0279] Additional exemplary TopI ADCs that can be used in the methods provided herein are described in WO21225892 (Shanghai Escugen Biotechnology). In some embodiments, the TopI ADC comprises a linker-payload conjugate having the structure:

[0280]

[0281] Attached with tumor antigen targeting antibodies.

[0282] Additional exemplary TopI ADCs that can be used in the methods provided herein are described in US20210101906 (Sichuan Kelun Pharmaceutical). In some embodiments, the TopI ADC includes a linker-payload conjugate (TL035) having the structure:

[0283]

[0284] Attached with tumor antigen targeting antibodies.

[0285] Additional exemplary TopI ADCs that can be used in the methods provided herein are described in US2016297890 (Daiichi Sankyo). In some embodiments, the TopI ADC comprises a linker-payload conjugate having the structure:

[0286]

[0287] Attached to a tumor antigen targeting antibody (e.g., trastuzumab). In some embodiments, the TopI ADC has a DAR of about 4. In some embodiments, the TopI ADC is trastuzumab-deludec (T-DXd).

[0288] Anti-PD-(L)1 antibodies

[0289] In some embodiments, the methods disclosed herein comprise administering an anti-PD-(L)1 antibody. As used herein, the term "anti-PD-(L)1 antibody" refers collectively to: (a) an anti-PD-1 antibody or a fragment thereof; and (b) an anti-PD-L1 antibody or a fragment thereof.

[0290] Exemplary anti-PD-(L) 1 antibodies that can be used in any of the methods provided herein include, for example, pembrolizumab, nivolumab, cemiprilimab, pidilizumab, spartalizumab, atezolizumab, avelumab, durvalumab, cocilimab, sazanlimab, tislelizumab, rivalizumab, batilizumab, toripalimab, sitrilimab, genoluzumab, palolizumab, lodalizumab, camrelizumab, budigalimab, avelumab, dotalimumab, envolimab, sintilimab, and sepalizumab. In some embodiments, the anti-PD-(L) 1 antibody is sepalizumab. In some embodiments, the anti-PD-(L) 1 antibody is pembrolizumab. In some embodiments, the anti-PD-(L) 1 antibody is durvalumab. In some embodiments, the anti-PD-(L)1 antibody is atezolizumab.

[0291] In some embodiments, the anti-PD-(L)1 antibody is an Fc-silent antibody. In some embodiments, the anti-PD-(L)1 antibody comprises one or more mutations in the Fc region to reduce, prevent, or eliminate binding to an Fc receptor. In some embodiments, the anti-PD-(L)1 antibody comprises one or more mutations in the Fc region to reduce, prevent, or eliminate binding to an FcγR. In some embodiments, any of the antibodies disclosed herein comprises 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 comprises one or more mutations in the Fc region to reduce, prevent, or eliminate binding to FcγRIV. In some embodiments, the anti-PD-(L)1 antibody comprises one or more mutations in the Fc region to reduce, prevent, or eliminate ADCC, ADCP, and / or CDC. In some embodiments, the anti-PD-(L)1 antibody comprises one or more substitutions in the Fc region to reduce, prevent, or eliminate binding to an Fc receptor, wherein the one or more substitutions occur at EU index positions 228, 233, 234, 235, 235, 235, 236, 237, 265, 297, 322, 327, 328, 330, 331, and any combination of these positions. In some embodiments, the anti-PD-(L)1 antibody comprises one or more substitutions in the Fc region to reduce, prevent, or eliminate binding to an Fc receptor, wherein the one or more substitutions include S228P, E233P, L234A, L235A, L235E, L235F, G236R, G237A, D265A, N297A, K322A, A327G, L328R, A330S, P331S, and any combination of these substitutions. Additional mutations in the Fc region that reduce, prevent, or eliminate binding to Fc receptors, and alternative strategies for reducing, preventing, or eliminating binding to Fc receptors are described, for example, in Saunders, 2019; Tao, 1993; Canfield and Morrison, 1991; Armour, 1999; Shields, 2001; and U.S. Patent No. 6,624,821.

[0292] In some embodiments, the anti-PD-(L)1 antibody is an Fc-enabled antibody. In some embodiments, the anti-PD-(L)1 antibody comprises one or more mutations in the Fc region to enable binding to or enhance binding to an Fc receptor. In some embodiments, the anti-PD-(L)1 antibody comprises one or more mutations in the Fc region to enable binding to or enhance binding to an FcγR. In some embodiments, any antibody disclosed herein comprises one or more mutations in the Fc region to enable binding to or enhance binding to FcγRIIIA. In some embodiments, any antibody disclosed herein comprises one or more mutations in the Fc region to enable binding to or enhance binding to FcγRIV. In some embodiments, the anti-PD-(L)1 antibody comprises one or more mutations in the Fc region to enable or enhance ADCC, ADCP, and / or CDC. In some embodiments, the anti-PD-(L)1 antibody comprises one or more substitutions in the Fc region to enhance or enable binding to an Fc receptor, wherein the one or more substitutions occur at EU index positions 234, 235, 236, 239, 243, 247, 267, 268, 292, 298, 300, 305, 324, 326, 330, 332, 333, 334, 339, 345, 396, 430, and any combination of these positions. In some embodiments, the anti-PD-(L)1 antibody comprises one or more substitutions in the Fc region to enhance or enable binding to an Fc receptor, wherein the one or more substitutions include F234L, L235V, G236A, S239D, F243L, P247I, S267E, H268E, R292P, S298A, Y300L, V305I, S324T, K326W, A330L, I332E, E333A, E333S, K334A, A339Q, E345G, P396L, E430G, and any combination of these substitutions. In some embodiments, the Fc-enabled antibody comprises a modified IgG1 domain characterized by substitutions at S239D, A330L, and I332E (Eu numbering). Alternatively, the anti-PD-(L)1 antibody contains or has a glycoform perturbation. In some embodiments, the anti-PD-(L)1 antibody contains or has N-linked Fc glycosylation. In some embodiments, the anti-PD-(L)1 antibody contains or has sialylation, galactosylation, bisecting sugars, fucosylation, or any combination thereof. Additional mutations in the Fc region that enhance or enable binding to Fc receptors, as well as alternative strategies for enhancing or enabling binding to Fc receptors, are described in Saunders, 2019.

[0293] In some embodiments, the anti-PD-(L) 1 antibody is an anti-PD-1 antibody. Exemplary anti-PD-1 antibodies that can be used in any of the methods provided herein include, for example, batilizumab, budigalizumab, camrelizumab, cemiplizumab, cetrilimab, dotalimumab, genoluzumab, nivolumab, pembrolizumab, pidilizumab, palolizumab, rivalizumab, sazanlizumab, sintilimab, spartalizumab, tislelizumab, toripalizumab, and sepalizumab. In some embodiments, the anti-PD-1 antibody is sepalizumab. In some embodiments, the anti-PD-1 antibody is pembrolizumab. In some embodiments, the anti-PD-1 antibody is an Fc-silent antibody. In some embodiments, the anti-PD-1 antibody is an Fc-enabled antibody.

[0294] In some embodiments, the anti-PD-(L) 1 antibody is an anti-PD-L1 antibody. Exemplary anti-PD-L1 antibodies that can be used in any of the methods provided herein include, for example, atezolizumab, avelumab, coxilimab, durvalumab, envolimab, and lodalimab. In some embodiments, the anti-PD-L1 antibody is atezolizumab. In some embodiments, the anti-PD-L1 antibody is durvalumab. In some embodiments, the anti-PD-L1 antibody is an Fc-silent antibody. In some embodiments, the anti-PD-L1 antibody is an Fc-enabled antibody.

[0295] Anti-TIGIT antibodies

[0296] In some embodiments, the methods disclosed herein include administering an anti-TIGIT antibody. Exemplary anti-TIGIT antibodies that can be used in any of the methods provided herein include, for example, AB308, AGEN-1307 (AGEN-1327), AGEN-1777, AK127, BMS-986207, dunalimab, EOS-448, eitinib, JS006, M6223, osperlimab (BGB-A1217), rapasumab, SEA-TGT (SGN-TGT), tislelizumab, and vebolimumab. In some embodiments, the anti-TIGIT antibody is dunalimab. In some embodiments, the anti-TIGIT antibody is AB308. In some embodiments, the anti-TIGIT antibody is rapasumab. In some embodiments, the anti-TIGIT antibody is tislelizumab. In some embodiments, the anti-TIGIT antibody is vebolimumab. In some embodiments, the anti-TIGIT antibody is M6223.

[0297] In some embodiments, the anti-TIGIT antibody is an Fc silent antibody. In some embodiments, the anti-TIGIT antibody comprises one or more mutations in the Fc region to reduce, prevent or eliminate binding to Fc receptors. In some embodiments, the anti-TIGIT antibody comprises one or more mutations in the Fc region to reduce, prevent or eliminate binding to FcγR. In some embodiments, any antibody disclosed herein comprises one or more mutations in the Fc region to reduce, prevent or eliminate binding to FcγRIIIA. In some embodiments, any antibody disclosed herein comprises one or more mutations in the Fc region to reduce, prevent or eliminate binding to FcγRIV. In some embodiments, the anti-TIGIT antibody comprises one or more mutations in the Fc region to reduce, prevent or eliminate ADCC, ADCP and / or CDC. In some embodiments, the anti-TIGIT antibody comprises one or more substitutions in the Fc region to reduce, prevent or eliminate binding to an Fc receptor, wherein the one or more substitutions occur at EU index positions 228, 233, 234, 235, 235, 235, 236, 237, 265, 297, 322, 327, 328, 330, 331, and any combination of these positions. In some embodiments, the anti-TIGIT antibody comprises one or more substitutions in the Fc region to reduce, prevent or eliminate binding to an Fc receptor, wherein the one or more substitutions include S228P, E233P, L234A, L235A, L235E, L235F, G236R, G237A, D265A, N297A, K322A, A327G, L328R, A330S, P331S, and any combination of these substitutions. Additional mutations in the Fc region that reduce, prevent, or eliminate binding to Fc receptors, as well as alternative strategies for reducing, preventing, or eliminating binding to Fc receptors, are described, for example, in Saunders, 2019; Tao, 1993; Canfield and Morrison, 1991; Armour, 1999; Shields, 2001; and U.S. Patent No. 6,624,821. In some embodiments, the Fc-silent anti-TIGIT antibody is dunalimab. In some embodiments, the Fc-silent anti-TIGIT antibody is BGB-A1217MF. In some embodiments, the Fc-silent anti-TIGIT antibody is BMS-986207. In some embodiments, the anti-TIGIT antibody is an Fc-enabled antibody. In some embodiments, the anti-TIGIT antibody comprises one or more mutations in the Fc region to enable or enhance binding to an Fc receptor. In some embodiments, the anti-TIGIT antibody comprises one or more mutations in the Fc region to enable or enhance binding to FcγRs.In some embodiments, any of the antibodies disclosed herein comprise one or more mutations in the Fc region to enable or enhance binding to FcγRIIIA. In some embodiments, any of the antibodies disclosed herein comprise one or more mutations in the Fc region to enable or enhance binding to FcγRIV. In some embodiments, the anti-TIGIT antibodies comprise one or more mutations in the Fc region to enable or enhance ADCC, ADCP, and / or CDC. In some embodiments, the anti-PD-(L)1 antibody comprises one or more substitutions in the Fc region to enhance or enable binding to an Fc receptor, wherein the one or more substitutions occur at EU index positions 234, 235, 236, 239, 243, 247, 267, 268, 292, 298, 300, 305, 324, 326, 330, 332, 333, 334, 339, 345, 396, 430, and any combination of these positions. In some embodiments, the anti-TIGIT antibody comprises one or more substitutions in the Fc region to enhance binding to or enable binding to an Fc receptor, wherein the one or more substitutions include F234L, L235V, G236A, S239D, F243L, P247I, S267E, H268E, R292P, S298A, Y300L, V305I, S324T, K326W, A330L, I332E, E333A, E333S, K334A, A339Q, E345G, P396L, E430G, and any combination of these substitutions. In some embodiments, the Fc-enabled antibody comprises a modified IgG1 domain characterized by substitutions at S239D, A330L, and I332E (Eu numbering). Alternatively, the anti-TIGIT antibody contains or has a glycoform perturbation. In some embodiments, the anti-TIGIT antibody contains or has N-linked Fc glycosylation. In some embodiments, the anti-TIGIT antibody contains or has sialylation, galactosylation, bisected sugars, fucosylation, or any combination thereof. Additional mutations in the Fc region that enhance or enable binding to Fc receptors, as well as alternative strategies for enhancing or enabling binding to Fc receptors, are described in Saunders, 2019. In some embodiments, the Fc-enabled anti-TIGIT antibody is AB308. In some embodiments, the Fc-enabled anti-TIGIT antibody is osperlimab. In some embodiments, the Fc-enabled anti-TIGIT antibody is rapasutumomab. In some embodiments, the Fc-enabled anti-TIGIT antibody is tisleliumab. In some embodiments, the Fc-enabled anti-TIGIT antibody is vebolizumab.In some embodiments, the Fc-enabled anti-TIGIT antibody is EOS- 448. In some embodiments, the Fc-enabled anti-TIGIT antibody is SEA-TGT.

[0298] Reagent test kit

[0299] Also disclosed herein are kits comprising any of the antibody drug conjugates (ADCs) disclosed herein (eg, anti-TROP-2 ADC or TOP-1 ADC), anti-PD-(L)1 antibodies, and / or anti-TIGIT antibodies.

[0300] Provided herein are kits for use as medicaments, wherein the kit comprises: a) a TROP-2 targeting antibody-drug conjugate (ADC) comprising an anti-TROP-2 antibody (anti-TROP-2 ADC); and b) an anti-PD-(L)1 antibody. In some embodiments, the kit comprises any anti-TROP-2 ADC disclosed herein. In some embodiments, the kit comprises any anti-PD-(L)1 antibody disclosed herein. In some embodiments, the kit further comprises any anti-TIGIT antibody disclosed herein.

[0301] Provided herein are kits for treating, alleviating, reducing, preventing, or delaying recurrence or metastasis of a TROP-2-positive cancer, wherein the kit comprises: a) a TROP-2-targeting antibody-drug conjugate (ADC) comprising an anti-TROP-2 antibody (anti-TROP-2 ADC); and b) an anti-PD-(L)1 antibody. In some embodiments, the kit comprises any anti-TROP-2 ADC disclosed herein. In some embodiments, the kit comprises any anti-PD-(L)1 antibody disclosed herein. In some embodiments, the kit further comprises any anti-TIGIT antibody disclosed herein.

[0302] Provided herein are kits for use as medicaments, wherein the kit comprises: a) a tumor antigen-targeting antibody-drug conjugate (ADC) comprising a topoisomerase I inhibitor (TopI ADC); and b) an anti-PD-(L)1 antibody. In some embodiments, the kit comprises any TopI ADC disclosed herein. In some embodiments, the kit comprises any anti-PD-(L)1 antibody disclosed herein. In some embodiments, the kit further comprises any anti-TIGIT antibody disclosed herein.

[0303] Provided herein are methods for treating, alleviating, reducing, preventing or delaying tumor antigen positive (TA +A kit for treating recurrence or metastasis of a 200-year-old cancer, wherein the kit comprises: a) a tumor antigen-targeting antibody-drug conjugate (ADC) comprising a topoisomerase I inhibitor (TopI ADC); and b) an anti-PD-(L)1 antibody. In some embodiments, the kit comprises any TopI ADC disclosed herein. In some embodiments, the kit comprises any anti-PD-(L)1 antibody disclosed herein. In some embodiments, the kit further comprises any anti-TIGIT antibody disclosed herein.

[0304] Also provided herein are kits for use as medicaments, wherein the kit comprises: a) gosartuzumab; and b) sepalizumab. In some embodiments, the kit further comprises any anti-TIGIT antibody disclosed herein.

[0305] Also provided herein are kits for treating, alleviating, reducing, preventing, or delaying recurrence or metastasis of urothelial carcinoma, wherein the kit comprises: a) gosartuzumab; and b) sepalizumab. In some embodiments, the kit further comprises any anti-TIGIT antibody disclosed herein.

[0306] Also provided herein is a kit for use as a medicament, wherein the kit comprises: a) gosartuzumab; b) sepalizumab; and c) dunarizumab.

[0307] Also provided herein are kits for treating, alleviating, reducing, preventing, or delaying recurrence or metastasis of urothelial carcinoma, wherein the kit comprises: a) gosartumomab; b) sepalizumab; and c) dunarizumab.

[0308] Exemplary embodiments

[0309] In some embodiments, provided herein are methods for treating, alleviating, reducing, preventing, or delaying recurrence or metastasis of a TROP-2-positive cancer, comprising co-administering to a subject an effective amount of: a) a TROP-2-targeting antibody-drug conjugate (ADC) comprising an anti-TROP-2 antibody (anti-TROP-2 ADC); b) an anti-PD-(L)1 antibody; and optionally, c) an anti-TIGIT antibody. In some embodiments, the anti-TROP-2 ADC comprises an anticancer agent payload. In some embodiments, the anticancer agent payload is selected from a microtubule inhibitor, a DNA cleavage agent, and a topoisomerase I inhibitor. In some embodiments, the anti-TROP-2 ADC comprises a topoisomerase I inhibitor. In some embodiments, the topoisomerase I inhibitor is selected from irinotecan, topotecan, and SN-38. In some embodiments, the anti-TROP-2 ADC has the structural formula mAb-CL2A-SN-38, which is represented by the following formula:

[0310]

[0311] (described, e.g., in U.S. Patent No. 7,999,083). In some embodiments, the anti-TROP-2 ADC comprises sacilotuzumab (hRS7; described, e.g., in WO2003074566). Figure 3 and Figure 4In some embodiments, the anti-TROP-2 ADC is selected from gosatuzumab, dedabrafenib (DS-1062), ESG-401, SKB-264, DAC-02, and BAT-8003. In some embodiments, the anti-TROP-2 ADC is gosatuzumab. In some embodiments, the anti-TROP-2 ADC comprises a microtubule inhibitor. In some embodiments, the microtubule inhibitor is selected from auristatins, taxanes, vinca alkaloids, epothilones, and maytansines. In some embodiments, the auristatin is selected from monomethyl auristatin E (MMAE) and monomethyl auristatin F (MMAF). In some embodiments, the maytansine alkaloid is selected from maytansine (DM1) and raftansine (DM4). In some embodiments, the anticancer agent payload is selected from anthracyclines (e.g., doxorubicin, daunorubicin, epirubicin, idarubicin), pyrrolobenzodiazepine (PBD) or dimers thereof, DNA cross-linker SC-DR002 (D6.5), duocarmycin, duocarmycins (A, B1, B2, C1, C2, D, SA, CC-1065), tubulysin B, and analogs thereof. In some embodiments, the anti-PD-(L)1 antibody is pembrolizumab, nivolumab, cemiprilimab, pidilizumab, spartalizumab, atezolizumab, avelumab, durvalumab, cocilimab, sazanlimab, tislelizumab, rivalizumab, batilizumab, toripalimab, sitrilimab, genoluzumab, palolizumab, lodalizumab, camrelizumab, budigalimab, avelumab, dotalimumab, envolimab, sintilimab, or sepalizumab. In some embodiments, the anti-PD-(L)1 antibody is sepalizumab. In some embodiments, the anti-PD-(L)1 antibody is durvalumab. In some embodiments, the anti-PD-(L)1 antibody is an Fc-silent antibody. In some embodiments, the anti-PD-(L)1 antibody is an Fc-enabled antibody. In some embodiments, any of the methods disclosed herein further comprise administering an anti-TIGIT antibody. In some embodiments, the anti-TIGIT antibody is AB308, AGEN-1307 (AGEN-1327), AGEN-1777, AK127, BMS-986207, dunalimab, EOS-448, eitinib, JS006, M6223, osperlimab, rapasumab, SEA-TGT (SGN-TGT), tisleliumab, or vembralizumab. In some embodiments, the anti-TIGIT antibody is dunalimab. In some embodiments, the anti-TIGIT antibody is M6223.In some embodiments, the anti-PD-(L)1 antibody and the anti-TIGIT antibody are a) sepalizumab and dunalizumab, b) sepalizumab and AB308, c) atezolizumab and tislelizumab, d) pembrolizumab and vembrolizumab, e) pembrolizumab and dunalizumab, f) pembrolizumab and AB308, g) MK-7684A (pembrolizumab / vembrolizumab co-formulation), h) durvalumab and dunalizumab, i) sepalizumab and rapasumab, or j) pembrolizumab and rapasumab. In some embodiments, the anti-PD-(L)1 antibody and the anti-TIGIT antibody are sepalizumab and dunalizumab. In some embodiments, the anti-PD-(L)1 antibody and the anti-TIGIT antibody are sepalizumab and dunalizumab. In some embodiments, the anti-PD-(L)1 antibody and the anti-TIGIT antibody are sepalizumab and rapasumab. In some embodiments, the anti-PD-(L)1 antibody and the anti-TIGIT antibody are durvalumab and dunalimab. In some embodiments, the method further comprises co-administering an additional therapeutic agent or treatment modality. In some embodiments, the additional therapeutic agent or treatment modality comprises one, two, three, or four additional therapeutic agents and / or treatment modalities. In some embodiments, the cancer is a solid epithelial cancer. In some embodiments, the solid epithelial cancer is selected from breast cancer (e.g., triple-negative breast cancer (TNBC), HR. + / Her2 - Breast cancer or HR + / Her2 低In some embodiments, the bladder cancer is urothelial carcinoma (UC). In some embodiments, the bladder cancer is (i) unresectable locally advanced bladder cancer, (ii) metastatic bladder cancer, or (iii) muscle-invasive bladder cancer. In some embodiments, the urothelial carcinoma is (i) unresectable locally advanced bladder cancer, (ii) metastatic bladder cancer, or (iii) muscle-invasive bladder cancer. In some embodiments, the lung cancer is non-small cell lung cancer (NSCLC). In some embodiments, the lung cancer is (i) advanced lung cancer or (ii) metastatic lung cancer. In some embodiments, the lung cancer is (i) advanced NSCLC or (ii) metastatic NSCLC. In some embodiments, the NSCLC is squamous NSCLC. In some embodiments, the NSCLC is non-squamous NSCLC. In some embodiments, the metastatic NSCLC is metastatic squamous NSCLC. In some embodiments, the metastatic NSCLC is metastatic non-squamous NSCLC. In some embodiments, the NSCLC is NSCLC without EGFR, ALK, or other actionable genomic alterations. In some embodiments, the cancer is (i) unresectable locally advanced cancer, (ii) metastatic cancer, or (iii) muscle-invasive cancer. In some embodiments, the cancer is (i) advanced cancer, or (ii) metastatic cancer. In some embodiments, the cancer has progressed after at least one prior anticancer therapy. In some embodiments, the subject is treatment-naive. In some embodiments, the subject has not received treatment in the metastatic or unresectable locally advanced setting (e.g., the subject has not received treatment for mUC and unresectable locally advanced UC). In some embodiments, the subject has not received treatment in the metastatic or unresectable locally advanced setting (e.g., the subject has not received treatment for metastatic and advanced lung cancer and NSCLC). In some embodiments, in a metastatic or unresectable locally advanced setting, the human patient does not meet the cisplatin criteria and has not received prior treatment. In some embodiments, the untreated subject has not received prior anticancer therapy for (i) unresectable locally advanced cancer, (ii) metastatic cancer, or (iii) muscle-invasive cancer. In some embodiments, the subject has received one or more anticancer therapies prior to administering the combination of ADC, anti-PD-(L)1 antibody, and optionally an anti-TIGIT antibody. In some embodiments, the subject is not untreated. In some embodiments, the subject has received one or more prior anticancer therapies for (i) unresectable locally advanced cancer, (ii) metastatic cancer, or (iii) muscle-invasive cancer.In some embodiments, the subject has received one or more anti-cancer therapies prior to administration of the combination of an ADC, an anti-PD-(L)1 antibody, and optionally an anti-TIGIT antibody. In some embodiments, the cancer is resistant to or refractory to one or more anti-cancer therapies. In some embodiments, the anti-cancer therapy is selected from surgery, radiation therapy, chemotherapy, and checkpoint inhibitor therapy. In some embodiments, the combination of an ADC, an anti-PD-(L)1 antibody, and optionally an anti-TIGIT antibody is administered in a neoadjuvant setting (e.g., in preparation for surgery or radiation therapy). In some embodiments, the combination of an ADC, an anti-PD-(L)1 antibody, and optionally an anti-TIGIT antibody is administered in an adjuvant setting (e.g., after primary therapy such as surgery or radiation therapy). In some embodiments, the combination of an ADC, an anti-PD-(L)1 antibody, and optionally an anti-TIGIT antibody is administered in a therapeutic setting (e.g., as a primary therapy). In some embodiments, the combination of an ADC, an anti-PD-(L)1 antibody, and optionally an anti-TIGIT antibody is administered in a maintenance setting. In some embodiments, the subject receives one or more doses of the ADC. In some embodiments, the subject receives one or more doses of an anti-PD-(L)1 antibody. In some embodiments, the subject receives one or more doses of an anti-TIGIT antibody. In some embodiments, the ADC and the anti-PD-(L)1 antibody are administered simultaneously. In some embodiments, the ADC and the anti-PD-(L)1 antibody are administered sequentially. In some embodiments, the ADC and the anti-TIGIT antibody are administered simultaneously. In some embodiments, the ADC and the anti-TIGIT antibody are administered sequentially. In some embodiments, the anti-PD-(L)1 antibody and the anti-TIGIT antibody are administered simultaneously. In some embodiments, the anti-PD-(L)1 antibody and the anti-TIGIT antibody are administered sequentially. In some embodiments, the subject is human. In some embodiments, the subject does not meet the criteria for cisplatin. In some embodiments, the ADC is administered in one or more doses ranging from 8 mg / kg to 10 mg / kg. In some embodiments, the ADC is administered in one or more doses of 8 mg / kg or 10 mg / kg. In some embodiments, the ADC is administered in one or more doses of 10 mg / kg. In some embodiments, the ADC is administered intravenously. In some embodiments, the ADC is administered on days 1 and 8 of a 21-day cycle. In some embodiments, the anti-PD-(L) 1 antibody is administered in one or more doses ranging from 300 mg to 400 mg. In some embodiments, the anti-PD-(L) 1 antibody is administered in a dose of 360 mg. In some embodiments, the anti-PD-(L) 1 antibody is administered intravenously. In some embodiments, the anti-PD-(L) 1 antibody is administered on day 1 of a 21-day cycle.In some embodiments, the anti-TIGIT antibody is administered in one or more doses ranging from 800 mg to 1600 mg. In some embodiments, the anti-TIGIT antibody is administered in a dose of 1200 mg. In some embodiments, the anti-TIGIT antibody is administered intravenously. In some embodiments, the anti-TIGIT antibody is administered on day 1 of a 21-day cycle. In some embodiments of the methods provided herein, an anti-CD47 antibody is not co-administered to the subject or human patient. In some embodiments, the anti-CD47 antibody is selected from mololimab, leszolimab, leterlimab, lefalimab, 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 anti-CD47 antibody is magrolimab. In some embodiments of the methods provided herein, MCL1 inhibitors are not co-administered to subjects or human patients. In some embodiments, MCL1 inhibitors are selected from GS-9716, AMG-176, AMG-397, S-64315, AZD-5991, 483-LM, A-1210477, UMI-77, and JKY-5-037. In some embodiments, MCL1 inhibitors are GS-9716. In some embodiments of the methods provided herein, FLT3 agonists are not administered to subjects or human patients. In some embodiments, FLT3 agonists are selected from GS-3583, CDX-301, TAK-605, ONCR-177, Alb-Ftl3L, and SYM-027. In some embodiments, FLT3 agonists are GS-3583.

[0312] In some embodiments, the methods provided herein are used to treat TROP-2-positive cancers, comprising co-administering to a subject an effective amount of: a) a TROP-2-targeting antibody-drug conjugate (ADC) comprising an anti-TROP-2 antibody (anti-TROP-2 ADC); b) an anti-PD-(L)1 antibody; and optionally, c) an anti-TIGIT antibody. In some embodiments, the anti-TROP-2 ADC comprises an anticancer agent payload. In some embodiments, the anticancer agent payload is selected from a microtubule inhibitor, a DNA cleavage agent, and a topoisomerase I inhibitor. In some embodiments, the anti-TROP-2 ADC comprises a topoisomerase I inhibitor. In some embodiments, the topoisomerase I inhibitor is selected from irinotecan, topotecan, and SN-38. In some embodiments, the anti-TROP-2 ADC has the structural formula mAb-CL2A-SN-38, which is represented by the following formula:

[0313]

[0314] (described, e.g., in U.S. Patent No. 7,999,083). In some embodiments, the anti-TROP-2 ADC comprises sacilotuzumab (hRS7; described, e.g., in WO2003074566). Figure 3 and Figure 4In some embodiments, the anti-TROP-2 ADC is selected from gosatuzumab, dedabrafenib (DS-1062), ESG-401, SKB-264, DAC-02, and BAT-8003. In some embodiments, the anti-TROP-2 ADC is gosatuzumab. In some embodiments, the anti-TROP-2 ADC comprises a microtubule inhibitor. In some embodiments, the microtubule inhibitor is selected from auristatins, taxanes, vinca alkaloids, epothilones, and maytansines. In some embodiments, the auristatin is selected from monomethyl auristatin E (MMAE) and monomethyl auristatin F (MMAF). In some embodiments, the maytansine alkaloid is selected from maytansine (DM1) and raftansine (DM4). In some embodiments, the anticancer agent payload is selected from anthracyclines (e.g., doxorubicin, daunorubicin, epirubicin, idarubicin), pyrrolobenzodiazepine (PBD) or dimers thereof, DNA cross-linker SC-DR002 (D6.5), duocarmycin, duocarmycins (A, B1, B2, C1, C2, D, SA, CC-1065), tubulysin B, and analogs thereof. In some embodiments, the anti-PD-(L)1 antibody is pembrolizumab, nivolumab, cemiprilimab, pidilizumab, spartalizumab, atezolizumab, avelumab, durvalumab, cocilimab, sazanlimab, tislelizumab, rivalizumab, batilizumab, toripalimab, sitrilimab, genoluzumab, palolizumab, lodalizumab, camrelizumab, budigalimab, avelumab, dotalimumab, envolimab, sintilimab, or sepalizumab. In some embodiments, the anti-PD-(L)1 antibody is sepalizumab. In some embodiments, the anti-PD-(L)1 antibody is durvalumab. In some embodiments, the anti-PD-(L)1 antibody is an Fc-silent antibody. In some embodiments, the anti-PD-(L)1 antibody is an Fc-enabled antibody. In some embodiments, any of the methods disclosed herein further comprise administering an anti-TIGIT antibody. In some embodiments, the anti-TIGIT antibody is AB308, AGEN-1307 (AGEN-1327), AGEN-1777, AK127, BMS-986207, dunalimab, EOS-448, eitinib, JS006, M6223, osperlimab, rapasumab, SEA-TGT (SGN-TGT), tisleliumab, or vembralizumab. In some embodiments, the anti-TIGIT antibody is dunalimab. In some embodiments, the anti-TIGIT antibody is M6223.In some embodiments, the anti-PD-(L)1 antibody and the anti-TIGIT antibody are a) sepalizumab and dunalizumab, b) sepalizumab and AB308, c) atezolizumab and tislelizumab, d) pembrolizumab and vembrolizumab, e) pembrolizumab and dunalizumab, f) pembrolizumab and AB308, g) MK-7684A (pembrolizumab / vembrolizumab co-formulation), h) durvalumab and dunalizumab, i) sepalizumab and rapasumab, or j) pembrolizumab and rapasumab. In some embodiments, the anti-PD-(L)1 antibody and the anti-TIGIT antibody are sepalizumab and dunalizumab. In some embodiments, the anti-PD-(L)1 antibody and the anti-TIGIT antibody are sepalizumab and dunalizumab. In some embodiments, the anti-PD-(L)1 antibody and the anti-TIGIT antibody are sepalizumab and rapasumab. In some embodiments, the anti-PD-(L)1 antibody and the anti-TIGIT antibody are durvalumab and dunalimab. In some embodiments, the method further comprises co-administering an additional therapeutic agent or treatment modality. In some embodiments, the additional therapeutic agent or treatment modality comprises one, two, three, or four additional therapeutic agents and / or treatment modalities. In some embodiments, the cancer is a solid epithelial cancer. In some embodiments, the solid epithelial cancer is selected from breast cancer (e.g., triple-negative breast cancer (TNBC), HR. + / Her2 - Breast cancer or HR + / Her2 低In some embodiments, the bladder cancer is urothelial carcinoma (UC). In some embodiments, the bladder cancer is (i) unresectable locally advanced bladder cancer, (ii) metastatic bladder cancer, or (iii) muscle-invasive bladder cancer. In some embodiments, the urothelial carcinoma is (i) unresectable locally advanced bladder cancer, (ii) metastatic bladder cancer, or (iii) muscle-invasive bladder cancer. In some embodiments, the lung cancer is non-small cell lung cancer (NSCLC). In some embodiments, the lung cancer is (i) advanced lung cancer or (ii) metastatic lung cancer. In some embodiments, the lung cancer is (i) advanced NSCLC or (ii) metastatic NSCLC. In some embodiments, the NSCLC is squamous NSCLC. In some embodiments, the NSCLC is non-squamous NSCLC. In some embodiments, the metastatic NSCLC is metastatic squamous NSCLC. In some embodiments, the metastatic NSCLC is metastatic non-squamous NSCLC. In some embodiments, the NSCLC is NSCLC without EGFR, ALK, or other actionable genomic alterations. In some embodiments, the cancer is (i) unresectable locally advanced cancer, (ii) metastatic cancer, or (iii) muscle-invasive cancer. In some embodiments, the cancer is (i) advanced cancer, or (ii) metastatic cancer. In some embodiments, the cancer has progressed after at least one prior anticancer therapy. In some embodiments, the subject is treatment-naive. In some embodiments, the subject has not received treatment in the metastatic or unresectable locally advanced setting (e.g., the subject has not received treatment for mUC and unresectable locally advanced UC). In some embodiments, the subject has not received treatment in the metastatic or unresectable locally advanced setting (e.g., the subject has not received treatment for metastatic and advanced lung cancer and NSCLC). In some embodiments, in a metastatic or unresectable locally advanced setting, the human patient does not meet the cisplatin criteria and has not received prior treatment. In some embodiments, the untreated subject has not received prior anticancer therapy for (i) unresectable locally advanced cancer, (ii) metastatic cancer, or (iii) muscle-invasive cancer. In some embodiments, the subject has received one or more anticancer therapies prior to administering the combination of ADC, anti-PD-(L)1 antibody, and optionally an anti-TIGIT antibody. In some embodiments, the subject is not untreated. In some embodiments, the subject has received one or more prior anticancer therapies for (i) unresectable locally advanced cancer, (ii) metastatic cancer, or (iii) muscle-invasive cancer.In some embodiments, the subject has received one or more anti-cancer therapies prior to administration of the combination of an ADC, an anti-PD-(L)1 antibody, and optionally an anti-TIGIT antibody. In some embodiments, the cancer is resistant to or refractory to one or more anti-cancer therapies. In some embodiments, the anti-cancer therapy is selected from surgery, radiation therapy, chemotherapy, and checkpoint inhibitor therapy. In some embodiments, the combination of an ADC, an anti-PD-(L)1 antibody, and optionally an anti-TIGIT antibody is administered in a neoadjuvant setting (e.g., in preparation for surgery or radiation therapy). In some embodiments, the combination of an ADC, an anti-PD-(L)1 antibody, and optionally an anti-TIGIT antibody is administered in an adjuvant setting (e.g., after primary therapy such as surgery or radiation therapy). In some embodiments, the combination of an ADC, an anti-PD-(L)1 antibody, and optionally an anti-TIGIT antibody is administered in a therapeutic setting (e.g., as a primary therapy). In some embodiments, the combination of an ADC, an anti-PD-(L)1 antibody, and optionally an anti-TIGIT antibody is administered in a maintenance setting. In some embodiments, the subject receives one or more doses of the ADC. In some embodiments, the subject receives one or more doses of an anti-PD-(L)1 antibody. In some embodiments, the subject receives one or more doses of an anti-TIGIT antibody. In some embodiments, the ADC and the anti-PD-(L)1 antibody are administered simultaneously. In some embodiments, the ADC and the anti-PD-(L)1 antibody are administered sequentially. In some embodiments, the ADC and the anti-TIGIT antibody are administered simultaneously. In some embodiments, the ADC and the anti-TIGIT antibody are administered sequentially. In some embodiments, the anti-PD-(L)1 antibody and the anti-TIGIT antibody are administered simultaneously. In some embodiments, the anti-PD-(L)1 antibody and the anti-TIGIT antibody are administered sequentially. In some embodiments, the subject is human. In some embodiments, the subject does not meet the criteria for cisplatin. In some embodiments, the ADC is administered in one or more doses ranging from 8 mg / kg to 10 mg / kg. In some embodiments, the ADC is administered in one or more doses of 8 mg / kg or 10 mg / kg. In some embodiments, the ADC is administered in one or more doses of 10 mg / kg. In some embodiments, the ADC is administered intravenously. In some embodiments, the ADC is administered on days 1 and 8 of a 21-day cycle. In some embodiments, the anti-PD-(L) 1 antibody is administered in one or more doses ranging from 300 mg to 400 mg. In some embodiments, the anti-PD-(L) 1 antibody is administered in a dose of 360 mg. In some embodiments, the anti-PD-(L) 1 antibody is administered intravenously. In some embodiments, the anti-PD-(L) 1 antibody is administered on day 1 of a 21-day cycle.In some embodiments, the anti-TIGIT antibody is administered in one or more doses ranging from 800 mg to 1600 mg. In some embodiments, the anti-TIGIT antibody is administered in a dose of 1200 mg. In some embodiments, the anti-TIGIT antibody is administered intravenously. In some embodiments, the anti-TIGIT antibody is administered on day 1 of a 21-day cycle. In some embodiments of the methods provided herein, an anti-CD47 antibody is not co-administered to the subject or human patient. In some embodiments, the anti-CD47 antibody is selected from mololimab, leszolimab, leterlimab, lefalimab, 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 anti-CD47 antibody is magrolimab. In some embodiments of the methods provided herein, MCL1 inhibitors are not co-administered to subjects or human patients. In some embodiments, MCL1 inhibitors are selected from GS-9716, AMG-176, AMG-397, S-64315, AZD-5991, 483-LM, A-1210477, UMI-77, and JKY-5-037. In some embodiments, MCL1 inhibitors are GS-9716. In some embodiments of the methods provided herein, FLT3 agonists are not administered to subjects or human patients. In some embodiments, FLT3 agonists are selected from GS-3583, CDX-301, TAK-605, ONCR-177, Alb-Ftl3L, and SYM-027. In some embodiments, FLT3 agonists are GS-3583.

[0315] In some embodiments, provided herein are methods for treating, alleviating, reducing, preventing, or delaying recurrence or metastasis of urothelial carcinoma (UC), comprising co-administering to a subject an effective amount of: a) a TROP-2-targeting antibody-drug conjugate (ADC) comprising an anti-TROP-2 antibody (anti-TROP-2 ADC); b) an anti-PD-(L)1 antibody; and optionally, c) an anti-TIGIT antibody. In some embodiments, the anti-TROP-2 ADC comprises an anticancer agent payload. In some embodiments, the anticancer agent payload is selected from a microtubule inhibitor, a DNA cleavage agent, and a topoisomerase I inhibitor. In some embodiments, the anti-TROP-2 ADC comprises a topoisomerase I inhibitor. In some embodiments, the topoisomerase I inhibitor is selected from irinotecan, topotecan, and SN-38. In some embodiments, the anti-TROP-2 ADC has the structural formula mAb-CL2A-SN-38, which is represented by the following formula:

[0316]

[0317] (described, e.g., in U.S. Patent No. 7,999,083). In some embodiments, the anti-TROP-2 ADC comprises sacilotuzumab (hRS7; described, e.g., in WO2003074566). Figure 3 and Figure 4In some embodiments, the anti-TROP-2 ADC is selected from gosatuzumab, dedabrafenib (DS-1062), ESG-401, SKB-264, DAC-02, and BAT-8003. In some embodiments, the anti-TROP-2 ADC is gosatuzumab. In some embodiments, the anti-TROP-2 ADC comprises a microtubule inhibitor. In some embodiments, the microtubule inhibitor is selected from auristatins, taxanes, vinca alkaloids, epothilones, and maytansines. In some embodiments, the auristatin is selected from monomethyl auristatin E (MMAE) and monomethyl auristatin F (MMAF). In some embodiments, the maytansine alkaloid is selected from maytansine (DM1) and raftansine (DM4). In some embodiments, the anticancer agent payload is selected from anthracyclines (e.g., doxorubicin, daunorubicin, epirubicin, idarubicin), pyrrolobenzodiazepine (PBD) or dimers thereof, DNA cross-linker SC-DR002 (D6.5), duocarmycin, duocarmycins (A, B1, B2, C1, C2, D, SA, CC-1065), tubulysin B, and analogs thereof. In some embodiments, the anti-PD-(L)1 antibody is pembrolizumab, nivolumab, cemiprilimab, pidilizumab, spartalizumab, atezolizumab, avelumab, durvalumab, cocilimab, sazanlimab, tislelizumab, rivalizumab, batilizumab, toripalimab, sitrilimab, genoluzumab, palolizumab, lodalizumab, camrelizumab, budigalimab, avelumab, dotalimumab, envolimab, sintilimab, or sepalizumab. In some embodiments, the anti-PD-(L)1 antibody is sepalizumab. In some embodiments, the anti-PD-(L)1 antibody is durvalumab. In some embodiments, the anti-PD-(L)1 antibody is an Fc-silent antibody. In some embodiments, the anti-PD-(L)1 antibody is an Fc-enabled antibody. In some embodiments, any of the methods disclosed herein further comprise administering an anti-TIGIT antibody. In some embodiments, the anti-TIGIT antibody is AB308, AGEN-1307 (AGEN-1327), AGEN-1777, AK127, BMS-986207, dunalimab, EOS-448, eitinib, JS006, M6223, osperlimab, rapasumab, SEA-TGT (SGN-TGT), tisleliumab, or vembralizumab. In some embodiments, the anti-TIGIT antibody is dunalimab. In some embodiments, the anti-TIGIT antibody is M6223.In some embodiments, the anti-PD-(L)1 antibody and the anti-TIGIT antibody are a) sepalizumab and dunalizumab, b) sepalizumab and AB308, c) atezolizumab and tislelizumab, d) pembrolizumab and vembrolizumab, e) pembrolizumab and dunalizumab, f) pembrolizumab and AB308, g) MK-7684A (pembrolizumab / vembrolizumab co-formulation), h) durvalumab and dunalizumab, i) sepalizumab and rapasumab, or j) pembrolizumab and rapasumab. In some embodiments, the anti-PD-(L)1 antibody and the anti-TIGIT antibody are sepalizumab and dunalizumab. In some embodiments, the anti-PD-(L)1 antibody and the anti-TIGIT antibody are sepalizumab and dunalizumab. In some embodiments, the anti-PD-(L)1 antibody and the anti-TIGIT antibody are sepalizumab and rapasumab. In some embodiments, the anti-PD-(L)1 antibody and the anti-TIGIT antibody are durvalumab and dunalimab. In some embodiments, the method further comprises co-administering an additional therapeutic agent or treatment modality. In some embodiments, the additional therapeutic agent or treatment modality comprises one, two, three, or four additional therapeutic agents and / or treatment modalities. In some embodiments, the cancer is a solid epithelial cancer. In some embodiments, the solid epithelial cancer is selected from breast cancer (e.g., triple-negative breast cancer (TNBC), HR. + / Her2 - Breast cancer or HR + / Her2 低In some embodiments, the bladder cancer is urothelial carcinoma (UC). In some embodiments, the bladder cancer is (i) unresectable locally advanced bladder cancer, (ii) metastatic bladder cancer, or (iii) muscle-invasive bladder cancer. In some embodiments, the urothelial carcinoma is (i) unresectable locally advanced bladder cancer, (ii) metastatic bladder cancer, or (iii) muscle-invasive bladder cancer. In some embodiments, the lung cancer is non-small cell lung cancer (NSCLC). In some embodiments, the lung cancer is (i) advanced lung cancer or (ii) metastatic lung cancer. In some embodiments, the lung cancer is (i) advanced NSCLC or (ii) metastatic NSCLC. In some embodiments, the NSCLC is squamous NSCLC. In some embodiments, the NSCLC is non-squamous NSCLC. In some embodiments, the metastatic NSCLC is metastatic squamous NSCLC. In some embodiments, the metastatic NSCLC is metastatic non-squamous NSCLC. In some embodiments, the NSCLC is NSCLC without EGFR, ALK, or other actionable genomic alterations. In some embodiments, the cancer is (i) unresectable locally advanced cancer, (ii) metastatic cancer, or (iii) muscle-invasive cancer. In some embodiments, the cancer is (i) advanced cancer, or (ii) metastatic cancer. In some embodiments, the cancer has progressed after at least one prior anticancer therapy. In some embodiments, the subject is treatment-naive. In some embodiments, the subject has not received treatment in the metastatic or unresectable locally advanced setting (e.g., the subject has not received treatment for mUC and unresectable locally advanced UC). In some embodiments, the subject has not received treatment in the metastatic or unresectable locally advanced setting (e.g., the subject has not received treatment for metastatic and advanced lung cancer and NSCLC). In some embodiments, in a metastatic or unresectable locally advanced setting, the human patient does not meet the cisplatin criteria and has not received prior treatment. In some embodiments, the untreated subject has not received prior anticancer therapy for (i) unresectable locally advanced cancer, (ii) metastatic cancer, or (iii) muscle-invasive cancer. In some embodiments, the subject has received one or more anticancer therapies prior to administering the combination of ADC, anti-PD-(L)1 antibody, and optionally an anti-TIGIT antibody. In some embodiments, the subject is not untreated. In some embodiments, the subject has received one or more prior anticancer therapies for (i) unresectable locally advanced cancer, (ii) metastatic cancer, or (iii) muscle-invasive cancer.In some embodiments, the subject has received one or more anti-cancer therapies prior to administration of the combination of an ADC, an anti-PD-(L)1 antibody, and optionally an anti-TIGIT antibody. In some embodiments, the cancer is resistant to or refractory to one or more anti-cancer therapies. In some embodiments, the anti-cancer therapy is selected from surgery, radiation therapy, chemotherapy, and checkpoint inhibitor therapy. In some embodiments, the combination of an ADC, an anti-PD-(L)1 antibody, and optionally an anti-TIGIT antibody is administered in a neoadjuvant setting (e.g., in preparation for surgery or radiation therapy). In some embodiments, the combination of an ADC, an anti-PD-(L)1 antibody, and optionally an anti-TIGIT antibody is administered in an adjuvant setting (e.g., after primary therapy such as surgery or radiation therapy). In some embodiments, the combination of an ADC, an anti-PD-(L)1 antibody, and optionally an anti-TIGIT antibody is administered in a therapeutic setting (e.g., as a primary therapy). In some embodiments, the combination of an ADC, an anti-PD-(L)1 antibody, and optionally an anti-TIGIT antibody is administered in a maintenance setting. In some embodiments, the subject receives one or more doses of the ADC. In some embodiments, the subject receives one or more doses of an anti-PD-(L)1 antibody. In some embodiments, the subject receives one or more doses of an anti-TIGIT antibody. In some embodiments, the ADC and the anti-PD-(L)1 antibody are administered simultaneously. In some embodiments, the ADC and the anti-PD-(L)1 antibody are administered sequentially. In some embodiments, the ADC and the anti-TIGIT antibody are administered simultaneously. In some embodiments, the ADC and the anti-TIGIT antibody are administered sequentially. In some embodiments, the anti-PD-(L)1 antibody and the anti-TIGIT antibody are administered simultaneously. In some embodiments, the anti-PD-(L)1 antibody and the anti-TIGIT antibody are administered sequentially. In some embodiments, the subject is human. In some embodiments, the subject does not meet the criteria for cisplatin. In some embodiments, the ADC is administered in one or more doses ranging from 8 mg / kg to 10 mg / kg. In some embodiments, the ADC is administered in one or more doses of 8 mg / kg or 10 mg / kg. In some embodiments, the ADC is administered in one or more doses of 10 mg / kg. In some embodiments, the ADC is administered intravenously. In some embodiments, the ADC is administered on days 1 and 8 of a 21-day cycle. In some embodiments, the anti-PD-(L) 1 antibody is administered in one or more doses ranging from 300 mg to 400 mg. In some embodiments, the anti-PD-(L) 1 antibody is administered in a dose of 360 mg. In some embodiments, the anti-PD-(L) 1 antibody is administered intravenously. In some embodiments, the anti-PD-(L) 1 antibody is administered on day 1 of a 21-day cycle.In some embodiments, the anti-TIGIT antibody is administered in one or more doses ranging from 800 mg to 1600 mg. In some embodiments, the anti-TIGIT antibody is administered in a dose of 1200 mg. In some embodiments, the anti-TIGIT antibody is administered intravenously. In some embodiments, the anti-TIGIT antibody is administered on day 1 of a 21-day cycle. In some embodiments of the methods provided herein, an anti-CD47 antibody is not co-administered to the subject or human patient. In some embodiments, the anti-CD47 antibody is selected from mololimab, leszolimab, leterlimab, lefalimab, 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 anti-CD47 antibody is magrolimab. In some embodiments of the methods provided herein, MCL1 inhibitors are not co-administered to subjects or human patients. In some embodiments, MCL1 inhibitors are selected from GS-9716, AMG-176, AMG-397, S-64315, AZD-5991, 483-LM, A-1210477, UMI-77, and JKY-5-037. In some embodiments, MCL1 inhibitors are GS-9716. In some embodiments of the methods provided herein, FLT3 agonists are not administered to subjects or human patients. In some embodiments, FLT3 agonists are selected from GS-3583, CDX-301, TAK-605, ONCR-177, Alb-Ftl3L, and SYM-027. In some embodiments, FLT3 agonists are GS-3583.

[0318] In some embodiments, the methods provided herein are used to treat urothelial carcinoma, comprising co-administering to a subject an effective amount of the following: a) a TROP-2 targeting antibody-drug conjugate (ADC) comprising an anti-TROP-2 antibody (anti-TROP-2 ADC); b) an anti-PD-(L)1 antibody; and optionally, c) an anti-TIGIT antibody. In some embodiments, the anti-TROP-2 ADC comprises an anticancer agent payload. In some embodiments, the anticancer agent payload is selected from a microtubule inhibitor, a DNA cleavage agent, and a topoisomerase I inhibitor. In some embodiments, the anti-TROP-2 ADC comprises a topoisomerase I inhibitor. In some embodiments, the topoisomerase I inhibitor is selected from irinotecan, topotecan, and SN-38. In some embodiments, the anti-TROP-2 ADC has the structural formula mAb-CL2A-SN-38, which is represented by the following formula:

[0319]

[0320] (described, e.g., in U.S. Patent No. 7,999,083). In some embodiments, the anti-TROP-2 ADC comprises sacilotuzumab (hRS7; described, e.g., in WO2003074566). Figure 3 and Figure 4In some embodiments, the anti-TROP-2 ADC is selected from gosatuzumab, dedabrafenib (DS-1062), ESG-401, SKB-264, DAC-02, and BAT-8003. In some embodiments, the anti-TROP-2 ADC is gosatuzumab. In some embodiments, the anti-TROP-2 ADC comprises a microtubule inhibitor. In some embodiments, the microtubule inhibitor is selected from auristatins, taxanes, vinca alkaloids, epothilones, and maytansines. In some embodiments, the auristatin is selected from monomethyl auristatin E (MMAE) and monomethyl auristatin F (MMAF). In some embodiments, the maytansine alkaloid is selected from maytansine (DM1) and raftansine (DM4). In some embodiments, the anticancer agent payload is selected from anthracyclines (e.g., doxorubicin, daunorubicin, epirubicin, idarubicin), pyrrolobenzodiazepine (PBD) or dimers thereof, DNA cross-linker SC-DR002 (D6.5), duocarmycin, duocarmycins (A, B1, B2, C1, C2, D, SA, CC-1065), tubulysin B, and analogs thereof. In some embodiments, the anti-PD-(L)1 antibody is pembrolizumab, nivolumab, cemiprilimab, pidilizumab, spartalizumab, atezolizumab, avelumab, durvalumab, cocilimab, sazanlimab, tislelizumab, rivalizumab, batilizumab, toripalimab, sitrilimab, genoluzumab, palolizumab, lodalizumab, camrelizumab, budigalimab, avelumab, dotalimumab, envolimab, sintilimab, or sepalizumab. In some embodiments, the anti-PD-(L)1 antibody is sepalizumab. In some embodiments, the anti-PD-(L)1 antibody is durvalumab. In some embodiments, the anti-PD-(L)1 antibody is an Fc-silent antibody. In some embodiments, the anti-PD-(L)1 antibody is an Fc-enabled antibody. In some embodiments, any of the methods disclosed herein further comprise administering an anti-TIGIT antibody. In some embodiments, the anti-TIGIT antibody is AB308, AGEN-1307 (AGEN-1327), AGEN-1777, AK127, BMS-986207, dunalimab, EOS-448, eitinib, JS006, M6223, osperlimab, rapasumab, SEA-TGT (SGN-TGT), tisleliumab, or vembralizumab. In some embodiments, the anti-TIGIT antibody is dunalimab. In some embodiments, the anti-TIGIT antibody is M6223.In some embodiments, the anti-PD-(L)1 antibody and the anti-TIGIT antibody are a) sepalizumab and dunalizumab, b) sepalizumab and AB308, c) atezolizumab and tislelizumab, d) pembrolizumab and vembrolizumab, e) pembrolizumab and dunalizumab, f) pembrolizumab and AB308, g) MK-7684A (pembrolizumab / vembrolizumab co-formulation), h) durvalumab and dunalizumab, i) sepalizumab and rapasumab, or j) pembrolizumab and rapasumab. In some embodiments, the anti-PD-(L)1 antibody and the anti-TIGIT antibody are sepalizumab and dunalizumab. In some embodiments, the anti-PD-(L)1 antibody and the anti-TIGIT antibody are sepalizumab and dunalizumab. In some embodiments, the anti-PD-(L)1 antibody and the anti-TIGIT antibody are sepalizumab and rapasumab. In some embodiments, the anti-PD-(L)1 antibody and the anti-TIGIT antibody are durvalumab and dunalimab. In some embodiments, the method further comprises co-administering an additional therapeutic agent or treatment modality. In some embodiments, the additional therapeutic agent or treatment modality comprises one, two, three, or four additional therapeutic agents and / or treatment modalities. In some embodiments, the cancer is a solid epithelial cancer. In some embodiments, the solid epithelial cancer is selected from breast cancer (e.g., triple-negative breast cancer (TNBC), HR. + / Her2 - Breast cancer or HR + / Her2 低In some embodiments, the bladder cancer is urothelial carcinoma (UC). In some embodiments, the bladder cancer is (i) unresectable locally advanced bladder cancer, (ii) metastatic bladder cancer, or (iii) muscle-invasive bladder cancer. In some embodiments, the urothelial carcinoma is (i) unresectable locally advanced bladder cancer, (ii) metastatic bladder cancer, or (iii) muscle-invasive bladder cancer. In some embodiments, the lung cancer is non-small cell lung cancer (NSCLC). In some embodiments, the lung cancer is (i) advanced lung cancer or (ii) metastatic lung cancer. In some embodiments, the lung cancer is (i) advanced NSCLC or (ii) metastatic NSCLC. In some embodiments, the NSCLC is squamous NSCLC. In some embodiments, the NSCLC is non-squamous NSCLC. In some embodiments, the metastatic NSCLC is metastatic squamous NSCLC. In some embodiments, the metastatic NSCLC is metastatic non-squamous NSCLC. In some embodiments, the NSCLC is NSCLC without EGFR, ALK, or other actionable genomic alterations. In some embodiments, the cancer is (i) unresectable locally advanced cancer, (ii) metastatic cancer, or (iii) muscle-invasive cancer. In some embodiments, the cancer is (i) advanced cancer, or (ii) metastatic cancer. In some embodiments, the cancer has progressed after at least one prior anticancer therapy. In some embodiments, the subject is treatment-naive. In some embodiments, the subject has not received treatment in the metastatic or unresectable locally advanced setting (e.g., the subject has not received treatment for mUC and unresectable locally advanced UC). In some embodiments, the subject has not received treatment in the metastatic or unresectable locally advanced setting (e.g., the subject has not received treatment for metastatic and advanced lung cancer and NSCLC). In some embodiments, in a metastatic or unresectable locally advanced setting, the human patient does not meet the cisplatin criteria and has not received prior treatment. In some embodiments, the untreated subject has not received prior anticancer therapy for (i) unresectable locally advanced cancer, (ii) metastatic cancer, or (iii) muscle-invasive cancer. In some embodiments, the subject has received one or more anticancer therapies prior to administering the combination of ADC, anti-PD-(L)1 antibody, and optionally an anti-TIGIT antibody. In some embodiments, the subject is not untreated. In some embodiments, the subject has received one or more prior anticancer therapies for (i) unresectable locally advanced cancer, (ii) metastatic cancer, or (iii) muscle-invasive cancer.In some embodiments, the subject has received one or more anti-cancer therapies prior to administration of the combination of an ADC, an anti-PD-(L)1 antibody, and optionally an anti-TIGIT antibody. In some embodiments, the cancer is resistant to or refractory to one or more anti-cancer therapies. In some embodiments, the anti-cancer therapy is selected from surgery, radiation therapy, chemotherapy, and checkpoint inhibitor therapy. In some embodiments, the combination of an ADC, an anti-PD-(L)1 antibody, and optionally an anti-TIGIT antibody is administered in a neoadjuvant setting (e.g., in preparation for surgery or radiation therapy). In some embodiments, the combination of an ADC, an anti-PD-(L)1 antibody, and optionally an anti-TIGIT antibody is administered in an adjuvant setting (e.g., after primary therapy such as surgery or radiation therapy). In some embodiments, the combination of an ADC, an anti-PD-(L)1 antibody, and optionally an anti-TIGIT antibody is administered in a therapeutic setting (e.g., as a primary therapy). In some embodiments, the combination of an ADC, an anti-PD-(L)1 antibody, and optionally an anti-TIGIT antibody is administered in a maintenance setting. In some embodiments, the subject receives one or more doses of the ADC. In some embodiments, the subject receives one or more doses of an anti-PD-(L)1 antibody. In some embodiments, the subject receives one or more doses of an anti-TIGIT antibody. In some embodiments, the ADC and the anti-PD-(L)1 antibody are administered simultaneously. In some embodiments, the ADC and the anti-PD-(L)1 antibody are administered sequentially. In some embodiments, the ADC and the anti-TIGIT antibody are administered simultaneously. In some embodiments, the ADC and the anti-TIGIT antibody are administered sequentially. In some embodiments, the anti-PD-(L)1 antibody and the anti-TIGIT antibody are administered simultaneously. In some embodiments, the anti-PD-(L)1 antibody and the anti-TIGIT antibody are administered sequentially. In some embodiments, the subject is human. In some embodiments, the subject does not meet the criteria for cisplatin. In some embodiments, the ADC is administered in one or more doses ranging from 8 mg / kg to 10 mg / kg. In some embodiments, the ADC is administered in one or more doses of 8 mg / kg or 10 mg / kg. In some embodiments, the ADC is administered in one or more doses of 10 mg / kg. In some embodiments, the ADC is administered intravenously. In some embodiments, the ADC is administered on days 1 and 8 of a 21-day cycle. In some embodiments, the anti-PD-(L) 1 antibody is administered in one or more doses ranging from 300 mg to 400 mg. In some embodiments, the anti-PD-(L) 1 antibody is administered in a dose of 360 mg. In some embodiments, the anti-PD-(L) 1 antibody is administered intravenously. In some embodiments, the anti-PD-(L) 1 antibody is administered on day 1 of a 21-day cycle.In some embodiments, the anti-TIGIT antibody is administered in one or more doses ranging from 800 mg to 1600 mg. In some embodiments, the anti-TIGIT antibody is administered in a dose of 1200 mg. In some embodiments, the anti-TIGIT antibody is administered intravenously. In some embodiments, the anti-TIGIT antibody is administered on day 1 of a 21-day cycle. In some embodiments of the methods provided herein, an anti-CD47 antibody is not co-administered to the subject or human patient. In some embodiments, the anti-CD47 antibody is selected from mololimab, leszolimab, leterlimab, lefalimab, 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 anti-CD47 antibody is magrolimab. In some embodiments of the methods provided herein, MCL1 inhibitors are not co-administered to subjects or human patients. In some embodiments, MCL1 inhibitors are selected from GS-9716, AMG-176, AMG-397, S-64315, AZD-5991, 483-LM, A-1210477, UMI-77, and JKY-5-037. In some embodiments, MCL1 inhibitors are GS-9716. In some embodiments of the methods provided herein, FLT3 agonists are not administered to subjects or human patients. In some embodiments, FLT3 agonists are selected from GS-3583, CDX-301, TAK-605, ONCR-177, Alb-Ftl3L, and SYM-027. In some embodiments, FLT3 agonists are GS-3583.

[0321] In some embodiments, provided herein are methods for treating, alleviating, reducing, preventing, or delaying the recurrence or metastasis of a Trop-2-positive cancer, comprising co-administering to a subject an effective amount of: (a) a TROP-2-targeting antibody-drug conjugate (ADC) comprising an anti-TROP-2 antibody (anti-TROP-2 ADC); (b) sepalizumab; and optionally, (c) an anti-TIGIT antibody. In some embodiments, the anti-TROP-2 ADC comprises an anticancer agent payload. In some embodiments, the anticancer agent payload is selected from a microtubule inhibitor, a DNA cleavage agent, and a topoisomerase I inhibitor. In some embodiments, the anti-TROP-2 ADC comprises a topoisomerase I inhibitor. In some embodiments, the topoisomerase I inhibitor is selected from irinotecan, topotecan, and SN-38. In some embodiments, the anti-TROP-2 ADC has the structural formula mAb-CL2A-SN-38, the structure of which is represented by the following formula:

[0322]

[0323] (described, e.g., in U.S. Patent No. 7,999,083). In some embodiments, the anti-TROP-2 ADC comprises sacilotuzumab (hRS7; described, e.g., in WO2003074566). Figure 3 and Figure 4 In some embodiments, the anti-TROP-2 ADC is selected from gosatuzumab, dedabrafenib (DS-1062), ESG-401, SKB-264, DAC-02, and BAT-8003. In some embodiments, the anti-TROP-2 ADC is gosatuzumab. In some embodiments, the anti-TROP-2 ADC comprises a microtubule inhibitor. In some embodiments, the microtubule inhibitor is selected from auristatins, taxanes, vinca alkaloids, epothilones, and maytansines. In some embodiments, the auristatin is selected from monomethyl auristatin E (MMAE) and monomethyl auristatin F (MMAF). In some embodiments, the maytansine alkaloid is selected from maytansine (DM1) and raftansine (DM4). In some embodiments, the anticancer agent payload is selected from an anthracycline (e.g., doxorubicin, daunorubicin, epirubicin, idarubicin), pyrrolobenzodiazepine (PBD) or a dimer thereof, DNA cross-linker SC-DR002 (D6.5), duocarmycin, duocarmycins (A, B1, B2, C1, C2, D, SA, CC-1065), tubulysin B, and analogs thereof. In some embodiments, the method further comprises administering an anti-TIGIT antibody. In some embodiments, the anti-TIGIT antibody is AB308, AGEN-1307 (AGEN-1327), AGEN-1777, AK127, BMS-986207, dunalimab, EOS-448, etilizumab, JS006, M6223, osperlimab, rapasumab, SEA-TGT (SGN-TGT), tisleliumab, or vembralizumab. In some embodiments, the anti-TIGIT antibody is dunalimab. In some embodiments, the anti-TIGIT antibody is M6223. In some embodiments, the method further comprises co-administering an additional therapeutic agent or treatment modality. In some embodiments, the additional therapeutic agent or treatment modality comprises one, two, three, or four additional therapeutic agents and / or treatment modalities. In some embodiments, the cancer is a solid epithelial cancer. In some embodiments, the solid epithelial cancer is selected from breast cancer (e.g., triple-negative breast cancer (TNBC), HR + / Her2 - Breast cancer or HR + / Her2 低In some embodiments, the bladder cancer is urothelial carcinoma (UC). In some embodiments, the bladder cancer is (i) unresectable locally advanced bladder cancer, (ii) metastatic bladder cancer, or (iii) muscle-invasive bladder cancer. In some embodiments, the urothelial carcinoma is (i) unresectable locally advanced bladder cancer, (ii) metastatic bladder cancer, or (iii) muscle-invasive bladder cancer. In some embodiments, the lung cancer is non-small cell lung cancer (NSCLC). In some embodiments, the lung cancer is (i) advanced lung cancer or (ii) metastatic lung cancer. In some embodiments, the lung cancer is (i) advanced NSCLC or (ii) metastatic NSCLC. In some embodiments, the NSCLC is squamous NSCLC. In some embodiments, the NSCLC is non-squamous NSCLC. In some embodiments, the metastatic NSCLC is metastatic squamous NSCLC. In some embodiments, the metastatic NSCLC is metastatic non-squamous NSCLC. In some embodiments, the NSCLC is NSCLC without EGFR, ALK, or other actionable genomic alterations. In some embodiments, the cancer is (i) unresectable locally advanced cancer, (ii) metastatic cancer, or (iii) muscle-invasive cancer. In some embodiments, the cancer is (i) advanced cancer, or (ii) metastatic cancer. In some embodiments, the cancer has progressed after at least one prior anticancer therapy. In some embodiments, the subject is treatment-naive. In some embodiments, the subject has not received treatment in the metastatic or unresectable locally advanced setting (e.g., the subject has not received treatment for mUC and unresectable locally advanced UC). In some embodiments, the subject has not received treatment in the metastatic or unresectable locally advanced setting (e.g., the subject has not received treatment for metastatic and advanced lung cancer and NSCLC). In some embodiments, in a metastatic or unresectable locally advanced setting, the human patient does not meet the cisplatin criteria and has not received treatment. In some embodiments, the untreated subject has not received previous anticancer therapy for (i) unresectable locally advanced cancer, (ii) metastatic cancer, or (iii) muscle-invasive cancer. In some embodiments, the subject has received one or more anticancer therapies before administering a combination of ADC, sepalimab, and optionally an anti-TIGIT antibody. In some embodiments, the subject is not untreated. In some embodiments, the subject has received one or more previous anticancer therapies for (i) unresectable locally advanced cancer, (ii) metastatic cancer, or (iii) muscle-invasive cancer.In some embodiments, the subject has received one or more anti-cancer therapies prior to administration of the combination of an ADC, sepalimumab, and optionally an anti-TIGIT antibody. In some embodiments, the cancer is resistant to or refractory to one or more anti-cancer therapies. In some embodiments, the anti-cancer therapy is selected from surgery, radiation therapy, chemotherapy, and checkpoint inhibitor therapy. In some embodiments, the combination of an ADC, sepalimumab, and optionally an anti-TIGIT antibody is administered in a neoadjuvant setting (e.g., in preparation for surgery or radiation therapy). In some embodiments, the combination of an ADC, sepalimumab, and optionally an anti-TIGIT antibody is administered in an adjuvant setting (e.g., after primary therapy such as surgery or radiation therapy). In some embodiments, the combination of an ADC, sepalimumab, and optionally an anti-TIGIT antibody is administered in a therapeutic setting (e.g., as primary therapy). In some embodiments, the combination of an ADC, sepalimumab, and optionally an anti-TIGIT antibody is administered in a maintenance setting. In some embodiments, the subject receives one or more doses of an ADC. In some embodiments, the subject receives one or more doses of sepalimumab. In some embodiments, the subject receives one or more doses of an anti-TIGIT antibody. In some embodiments, the ADC and sepalimumab are administered simultaneously. In some embodiments, the ADC and sepalimumab are administered sequentially. In some embodiments, the ADC and anti-TIGIT antibody are administered simultaneously. In some embodiments, the ADC and anti-TIGIT antibody are administered sequentially. In some embodiments, sepalimumab and anti-TIGIT antibody are administered simultaneously. In some embodiments, sepalimumab and anti-TIGIT antibody are administered sequentially. In some embodiments, the subject is human. In some embodiments, the subject does not meet the criteria for cisplatin. In some embodiments, the ADC is administered in one or more doses ranging from 8 mg / kg to 10 mg / kg. In some embodiments, the ADC is administered in one or more doses of 8 mg / kg or 10 mg / kg. In some embodiments, the ADC is administered in one or more doses of 10 mg / kg. In some embodiments, the ADC is administered intravenously. In some embodiments, the ADC is administered on days 1 and 8 of a 21-day cycle. In some embodiments, sepalimab is administered in one or more doses ranging from 300 mg to 400 mg. In some embodiments, sepalimab is administered in a dose of 360 mg. In some embodiments, sepalimab is administered intravenously. In some embodiments, sepalimab is administered on day 1 of a 21-day cycle. In some embodiments, the anti-TIGIT antibody is administered in one or more doses ranging from 800 mg to 1600 mg. In some embodiments, the anti-TIGIT antibody is administered in a dose of 1200 mg. In some embodiments, the anti-TIGIT antibody is administered intravenously.In some embodiments, the anti-TIGIT antibody is administered on day 1 of a 21-day cycle. In some embodiments of the methods provided herein, an anti-CD47 antibody is not co-administered to the subject or human patient. In some embodiments, the anti-CD47 antibody is selected from mololimab, leszolimab, leterlimab, lefarlimab, 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 anti-CD47 antibody is magrolimab. In some embodiments of the methods provided herein, an MCL1 inhibitor is not co-administered to the subject or human patient. In some embodiments, the MCL1 inhibitor is selected from GS-9716, AMG-176, AMG-397, S-64315, AZD-5991, 483-LM, A-1210477, UMI-77 and JKY-5-037. In some embodiments, the MCL1 inhibitor is GS-9716. In some embodiments of the methods provided herein, the FLT3 agonist is not 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-Ftl3L and SYM-027. In some embodiments, the FLT3 agonist is GS-3583.

[0324] In some embodiments, provided herein are methods for treating a TROP-2-positive cancer, comprising co-administering to a subject an effective amount of: (a) a TROP-2-targeting antibody-drug conjugate (ADC) comprising an anti-TROP-2 antibody (anti-TROP-2 ADC); (b) sepalizumab; and optionally, (c) an anti-TIGIT antibody. In some embodiments, the anti-TROP-2 ADC comprises an anticancer agent payload. In some embodiments, the anticancer agent payload is selected from a microtubule inhibitor, a DNA cleavage agent, and a topoisomerase I inhibitor. In some embodiments, the anti-TROP-2 ADC comprises a topoisomerase I inhibitor. In some embodiments, the topoisomerase I inhibitor is selected from irinotecan, topotecan, and SN-38. In some embodiments, the anti-TROP-2 ADC has the structural formula mAb-CL2A-SN-38, the structure of which is represented by the following formula:

[0325]

[0326] (described, e.g., in U.S. Patent No. 7,999,083). In some embodiments, the anti-TROP-2 ADC comprises sacilotuzumab (hRS7; described, e.g., in WO2003074566). Figure 3 and Figure 4 In some embodiments, the anti-TROP-2 ADC is selected from gosatuzumab, dedabrafenib (DS-1062), ESG-401, SKB-264, DAC-02, and BAT-8003. In some embodiments, the anti-TROP-2 ADC is gosatuzumab. In some embodiments, the anti-TROP-2 ADC comprises a microtubule inhibitor. In some embodiments, the microtubule inhibitor is selected from auristatins, taxanes, vinca alkaloids, epothilones, and maytansines. In some embodiments, the auristatin is selected from monomethyl auristatin E (MMAE) and monomethyl auristatin F (MMAF). In some embodiments, the maytansine alkaloid is selected from maytansine (DM1) and raftansine (DM4). In some embodiments, the anticancer agent payload is selected from an anthracycline (e.g., doxorubicin, daunorubicin, epirubicin, idarubicin), pyrrolobenzodiazepine (PBD) or a dimer thereof, DNA cross-linker SC-DR002 (D6.5), duocarmycin, duocarmycins (A, B1, B2, C1, C2, D, SA, CC-1065), tubulysin B, and analogs thereof. In some embodiments, the method further comprises administering an anti-TIGIT antibody. In some embodiments, the anti-TIGIT antibody is AB308, AGEN-1307 (AGEN-1327), AGEN-1777, AK127, BMS-986207, dunalimab, EOS-448, etilizumab, JS006, M6223, osperlimab, rapasumab, SEA-TGT (SGN-TGT), tisleliumab, or vembralizumab. In some embodiments, the anti-TIGIT antibody is dunalimab. In some embodiments, the anti-TIGIT antibody is M6223. In some embodiments, the method further comprises co-administering an additional therapeutic agent or treatment modality. In some embodiments, the additional therapeutic agent or treatment modality comprises one, two, three, or four additional therapeutic agents and / or treatment modalities. In some embodiments, the cancer is a solid epithelial cancer. In some embodiments, the solid epithelial cancer is selected from breast cancer (e.g., triple-negative breast cancer (TNBC), HR + / Her2 - Breast cancer or HR + / Her2 低In some embodiments, the bladder cancer is urothelial carcinoma (UC). In some embodiments, the bladder cancer is (i) unresectable locally advanced bladder cancer, (ii) metastatic bladder cancer, or (iii) muscle-invasive bladder cancer. In some embodiments, the urothelial carcinoma is (i) unresectable locally advanced bladder cancer, (ii) metastatic bladder cancer, or (iii) muscle-invasive bladder cancer. In some embodiments, the lung cancer is non-small cell lung cancer (NSCLC). In some embodiments, the lung cancer is (i) advanced lung cancer or (ii) metastatic lung cancer. In some embodiments, the lung cancer is (i) advanced NSCLC or (ii) metastatic NSCLC. In some embodiments, the NSCLC is squamous NSCLC. In some embodiments, the NSCLC is non-squamous NSCLC. In some embodiments, the metastatic NSCLC is metastatic squamous NSCLC. In some embodiments, the metastatic NSCLC is metastatic non-squamous NSCLC. In some embodiments, the NSCLC is NSCLC without EGFR, ALK, or other actionable genomic alterations. In some embodiments, the cancer is (i) unresectable locally advanced cancer, (ii) metastatic cancer, or (iii) muscle-invasive cancer. In some embodiments, the cancer is (i) advanced cancer, or (ii) metastatic cancer. In some embodiments, the cancer has progressed after at least one prior anticancer therapy. In some embodiments, the subject is treatment-naive. In some embodiments, the subject is treatment-naive in the metastatic or unresectable locally advanced setting (e.g., the subject has not received treatment for mUC and unresectable locally advanced UC). In some embodiments, the subject is treatment-naive in the metastatic or advanced setting (e.g., the subject has not received treatment for metastatic and advanced lung cancer and NSCLC). In some embodiments, the human patient is cisplatin-ineligible and has not received treatment in the metastatic or unresectable locally advanced setting. In some embodiments, the treatment-naive subject has not received prior anticancer therapy for (i) unresectable locally advanced cancer, (ii) metastatic cancer, or (iii) muscle-invasive cancer. In some embodiments, the subject has received one or more anticancer therapies prior to administering the combination of ADC, sepalizumab, and optionally an anti-TIGIT antibody. In some embodiments, the subject is not treatment-naive. In some embodiments, the subject has received one or more prior anticancer therapies for (i) unresectable locally advanced cancer, (ii) metastatic cancer, or (iii) muscle-invasive cancer.In some embodiments, the subject has received one or more anti-cancer therapies prior to administration of the combination of an ADC, sepalimumab, and optionally an anti-TIGIT antibody. In some embodiments, the cancer is resistant to or refractory to one or more anti-cancer therapies. In some embodiments, the anti-cancer therapy is selected from surgery, radiation therapy, chemotherapy, and checkpoint inhibitor therapy. In some embodiments, the combination of an ADC, sepalimumab, and optionally an anti-TIGIT antibody is administered in a neoadjuvant setting (e.g., in preparation for surgery or radiation therapy). In some embodiments, the combination of an ADC, sepalimumab, and optionally an anti-TIGIT antibody is administered in an adjuvant setting (e.g., after primary therapy such as surgery or radiation therapy). In some embodiments, the combination of an ADC, sepalimumab, and optionally an anti-TIGIT antibody is administered in a therapeutic setting (e.g., as primary therapy). In some embodiments, the combination of an ADC, sepalimumab, and optionally an anti-TIGIT antibody is administered in a maintenance setting. In some embodiments, the subject receives one or more doses of an ADC. In some embodiments, the subject receives one or more doses of sepalimumab. In some embodiments, the subject receives one or more doses of an anti-TIGIT antibody. In some embodiments, the ADC and sepalimumab are administered simultaneously. In some embodiments, the ADC and sepalimumab are administered sequentially. In some embodiments, the ADC and anti-TIGIT antibody are administered simultaneously. In some embodiments, the ADC and anti-TIGIT antibody are administered sequentially. In some embodiments, sepalimumab and anti-TIGIT antibody are administered simultaneously. In some embodiments, sepalimumab and anti-TIGIT antibody are administered sequentially. In some embodiments, the subject is human. In some embodiments, the subject does not meet the criteria for cisplatin. In some embodiments, the ADC is administered in one or more doses ranging from 8 mg / kg to 10 mg / kg. In some embodiments, the ADC is administered in one or more doses of 8 mg / kg or 10 mg / kg. In some embodiments, the ADC is administered in one or more doses of 10 mg / kg. In some embodiments, the ADC is administered intravenously. In some embodiments, the ADC is administered on days 1 and 8 of a 21-day cycle. In some embodiments, sepalimab is administered in one or more doses ranging from 300 mg to 400 mg. In some embodiments, sepalimab is administered in a dose of 360 mg. In some embodiments, sepalimab is administered intravenously. In some embodiments, sepalimab is administered on day 1 of a 21-day cycle. In some embodiments, the anti-TIGIT antibody is administered in one or more doses ranging from 800 mg to 1600 mg. In some embodiments, the anti-TIGIT antibody is administered in a dose of 1200 mg. In some embodiments, the anti-TIGIT antibody is administered intravenously.In some embodiments, the anti-TIGIT antibody is administered on day 1 of a 21-day cycle. In some embodiments of the methods provided herein, an anti-CD47 antibody is not co-administered to the subject or human patient. In some embodiments, the anti-CD47 antibody is selected from mololimab, leszolimab, leterlimab, lefarlimab, 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 anti-CD47 antibody is magrolimab. In some embodiments of the methods provided herein, an MCL1 inhibitor is not co-administered to the subject or human patient. In some embodiments, the MCL1 inhibitor is selected from GS-9716, AMG-176, AMG-397, S-64315, AZD-5991, 483-LM, A-1210477, UMI-77 and JKY-5-037. In some embodiments, the MCL1 inhibitor is GS-9716. In some embodiments of the methods provided herein, the FLT3 agonist is not 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-Ftl3L and SYM-027. In some embodiments, the FLT3 agonist is GS-3583.

[0327] In some embodiments, provided herein are methods for treating, alleviating, reducing, preventing, or delaying recurrence or metastasis of a TROP-2-positive cancer, comprising co-administering to a subject an effective amount of: (a) a TROP-2-targeting antibody-drug conjugate (ADC) comprising an anti-TROP-2 antibody (anti-TROP-2 ADC); (b) sepalizumab; and optionally, (c) dunalimumab. In some embodiments, the anti-TROP-2 ADC comprises an anticancer agent payload. In some embodiments, the anticancer agent payload is selected from a microtubule inhibitor, a DNA cleavage agent, and a topoisomerase I inhibitor. In some embodiments, the anti-TROP-2 ADC comprises a topoisomerase I inhibitor. In some embodiments, the topoisomerase I inhibitor is selected from irinotecan, topotecan, and SN-38. In some embodiments, the anti-TROP-2 ADC has the structural formula mAb-CL2A-SN-38, which is represented by the following formula:

[0328]

[0329] (described, e.g., in U.S. Patent No. 7,999,083). In some embodiments, the anti-TROP-2 ADC comprises sacilotuzumab (hRS7; described, e.g., in WO2003074566). Figure 3 and Figure 4 In some embodiments, the anti-TROP-2 ADC is selected from gosatuzumab, dedabrafenib (DS-1062), ESG-401, SKB-264, DAC-02, and BAT-8003. In some embodiments, the anti-TROP-2 ADC is gosatuzumab. In some embodiments, the anti-TROP-2 ADC comprises a microtubule inhibitor. In some embodiments, the microtubule inhibitor is selected from auristatins, taxanes, vinca alkaloids, epothilones, and maytansines. In some embodiments, the auristatin is selected from monomethyl auristatin E (MMAE) and monomethyl auristatin F (MMAF). In some embodiments, the maytansine alkaloid is selected from maytansine (DM1) and raftansine (DM4). In some embodiments, the anticancer agent payload is selected from anthracyclines (e.g., doxorubicin, daunorubicin, epirubicin, idarubicin), pyrrolobenzodiazepines (PBD) or dimers thereof, DNA crosslinker SC-DR002 (D6.5), duocarmycins, duocarmycins (A, B1, B2, C1, C2, D, SA, CC-1065), tubulysin B, and analogs thereof. In some embodiments, the method further comprises administering dunalimab. In some embodiments, the method further comprises co-administering an additional therapeutic agent or treatment modality. In some embodiments, the additional therapeutic agent or treatment modality comprises one, two, three, or four additional therapeutic agents and / or treatment modalities. In some embodiments, the cancer is a solid epithelial cancer. In some embodiments, the solid epithelial cancer is selected from breast cancer (e.g., triple-negative breast cancer (TNBC), HR + / Her2 - Breast cancer or HR + / Her2 低In some embodiments, the bladder cancer is urothelial carcinoma (UC). In some embodiments, the bladder cancer is (i) unresectable locally advanced bladder cancer, (ii) metastatic bladder cancer, or (iii) muscle-invasive bladder cancer. In some embodiments, the urothelial carcinoma is (i) unresectable locally advanced bladder cancer, (ii) metastatic bladder cancer, or (iii) muscle-invasive bladder cancer. In some embodiments, the lung cancer is non-small cell lung cancer (NSCLC). In some embodiments, the lung cancer is (i) advanced lung cancer or (ii) metastatic lung cancer. In some embodiments, the lung cancer is (i) advanced NSCLC or (ii) metastatic NSCLC. In some embodiments, the NSCLC is squamous NSCLC. In some embodiments, the NSCLC is non-squamous NSCLC. In some embodiments, the metastatic NSCLC is metastatic squamous NSCLC. In some embodiments, the metastatic NSCLC is metastatic non-squamous NSCLC. In some embodiments, the NSCLC is NSCLC without EGFR, ALK, or other actionable genomic alterations. In some embodiments, the cancer is (i) unresectable locally advanced cancer, (ii) metastatic cancer, or (iii) muscle-invasive cancer. In some embodiments, the cancer is (i) advanced cancer, or (ii) metastatic cancer. In some embodiments, the cancer has progressed after at least one prior anticancer therapy. In some embodiments, the subject is treatment-naive. In some embodiments, the subject is treatment-naive in the metastatic or unresectable locally advanced setting (e.g., the subject has not received treatment for mUC and unresectable locally advanced UC). In some embodiments, the subject is treatment-naive in the metastatic or advanced setting (e.g., the subject has not received treatment for metastatic and advanced lung cancer and NSCLC). In some embodiments, the human patient is cisplatin-ineligible and has not received treatment in the metastatic or unresectable locally advanced setting. In some embodiments, the treatment-naive subject has not received prior anticancer therapy for (i) unresectable locally advanced cancer, (ii) metastatic cancer, or (iii) muscle-invasive cancer. In some embodiments, the subject has received one or more anticancer therapies prior to administration of the combination of ADC, sepalizumab, and optionally dunalimab. In some embodiments, the subject is not treatment-naive. In some embodiments, the subject has received one or more prior anticancer therapies for (i) unresectable locally advanced cancer, (ii) metastatic cancer, or (iii) muscle-invasive cancer.In some embodiments, the subject has received one or more anticancer therapies prior to administration of the combination of an ADC, sepalizumab, and optionally dunalizumab. In some embodiments, the cancer is resistant to or refractory to one or more anticancer therapies. In some embodiments, the anticancer therapy is selected from surgery, radiation therapy, chemotherapy, and checkpoint inhibitor therapy. In some embodiments, the combination of an ADC, sepalizumab, and optionally dunalizumab is administered in a neoadjuvant setting (e.g., in preparation for surgery or radiation therapy). In some embodiments, the combination of an ADC, sepalizumab, and optionally dunalizumab is administered in an adjuvant setting (e.g., after primary therapy such as surgery or radiation therapy). In some embodiments, the combination of an ADC, sepalizumab, and optionally dunalizumab is administered in a treatment setting (e.g., as primary therapy). In some embodiments, the combination of an ADC, sepalizumab, and optionally dunalizumab is administered in a maintenance setting. In some embodiments, the subject receives one or more doses of an ADC. In some embodiments, the subject receives one or more doses of sepalizumab. In some embodiments, the subject receives one or more doses of dunalimab. In some embodiments, the ADC and sepalizumab are administered simultaneously. In some embodiments, the ADC and sepalizumab are administered sequentially. In some embodiments, the ADC and dunalimab are administered simultaneously. In some embodiments, the ADC and dunalimab are administered sequentially. In some embodiments, sepalizumab and dunalimab are administered simultaneously. In some embodiments, sepalizumab and dunalimab are administered sequentially. In some embodiments, the subject is human. In some embodiments, the subject does not meet the criteria for cisplatin. In some embodiments, the ADC is administered in one or more doses ranging from 8 mg / kg to 10 mg / kg. In some embodiments, the ADC is administered in one or more doses of 8 mg / kg or 10 mg / kg. In some embodiments, the ADC is administered in one or more doses of 10 mg / kg. In some embodiments, the ADC is administered intravenously. In some embodiments, the ADC is administered on days 1 and 8 of a 21-day cycle. In some embodiments, sepalizumab is administered in one or more doses ranging from 300 mg to 400 mg. In some embodiments, sepalizumab is administered in a dose of 360 mg. In some embodiments, sepalizumab is administered intravenously. In some embodiments, sepalizumab is administered on day 1 of a 21-day cycle. In some embodiments, dunalizumab is administered in one or more doses ranging from 800 mg to 1600 mg. In some embodiments, dunalizumab is administered in a dose of 1200 mg. In some embodiments, dunalizumab is administered intravenously. In some embodiments, dunalizumab is administered on day 1 of a 21-day cycle.In some embodiments of the methods provided herein, an anti-CD47 antibody is not co-administered to the subject or human patient. In some embodiments, the anti-CD47 antibody is selected from mololimab, leszolimab, leterlimab, lefalimab, 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 anti-CD47 antibody is magrolimab. In some embodiments of the methods provided herein, an MCL1 inhibitor is not co-administered to the subject or human patient. In some embodiments, the MCL1 inhibitor is selected from GS-9716, AMG-176, AMG-397, S-64315, AZD-5991, 483-LM, A-1210477, UMI-77 and JKY-5-037. In some embodiments, the MCL1 inhibitor is GS-9716. In some embodiments of the methods provided herein, the FLT3 agonist is not 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-Ftl3L and SYM-027. In some embodiments, the FLT3 agonist is GS-3583.

[0330] In some embodiments, provided herein are methods for treating a TROP-2-positive cancer, comprising co-administering to a subject an effective amount of: (a) a TROP-2-targeting antibody-drug conjugate (ADC) comprising an anti-TROP-2 antibody (anti-TROP-2 ADC); (b) sepalizumab; and optionally, (c) dunalimab. In some embodiments, the anti-TROP-2 ADC comprises an anticancer agent payload. In some embodiments, the anticancer agent payload is selected from a microtubule inhibitor, a DNA cleaving agent, and a topoisomerase I inhibitor. In some embodiments, the anti-TROP-2 ADC comprises a topoisomerase I inhibitor. In some embodiments, the topoisomerase I inhibitor is selected from irinotecan, topotecan, and SN-38. In some embodiments, the anti-TROP-2 ADC has the structural formula mAb-CL2A-SN-38, which is represented by the following formula:

[0331]

[0332] (described, e.g., in U.S. Patent No. 7,999,083). In some embodiments, the anti-TROP-2 ADC comprises sacilotuzumab (hRS7; described, e.g., in WO2003074566). Figure 3 and Figure 4In some embodiments, the anti-TROP-2 ADC is selected from gosatuzumab, dedabrafenib (DS-1062), ESG-401, SKB-264, DAC-02, and BAT-8003. In some embodiments, the anti-TROP-2 ADC is gosatuzumab. In some embodiments, the anti-TROP-2 ADC comprises a microtubule inhibitor. In some embodiments, the microtubule inhibitor is selected from auristatins, taxanes, vinca alkaloids, epothilones, and maytansines. In some embodiments, the auristatin is selected from monomethyl auristatin E (MMAE) and monomethyl auristatin F (MMAF). In some embodiments, the maytansine alkaloid is selected from maytansine (DM1) and raftansine (DM4). In some embodiments, the anticancer agent payload is selected from anthracyclines (e.g., doxorubicin, daunorubicin, epirubicin, idarubicin), pyrrolobenzodiazepines (PBD) or dimers thereof, DNA crosslinker SC-DR002 (D6.5), duocarmycins, duocarmycins (A, B1, B2, C1, C2, D, SA, CC-1065), tubulysin B, and analogs thereof. In some embodiments, the method further comprises administering dunalimab. In some embodiments, the method further comprises co-administering an additional therapeutic agent or treatment modality. In some embodiments, the additional therapeutic agent or treatment modality comprises one, two, three, or four additional therapeutic agents and / or treatment modalities. In some embodiments, the cancer is a solid epithelial cancer. In some embodiments, the solid epithelial cancer is selected from breast cancer (e.g., triple-negative breast cancer (TNBC), HR + / Her2 - Breast cancer or HR + / Her2 低In some embodiments, the bladder cancer is urothelial carcinoma (UC). In some embodiments, the bladder cancer is (i) unresectable locally advanced bladder cancer, (ii) metastatic bladder cancer, or (iii) muscle-invasive bladder cancer. In some embodiments, the urothelial carcinoma is (i) unresectable locally advanced bladder cancer, (ii) metastatic bladder cancer, or (iii) muscle-invasive bladder cancer. In some embodiments, the lung cancer is non-small cell lung cancer (NSCLC). In some embodiments, the lung cancer is (i) advanced lung cancer or (ii) metastatic lung cancer. In some embodiments, the lung cancer is (i) advanced NSCLC or (ii) metastatic NSCLC. In some embodiments, the NSCLC is squamous NSCLC. In some embodiments, the NSCLC is non-squamous NSCLC. In some embodiments, the metastatic NSCLC is metastatic squamous NSCLC. In some embodiments, the metastatic NSCLC is metastatic non-squamous NSCLC. In some embodiments, the NSCLC is NSCLC without EGFR, ALK, or other actionable genomic alterations. In some embodiments, the cancer is (i) unresectable locally advanced cancer, (ii) metastatic cancer, or (iii) muscle-invasive cancer. In some embodiments, the cancer is (i) advanced cancer, or (ii) metastatic cancer. In some embodiments, the cancer has progressed after at least one prior anticancer therapy. In some embodiments, the subject is treatment-naive. In some embodiments, the subject is treatment-naive in the metastatic or unresectable locally advanced setting (e.g., the subject has not received treatment for mUC and unresectable locally advanced UC). In some embodiments, the subject is treatment-naive in the metastatic or advanced setting (e.g., the subject has not received treatment for metastatic and advanced lung cancer and NSCLC). In some embodiments, the human patient is cisplatin-ineligible and has not received treatment in the metastatic or unresectable locally advanced setting. In some embodiments, the treatment-naive subject has not received prior anticancer therapy for (i) unresectable locally advanced cancer, (ii) metastatic cancer, or (iii) muscle-invasive cancer. In some embodiments, the subject has received one or more anticancer therapies prior to administration of the combination of ADC, sepalizumab, and optionally dunalimab. In some embodiments, the subject is not treatment-naive. In some embodiments, the subject has received one or more prior anticancer therapies for (i) unresectable locally advanced cancer, (ii) metastatic cancer, or (iii) muscle-invasive cancer.In some embodiments, the subject has received one or more anticancer therapies prior to administration of the combination of an ADC, sepalizumab, and optionally dunalizumab. In some embodiments, the cancer is resistant to or refractory to one or more anticancer therapies. In some embodiments, the anticancer therapy is selected from surgery, radiation therapy, chemotherapy, and checkpoint inhibitor therapy. In some embodiments, the combination of an ADC, sepalizumab, and optionally dunalizumab is administered in a neoadjuvant setting (e.g., in preparation for surgery or radiation therapy). In some embodiments, the combination of an ADC, sepalizumab, and optionally dunalizumab is administered in an adjuvant setting (e.g., after primary therapy such as surgery or radiation therapy). In some embodiments, the combination of an ADC, sepalizumab, and optionally dunalizumab is administered in a treatment setting (e.g., as primary therapy). In some embodiments, the combination of an ADC, sepalizumab, and optionally dunalizumab is administered in a maintenance setting. In some embodiments, the subject receives one or more doses of an ADC. In some embodiments, the subject receives one or more doses of sepalizumab. In some embodiments, the subject receives one or more doses of dunalimab. In some embodiments, the ADC and sepalizumab are administered simultaneously. In some embodiments, the ADC and sepalizumab are administered sequentially. In some embodiments, the ADC and dunalimab are administered simultaneously. In some embodiments, the ADC and dunalimab are administered sequentially. In some embodiments, sepalizumab and dunalimab are administered simultaneously. In some embodiments, sepalizumab and dunalimab are administered sequentially. In some embodiments, the subject is human. In some embodiments, the subject does not meet the criteria for cisplatin. In some embodiments, the ADC is administered in one or more doses ranging from 8 mg / kg to 10 mg / kg. In some embodiments, the ADC is administered in one or more doses of 8 mg / kg or 10 mg / kg. In some embodiments, the ADC is administered in one or more doses of 10 mg / kg. In some embodiments, the ADC is administered intravenously. In some embodiments, the ADC is administered on days 1 and 8 of a 21-day cycle. In some embodiments, sepalizumab is administered in one or more doses ranging from 300 mg to 400 mg. In some embodiments, sepalizumab is administered in a dose of 360 mg. In some embodiments, sepalizumab is administered intravenously. In some embodiments, sepalizumab is administered on day 1 of a 21-day cycle. In some embodiments, dunalizumab is administered in one or more doses ranging from 800 mg to 1600 mg. In some embodiments, dunalizumab is administered in a dose of 1200 mg. In some embodiments, dunalizumab is administered intravenously. In some embodiments, dunalizumab is administered on day 1 of a 21-day cycle.In some embodiments of the methods provided herein, an anti-CD47 antibody is not co-administered to the subject or human patient. In some embodiments, the anti-CD47 antibody is selected from mololimab, leszolimab, leterlimab, lefalimab, 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 anti-CD47 antibody is magrolimab. In some embodiments of the methods provided herein, an MCL1 inhibitor is not co-administered to the subject or human patient. In some embodiments, the MCL1 inhibitor is selected from GS-9716, AMG-176, AMG-397, S-64315, AZD-5991, 483-LM, A-1210477, UMI-77 and JKY-5-037. In some embodiments, the MCL1 inhibitor is GS-9716. In some embodiments of the methods provided herein, the FLT3 agonist is not 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-Ftl3L and SYM-027. In some embodiments, the FLT3 agonist is GS-3583.

[0333] In some embodiments, provided herein are methods for treating, alleviating, reducing, preventing, or delaying recurrence or metastasis of a TROP-2-positive cancer, comprising co-administering to a subject an effective amount of: (a) a TROP-2-targeting antibody-drug conjugate (ADC) comprising an anti-TROP-2 antibody (anti-TROP-2 ADC); (b) an anti-PD-(L)1 antibody; and optionally, (c) dunalimab. In some embodiments, the anti-TROP-2 ADC comprises an anticancer agent payload. In some embodiments, the anticancer agent payload is selected from a microtubule inhibitor, a DNA cleavage agent, and a topoisomerase I inhibitor. In some embodiments, the anti-TROP-2 ADC comprises a topoisomerase I inhibitor. In some embodiments, the topoisomerase I inhibitor is selected from irinotecan, topotecan, and SN-38. In some embodiments, the anti-TROP-2 ADC has the structural formula mAb-CL2A-SN-38, which is represented by the following formula:

[0334]

[0335] (described, e.g., in U.S. Patent No. 7,999,083). In some embodiments, the anti-TROP-2 ADC comprises sacilotuzumab (hRS7; described, e.g., in WO2003074566). Figure 3 and Figure 4 In some embodiments, the anti-TROP-2 ADC is selected from gosatuzumab, dedabrafenib (DS-1062), ESG-401, SKB-264, DAC-02, and BAT-8003. In some embodiments, the anti-TROP-2 ADC is gosatuzumab. In some embodiments, the anti-TROP-2 ADC comprises a microtubule inhibitor. In some embodiments, the microtubule inhibitor is selected from auristatins, taxanes, vinca alkaloids, epothilones, and maytansines. In some embodiments, the auristatin is selected from monomethyl auristatin E (MMAE) and monomethyl auristatin F (MMAF). In some embodiments, the maytansine alkaloid is selected from maytansine (DM1) and raftansine (DM4). In some embodiments, the anticancer agent payload is selected from anthracyclines (e.g., doxorubicin, daunorubicin, epirubicin, idarubicin), pyrrolobenzodiazepine (PBD) or dimers thereof, DNA cross-linker SC-DR002 (D6.5), duocarmycin, duocarmycins (A, B1, B2, C1, C2, D, SA, CC-1065), tubulysin B, and analogs thereof. In some embodiments, the anti-PD-(L)1 antibody is pembrolizumab, nivolumab, cemiprilimab, pidilizumab, spartalizumab, atezolizumab, avelumab, durvalumab, cocilimab, sazanlimab, tislelizumab, rivalizumab, batilizumab, toripalimab, sitrilimab, genoluzumab, palolizumab, lodalizumab, camrelizumab, budigalimab, avelumab, dotalimumab, envolimab, sintilimab, or sepalizumab. In some embodiments, the anti-PD-(L)1 antibody is sepalizumab. In some embodiments, the anti-PD-(L)1 antibody is durvalumab. In some embodiments, the anti-PD-(L)1 antibody is an Fc-silent antibody. In some embodiments, the anti-PD-(L)1 antibody is an Fc-enabled antibody. In some embodiments, the method further comprises administering dunarizumab. In some embodiments, the method further comprises co-administering an additional therapeutic agent or treatment modality. In some embodiments, the additional therapeutic agent or treatment modality comprises one, two, three, or four additional therapeutic agents and / or treatment modalities. In some embodiments, the cancer is a solid epithelial cancer. In some embodiments, the solid epithelial cancer is selected from breast cancer (e.g., triple-negative breast cancer (TNBC), HR + / Her2 - Breast cancer or HR + / Her2 低In some embodiments, the bladder cancer is urothelial carcinoma (UC). In some embodiments, the bladder cancer is (i) unresectable locally advanced bladder cancer, (ii) metastatic bladder cancer, or (iii) muscle-invasive bladder cancer. In some embodiments, the urothelial carcinoma is (i) unresectable locally advanced bladder cancer, (ii) metastatic bladder cancer, or (iii) muscle-invasive bladder cancer. In some embodiments, the lung cancer is non-small cell lung cancer (NSCLC). In some embodiments, the lung cancer is (i) advanced lung cancer or (ii) metastatic lung cancer. In some embodiments, the lung cancer is (i) advanced NSCLC or (ii) metastatic NSCLC. In some embodiments, the NSCLC is squamous NSCLC. In some embodiments, the NSCLC is non-squamous NSCLC. In some embodiments, the metastatic NSCLC is metastatic squamous NSCLC. In some embodiments, the metastatic NSCLC is metastatic non-squamous NSCLC. In some embodiments, the NSCLC is NSCLC without EGFR, ALK, or other actionable genomic alterations. In some embodiments, the cancer is (i) unresectable locally advanced cancer, (ii) metastatic cancer, or (iii) muscle-invasive cancer. In some embodiments, the cancer is (i) advanced cancer, or (ii) metastatic cancer. In some embodiments, the cancer has progressed after at least one prior anticancer therapy. In some embodiments, the subject is treatment-naive. In some embodiments, the subject has not received treatment in the metastatic or unresectable locally advanced setting (e.g., the subject has not received treatment for mUC and unresectable locally advanced UC). In some embodiments, the subject has not received treatment in the metastatic or unresectable locally advanced setting (e.g., the subject has not received treatment for metastatic and advanced lung cancer and NSCLC). In some embodiments, the human patient is cisplatin-ineligible and has not received prior treatment in the setting of metastatic or unresectable locally advanced disease. In some embodiments, the untreated subject has not received prior anticancer therapy for (i) unresectable locally advanced cancer, (ii) metastatic cancer, or (iii) muscle-invasive cancer. In some embodiments, the untreated subject has not received prior anticancer therapy for (i) advanced cancer or (ii) metastatic cancer. In some embodiments, the subject has received one or more anticancer therapies prior to administration of the combination of ADC, anti-PD-(L)1 antibody, and optionally dunalimab. In some embodiments, the subject is not untreated.In some embodiments, the subject has received one or more prior anticancer therapies for (i) unresectable locally advanced cancer, (ii) metastatic cancer, or (iii) muscle-invasive cancer. In some embodiments, the subject has received one or more prior anticancer therapies for (i) advanced cancer or (ii) metastatic cancer. In some embodiments, the subject has received one or more prior anticancer therapies prior to administration of the combination of an ADC, an anti-PD-(L)1 antibody, and optionally, dunalimab. In some embodiments, the cancer is resistant to or refractory to one or more anticancer therapies. In some embodiments, the anticancer therapy is selected from surgery, radiation therapy, chemotherapy, and checkpoint inhibitor therapy. In some embodiments, the combination of an ADC, an anti-PD-(L)1 antibody, and optionally, dunalimab is administered in a neoadjuvant setting (e.g., in preparation for surgery or radiation therapy). In some embodiments, the combination of an ADC, an anti-PD-(L)1 antibody, and optionally, dunalimab is administered in an adjuvant setting (e.g., following primary treatment such as surgery or radiation therapy). In some embodiments, the combination of an ADC, an anti-PD-(L)1 antibody, and optionally dunalizumab is administered in a treatment setting (e.g., as primary therapy). In some embodiments, the combination of an ADC, an anti-PD-(L)1 antibody, and optionally dunalizumab is administered in a maintenance setting. In some embodiments, the subject receives one or more doses of an ADC. In some embodiments, the subject receives one or more doses of an anti-PD-(L)1 antibody. In some embodiments, the subject receives one or more doses of dunalizumab. In some embodiments, the ADC and anti-PD-(L)1 antibody are administered simultaneously. In some embodiments, the ADC and anti-PD-(L)1 antibody are administered sequentially. In some embodiments, the ADC and dunalizumab are administered simultaneously. In some embodiments, the ADC and dunalizumab are administered sequentially. In some embodiments, the anti-PD-(L)1 antibody and dunalizumab are administered simultaneously. In some embodiments, the anti-PD-(L)1 antibody and dunalizumab are administered sequentially. In some embodiments, the subject is human. In some embodiments, the subject does not meet criteria for cisplatin. In some embodiments, the ADC is administered in one or more doses ranging from 8 mg / kg to 10 mg / kg. In some embodiments, the ADC is administered in one or more doses of 8 mg / kg or 10 mg / kg. In some embodiments, the ADC is administered in one or more doses of 10 mg / kg. In some embodiments, the ADC is administered intravenously. In some embodiments, the ADC is administered on days 1 and 8 of a 21-day cycle. In some embodiments, the anti-PD-(L)1 antibody is administered in one or more doses ranging from 300 mg to 400 mg. In some embodiments, the anti-PD-(L)1 antibody is administered in a dose of 360 mg.In some embodiments, the anti-PD-(L)1 antibody is administered intravenously. In some embodiments, the anti-PD-(L)1 antibody is administered on day 1 of a 21-day cycle. In some embodiments, dunalizumab is administered in one or more doses ranging from 800 mg to 1600 mg. In some embodiments, dunalizumab is administered in a dose of 1200 mg. In some embodiments, dunalizumab is administered intravenously. In some embodiments, dunalizumab is administered on day 1 of a 21-day cycle. In some embodiments of the methods provided herein, an anti-CD47 antibody is not co-administered to the subject or human patient. In some embodiments, the anti-CD47 antibody is selected from mololimab, leszolimab, leterlimab, lefalimab, 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 anti-CD47 antibody is magrolimab. In some embodiments of the methods provided herein, an MCL1 inhibitor is not co-administered to the subject or human patient. In some embodiments, the MCL1 inhibitor is selected from GS-9716, AMG-176, AMG-397, S-64315, AZD-5991, 483-LM, A-1210477, UMI-77, and JKY-5-037. In some embodiments, the MCL1 inhibitor is GS-9716. In some embodiments of the methods provided herein, a FLT3 agonist is not administered to a subject or human patient. In some embodiments, the FLT3 agonist is selected from GS-3583, CDX-301, TAK-605, ONCR-177, Alb-Ftl3L, and SYM-027. In some embodiments, the FLT3 agonist is GS-3583.

[0336] In some embodiments, provided herein are methods for treating a TROP-2-positive cancer, comprising co-administering to a subject an effective amount of: (a) a TROP-2-targeting antibody-drug conjugate (ADC) comprising an anti-TROP-2 antibody (anti-TROP-2 ADC); (b) an anti-PD-(L)1 antibody; and optionally, (c) dunalimab. In some embodiments, the anti-TROP-2 ADC comprises an anticancer agent payload. In some embodiments, the anticancer agent payload is selected from a microtubule inhibitor, a DNA cleavage agent, and a topoisomerase I inhibitor. In some embodiments, the anti-TROP-2 ADC comprises a topoisomerase I inhibitor. In some embodiments, the topoisomerase I inhibitor is selected from irinotecan, topotecan, and SN-38. In some embodiments, the anti-TROP-2 ADC has the structural formula mAb-CL2A-SN-38, which is represented by the following formula:

[0337]

[0338] (described, e.g., in U.S. Patent No. 7,999,083). In some embodiments, the anti-TROP-2 ADC comprises sacilotuzumab (hRS7; described, e.g., in WO2003074566). Figure 3 and Figure 4In some embodiments, the anti-TROP-2 ADC is selected from gosatuzumab, dedabrafenib (DS-1062), ESG-401, SKB-264, DAC-02, and BAT-8003. In some embodiments, the anti-TROP-2 ADC is gosatuzumab. In some embodiments, the anti-TROP-2 ADC comprises a microtubule inhibitor. In some embodiments, the microtubule inhibitor is selected from auristatins, taxanes, vinca alkaloids, epothilones, and maytansines. In some embodiments, the auristatin is selected from monomethyl auristatin E (MMAE) and monomethyl auristatin F (MMAF). In some embodiments, the maytansine alkaloid is selected from maytansine (DM1) and raftansine (DM4). In some embodiments, the anticancer agent payload is selected from anthracyclines (e.g., doxorubicin, daunorubicin, epirubicin, idarubicin), pyrrolobenzodiazepine (PBD) or dimers thereof, DNA cross-linker SC-DR002 (D6.5), duocarmycin, duocarmycins (A, B1, B2, C1, C2, D, SA, CC-1065), tubulysin B, and analogs thereof. In some embodiments, the anti-PD-(L)1 antibody is pembrolizumab, nivolumab, cemiprilimab, pidilizumab, spartalizumab, atezolizumab, avelumab, durvalumab, cocilimab, sazanlimab, tislelizumab, rivalizumab, batilizumab, toripalimab, sitrilimab, genoluzumab, palolizumab, lodalizumab, camrelizumab, budigalimab, avelumab, dotalimumab, envolimab, sintilimab, or sepalizumab. In some embodiments, the anti-PD-(L)1 antibody is sepalizumab. In some embodiments, the anti-PD-(L)1 antibody is durvalumab. In some embodiments, the anti-PD-(L)1 antibody is an Fc-silent antibody. In some embodiments, the anti-PD-(L)1 antibody is an Fc-enabled antibody. In some embodiments, the method further comprises administering dunarizumab. In some embodiments, the method further comprises co-administering an additional therapeutic agent or treatment modality. In some embodiments, the additional therapeutic agent or treatment modality comprises one, two, three, or four additional therapeutic agents and / or treatment modalities. In some embodiments, the cancer is a solid epithelial cancer. In some embodiments, the solid epithelial cancer is selected from breast cancer (e.g., triple-negative breast cancer (TNBC), HR + / Her2 - Breast cancer or HR + / Her2 低In some embodiments, the bladder cancer is urothelial carcinoma (UC). In some embodiments, the bladder cancer is (i) unresectable locally advanced bladder cancer, (ii) metastatic bladder cancer, or (iii) muscle-invasive bladder cancer. In some embodiments, the urothelial carcinoma is (i) unresectable locally advanced bladder cancer, (ii) metastatic bladder cancer, or (iii) muscle-invasive bladder cancer. In some embodiments, the lung cancer is non-small cell lung cancer (NSCLC). In some embodiments, the lung cancer is (i) advanced lung cancer or (ii) metastatic lung cancer. In some embodiments, the lung cancer is (i) advanced NSCLC or (ii) metastatic NSCLC. In some embodiments, the NSCLC is squamous NSCLC. In some embodiments, the NSCLC is non-squamous NSCLC. In some embodiments, the metastatic NSCLC is metastatic squamous NSCLC. In some embodiments, the metastatic NSCLC is metastatic non-squamous NSCLC. In some embodiments, the NSCLC is NSCLC without EGFR, ALK, or other actionable genomic alterations. In some embodiments, the cancer is (i) unresectable locally advanced cancer, (ii) metastatic cancer, or (iii) muscle-invasive cancer. In some embodiments, the cancer is (i) advanced cancer, or (ii) metastatic cancer. In some embodiments, the cancer has progressed after at least one prior anticancer therapy. In some embodiments, the subject is treatment-naive. In some embodiments, the subject has not received treatment in the metastatic or unresectable locally advanced setting (e.g., the subject has not received treatment for mUC and unresectable locally advanced UC). In some embodiments, the subject has not received treatment in the metastatic or unresectable locally advanced setting (e.g., the subject has not received treatment for metastatic and advanced lung cancer and NSCLC). In some embodiments, the human patient is cisplatin-ineligible and has not received prior treatment in the setting of metastatic or unresectable locally advanced disease. In some embodiments, the untreated subject has not received prior anticancer therapy for (i) unresectable locally advanced cancer, (ii) metastatic cancer, or (iii) muscle-invasive cancer. In some embodiments, the untreated subject has not received prior anticancer therapy for (i) advanced cancer or (ii) metastatic cancer. In some embodiments, the subject has received one or more anticancer therapies prior to administration of the combination of ADC, anti-PD-(L)1 antibody, and optionally dunalimab. In some embodiments, the subject is not untreated.In some embodiments, the subject has received one or more prior anticancer therapies for (i) unresectable locally advanced cancer, (ii) metastatic cancer, or (iii) muscle-invasive cancer. In some embodiments, the subject has received one or more prior anticancer therapies for (i) advanced cancer or (ii) metastatic cancer. In some embodiments, the subject has received one or more prior anticancer therapies prior to administration of the combination of an ADC, an anti-PD-(L)1 antibody, and optionally, dunalimab. In some embodiments, the cancer is resistant to or refractory to one or more anticancer therapies. In some embodiments, the anticancer therapy is selected from surgery, radiation therapy, chemotherapy, and checkpoint inhibitor therapy. In some embodiments, the combination of an ADC, an anti-PD-(L)1 antibody, and optionally, dunalimab is administered in a neoadjuvant setting (e.g., in preparation for surgery or radiation therapy). In some embodiments, the combination of an ADC, an anti-PD-(L)1 antibody, and optionally, dunalimab is administered in an adjuvant setting (e.g., following primary treatment such as surgery or radiation therapy). In some embodiments, the combination of an ADC, an anti-PD-(L)1 antibody, and optionally dunalizumab is administered in a treatment setting (e.g., as primary therapy). In some embodiments, the combination of an ADC, an anti-PD-(L)1 antibody, and optionally dunalizumab is administered in a maintenance setting. In some embodiments, the subject receives one or more doses of an ADC. In some embodiments, the subject receives one or more doses of an anti-PD-(L)1 antibody. In some embodiments, the subject receives one or more doses of dunalizumab. In some embodiments, the ADC and anti-PD-(L)1 antibody are administered simultaneously. In some embodiments, the ADC and anti-PD-(L)1 antibody are administered sequentially. In some embodiments, the ADC and dunalizumab are administered simultaneously. In some embodiments, the ADC and dunalizumab are administered sequentially. In some embodiments, the anti-PD-(L)1 antibody and dunalizumab are administered simultaneously. In some embodiments, the anti-PD-(L)1 antibody and dunalizumab are administered sequentially. In some embodiments, the subject is human. In some embodiments, the subject does not meet criteria for cisplatin. In some embodiments, the ADC is administered in one or more doses ranging from 8 mg / kg to 10 mg / kg. In some embodiments, the ADC is administered in one or more doses of 8 mg / kg or 10 mg / kg. In some embodiments, the ADC is administered in one or more doses of 10 mg / kg. In some embodiments, the ADC is administered intravenously. In some embodiments, the ADC is administered on days 1 and 8 of a 21-day cycle. In some embodiments, the anti-PD-(L)1 antibody is administered in one or more doses ranging from 300 mg to 400 mg. In some embodiments, the anti-PD-(L)1 antibody is administered in a dose of 360 mg.In some embodiments, the anti-PD-(L)1 antibody is administered intravenously. In some embodiments, the anti-PD-(L)1 antibody is administered on day 1 of a 21-day cycle. In some embodiments, dunalizumab is administered in one or more doses ranging from 800 mg to 1600 mg. In some embodiments, dunalizumab is administered in a dose of 1200 mg. In some embodiments, dunalizumab is administered intravenously. In some embodiments, dunalizumab is administered on day 1 of a 21-day cycle. In some embodiments of the methods provided herein, an anti-CD47 antibody is not co-administered to the subject or human patient. In some embodiments, the anti-CD47 antibody is selected from mololimab, leszolimab, leterlimab, lefalimab, 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 anti-CD47 antibody is magrolimab. In some embodiments of the methods provided herein, an MCL1 inhibitor is not co-administered to the subject or human patient. In some embodiments, the MCL1 inhibitor is selected from GS-9716, AMG-176, AMG-397, S-64315, AZD-5991, 483-LM, A-1210477, UMI-77, and JKY-5-037. In some embodiments, the MCL1 inhibitor is GS-9716. In some embodiments of the methods provided herein, a FLT3 agonist is not administered to a subject or human patient. In some embodiments, the FLT3 agonist is selected from GS-3583, CDX-301, TAK-605, ONCR-177, Alb-Ftl3L, and SYM-027. In some embodiments, the FLT3 agonist is GS-3583.

[0339] In some embodiments, provided herein are methods for treating, alleviating, reducing, preventing, or delaying the recurrence or metastasis of urothelial carcinoma, comprising co-administering to a subject an effective amount of: (a) a TROP-2 targeting antibody-drug conjugate (ADC) comprising an anti-TROP-2 antibody (anti-TROP-2 ADC); (b) sepalizumab; and optionally, (c) an anti-TIGIT antibody. In some embodiments, the anti-TROP-2 ADC comprises an anticancer agent payload. In some embodiments, the anticancer agent payload is selected from a microtubule inhibitor, a DNA cleavage agent, and a topoisomerase I inhibitor. In some embodiments, the anti-TROP-2 ADC comprises a topoisomerase I inhibitor. In some embodiments, the topoisomerase I inhibitor is selected from irinotecan, topotecan, and SN-38. In some embodiments, the anti-TROP-2 ADC has the structural formula mAb-CL2A-SN-38, the structure of which is represented by the following formula:

[0340]

[0341] (described, e.g., in U.S. Patent No. 7,999,083). In some embodiments, the anti-TROP-2 ADC comprises sacilotuzumab (hRS7; described, e.g., in WO2003074566). Figure 3 and Figure 4In some embodiments, the anti-TROP-2 ADC is selected from gosatuzumab, dedabrafenib (DS-1062), ESG-401, SKB-264, DAC-02, and BAT-8003. In some embodiments, the anti-TROP-2 ADC is gosatuzumab. In some embodiments, the anti-TROP-2 ADC comprises a microtubule inhibitor. In some embodiments, the microtubule inhibitor is selected from auristatins, taxanes, vinca alkaloids, epothilones, and maytansines. In some embodiments, the auristatin is selected from monomethyl auristatin E (MMAE) and monomethyl auristatin F (MMAF). In some embodiments, the maytansine alkaloid is selected from maytansine (DM1) and raftansine (DM4). In some embodiments, the anticancer agent payload is selected from an anthracycline (e.g., doxorubicin, daunorubicin, epirubicin, idarubicin), pyrrolobenzodiazepine (PBD) or a dimer thereof, DNA cross-linker SC-DR002 (D6.5), duocarmycin, duocarmycins (A, B1, B2, C1, C2, D, SA, CC-1065), tubulysin B, and analogs thereof. In some embodiments, the method further comprises administering an anti-TIGIT antibody. In some embodiments, the anti-TIGIT antibody is AB308, AGEN-1307 (AGEN-1327), AGEN-1777, AK127, BMS-986207, dunalimab, EOS-448, eitinib, JS006, M6223, osperlimab, rapasumab, SEA-TGT (SGN-TGT), tisleliumab, or vembrin. In some embodiments, the anti-TIGIT antibody is dunalimab. In some embodiments, the anti-TIGIT antibody is M6223. In some embodiments, the method further comprises co-administering an additional therapeutic agent or treatment modality. In some embodiments, the additional therapeutic agent or treatment modality includes one, two, three, or four additional therapeutic agents and / or treatment modalities. In some embodiments, the cancer is (i) unresectable locally advanced cancer, (ii) metastatic cancer, or (iii) muscle-invasive cancer. In some embodiments, the cancer has progressed after at least one prior anticancer therapy. In some embodiments, the subject is treatment naive. In some embodiments, the subject is treatment naive in the metastatic or unresectable locally advanced setting (e.g., the subject has not received treatment for mUC and unresectable locally advanced UC). In some embodiments, the human patient is cisplatin ineligible and has not received treatment in the metastatic or unresectable locally advanced setting. In some embodiments, the treatment naive subject has not received prior anticancer therapy for (i) unresectable locally advanced cancer, (ii) metastatic cancer, or (iii) muscle invasive cancer.In some embodiments, the subject has received one or more anti-cancer therapies prior to administration of the combination of ADC, sepalimumab, and optionally an anti-TIGIT antibody. In some embodiments, the subject is not treatment naive. In some embodiments, the subject has received one or more previous anti-cancer therapies for (i) unresectable locally advanced cancer, (ii) metastatic cancer, or (iii) muscle-invasive cancer. In some embodiments, the subject has received one or more anti-cancer therapies prior to administration of the combination of ADC, sepalimumab, and optionally an anti-TIGIT antibody. In some embodiments, the cancer is resistant to or refractory to one or more anti-cancer therapies. In some embodiments, the anti-cancer therapy is selected from surgery, radiotherapy, chemotherapy, and checkpoint inhibitor therapy. In some embodiments, the combination of ADC, sepalimumab, and optionally an anti-TIGIT antibody is administered in a neoadjuvant setting (e.g., in preparation for surgery or radiotherapy). In some embodiments, the combination of ADC, sepalimumab, and optionally an anti-TIGIT antibody is administered in an adjuvant setting (e.g., after primary treatment such as surgery or radiotherapy). In some embodiments, the combination of ADC, sepalimumab, and optionally an anti-TIGIT antibody is administered in a therapeutic setting (e.g., as a primary therapy). In some embodiments, the combination of ADC, sepalimumab, and optionally an anti-TIGIT antibody is administered in a maintenance setting. In some embodiments, the subject receives one or more doses of the ADC. In some embodiments, the subject receives one or more doses of sepalimumab. In some embodiments, the subject receives one or more doses of the anti-TIGIT antibody. In some embodiments, the ADC and sepalimumab are administered simultaneously. In some embodiments, the ADC and sepalimumab are administered sequentially. In some embodiments, the ADC and anti-TIGIT antibody are administered simultaneously. In some embodiments, the ADC and anti-TIGIT antibody are administered sequentially. In some embodiments, sepalimumab and anti-TIGIT antibody are administered simultaneously. In some embodiments, sepalimumab and anti-TIGIT antibody are administered sequentially. In some embodiments, the subject is human. In some embodiments, the subject does not meet criteria for cisplatin. In some embodiments, the ADC is administered in one or more doses ranging from 8 mg / kg to 10 mg / kg. In some embodiments, the ADC is administered at one or more doses of 8 mg / kg or 10 mg / kg. In some embodiments, the ADC is administered at one or more doses of 10 mg / kg. In some embodiments, the ADC is administered intravenously. In some embodiments, the ADC is administered on days 1 and 8 of a 21-day cycle. In some embodiments, sepalizumab is administered at one or more doses ranging from 300 mg to 400 mg. In some embodiments, sepalizumab is administered at a dose of 360 mg.In some embodiments, sepalizumab is administered intravenously. In some embodiments, sepalizumab is administered on day 1 of a 21-day cycle. In some embodiments, the anti-TIGIT antibody is administered in one or more doses ranging from 800 mg to 1600 mg. In some embodiments, the anti-TIGIT antibody is administered in a dose of 1200 mg. In some embodiments, the anti-TIGIT antibody is administered intravenously. In some embodiments, the anti-TIGIT antibody is administered on day 1 of a 21-day cycle. In some embodiments of the methods provided herein, an anti-CD47 antibody is not co-administered to the subject or human patient. In some embodiments, the anti-CD47 antibody is selected from mololimab, leszolimab, leterlimab, lefalimab, 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 anti-CD47 antibody is magrolimab. In some embodiments of the methods provided herein, an MCL1 inhibitor is not co-administered to a subject or human patient. In some embodiments, the MCL1 inhibitor is selected from GS-9716, AMG-176, AMG-397, S-64315, AZD-5991, 483-LM, A-1210477, UMI-77, and JKY-5-037. In some embodiments, the MCL1 inhibitor is GS-9716. In some embodiments of the methods provided herein, a FLT3 agonist is not administered to a subject or human patient. In some embodiments, the FLT3 agonist is selected from GS-3583, CDX-301, TAK-605, ONCR-177, Alb-Ftl3L, and SYM-027. In some embodiments, the FLT3 agonist is GS-3583.

[0342] In some embodiments, provided herein are methods for treating urothelial carcinoma comprising co-administering to a subject an effective amount of: (a) a TROP-2 targeting antibody-drug conjugate (ADC) comprising an anti-TROP-2 antibody (anti-TROP-2 ADC); (b) sepalizumab; and optionally, (c) an anti-TIGIT antibody. In some embodiments, the anti-TROP-2 ADC comprises an anticancer agent payload. In some embodiments, the anticancer agent payload is selected from a microtubule inhibitor, a DNA cleavage agent, and a topoisomerase I inhibitor. In some embodiments, the anti-TROP-2 ADC comprises a topoisomerase I inhibitor. In some embodiments, the topoisomerase I inhibitor is selected from irinotecan, topotecan, and SN-38. In some embodiments, the anti-TROP-2 ADC has the structural formula mAb-CL2A-SN-38, the structure of which is represented by the following formula:

[0343]

[0344] (described, e.g., in U.S. Patent No. 7,999,083). In some embodiments, the anti-TROP-2 ADC comprises sacilotuzumab (hRS7; described, e.g., in WO2003074566). Figure 3 and Figure 4In some embodiments, the anti-TROP-2 ADC is selected from gosatuzumab, dedabrafenib (DS-1062), ESG-401, SKB-264, DAC-02, and BAT-8003. In some embodiments, the anti-TROP-2 ADC is gosatuzumab. In some embodiments, the anti-TROP-2 ADC comprises a microtubule inhibitor. In some embodiments, the microtubule inhibitor is selected from auristatins, taxanes, vinca alkaloids, epothilones, and maytansines. In some embodiments, the auristatin is selected from monomethyl auristatin E (MMAE) and monomethyl auristatin F (MMAF). In some embodiments, the maytansine alkaloid is selected from maytansine (DM1) and raftansine (DM4). In some embodiments, the anticancer agent payload is selected from an anthracycline (e.g., doxorubicin, daunorubicin, epirubicin, idarubicin), pyrrolobenzodiazepine (PBD) or a dimer thereof, DNA cross-linker SC-DR002 (D6.5), duocarmycin, duocarmycins (A, B1, B2, C1, C2, D, SA, CC-1065), tubulysin B, and analogs thereof. In some embodiments, the method further comprises administering an anti-TIGIT antibody. In some embodiments, the anti-TIGIT antibody is AB308, AGEN-1307 (AGEN-1327), AGEN-1777, AK127, BMS-986207, dunalimab, EOS-448, eitinib, JS006, M6223, osperlimab, rapasumab, SEA-TGT (SGN-TGT), tisleliumab, or vembrin. In some embodiments, the anti-TIGIT antibody is dunalimab. In some embodiments, the anti-TIGIT antibody is M6223. In some embodiments, the method further comprises co-administering an additional therapeutic agent or treatment modality. In some embodiments, the additional therapeutic agent or treatment modality includes one, two, three, or four additional therapeutic agents and / or treatment modalities. In some embodiments, the cancer is (i) unresectable locally advanced cancer, (ii) metastatic cancer, or (iii) muscle-invasive cancer. In some embodiments, the cancer has progressed after at least one prior anticancer therapy. In some embodiments, the subject is treatment naive. In some embodiments, the subject is treatment naive in the metastatic or unresectable locally advanced setting (e.g., the subject has not received treatment for mUC and unresectable locally advanced UC). In some embodiments, the human patient is cisplatin ineligible and has not received treatment in the metastatic or unresectable locally advanced setting. In some embodiments, the treatment naive subject has not received prior anticancer therapy for (i) unresectable locally advanced cancer, (ii) metastatic cancer, or (iii) muscle invasive cancer.In some embodiments, the subject has received one or more anti-cancer therapies prior to administration of the combination of ADC, sepalimumab, and optionally an anti-TIGIT antibody. In some embodiments, the subject is not treatment naive. In some embodiments, the subject has received one or more previous anti-cancer therapies for (i) unresectable locally advanced cancer, (ii) metastatic cancer, or (iii) muscle-invasive cancer. In some embodiments, the subject has received one or more anti-cancer therapies prior to administration of the combination of ADC, sepalimumab, and optionally an anti-TIGIT antibody. In some embodiments, the cancer is resistant to or refractory to one or more anti-cancer therapies. In some embodiments, the anti-cancer therapy is selected from surgery, radiotherapy, chemotherapy, and checkpoint inhibitor therapy. In some embodiments, the combination of ADC, sepalimumab, and optionally an anti-TIGIT antibody is administered in a neoadjuvant setting (e.g., in preparation for surgery or radiotherapy). In some embodiments, the combination of ADC, sepalimumab, and optionally an anti-TIGIT antibody is administered in an adjuvant setting (e.g., after primary treatment such as surgery or radiotherapy). In some embodiments, the combination of ADC, sepalimumab, and optionally an anti-TIGIT antibody is administered in a therapeutic setting (e.g., as a primary therapy). In some embodiments, the combination of ADC, sepalimumab, and optionally an anti-TIGIT antibody is administered in a maintenance setting. In some embodiments, the subject receives one or more doses of the ADC. In some embodiments, the subject receives one or more doses of sepalimumab. In some embodiments, the subject receives one or more doses of the anti-TIGIT antibody. In some embodiments, the ADC and sepalimumab are administered simultaneously. In some embodiments, the ADC and sepalimumab are administered sequentially. In some embodiments, the ADC and anti-TIGIT antibody are administered simultaneously. In some embodiments, the ADC and anti-TIGIT antibody are administered sequentially. In some embodiments, sepalimumab and anti-TIGIT antibody are administered simultaneously. In some embodiments, sepalimumab and anti-TIGIT antibody are administered sequentially. In some embodiments, the subject is human. In some embodiments, the subject does not meet criteria for cisplatin. In some embodiments, the ADC is administered in one or more doses ranging from 8 mg / kg to 10 mg / kg. In some embodiments, the ADC is administered at one or more doses of 8 mg / kg or 10 mg / kg. In some embodiments, the ADC is administered at one or more doses of 10 mg / kg. In some embodiments, the ADC is administered intravenously. In some embodiments, the ADC is administered on days 1 and 8 of a 21-day cycle. In some embodiments, sepalizumab is administered at one or more doses ranging from 300 mg to 400 mg. In some embodiments, sepalizumab is administered at a dose of 360 mg.In some embodiments, sepalizumab is administered intravenously. In some embodiments, sepalizumab is administered on day 1 of a 21-day cycle. In some embodiments, the anti-TIGIT antibody is administered in one or more doses ranging from 800 mg to 1600 mg. In some embodiments, the anti-TIGIT antibody is administered in a dose of 1200 mg. In some embodiments, the anti-TIGIT antibody is administered intravenously. In some embodiments, the anti-TIGIT antibody is administered on day 1 of a 21-day cycle. In some embodiments of the methods provided herein, an anti-CD47 antibody is not co-administered to the subject or human patient. In some embodiments, the anti-CD47 antibody is selected from mololimab, leszolimab, leterlimab, lefalimab, 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 anti-CD47 antibody is magrolimab. In some embodiments of the methods provided herein, an MCL1 inhibitor is not co-administered to a subject or human patient. In some embodiments, the MCL1 inhibitor is selected from GS-9716, AMG-176, AMG-397, S-64315, AZD-5991, 483-LM, A-1210477, UMI-77, and JKY-5-037. In some embodiments, the MCL1 inhibitor is GS-9716. In some embodiments of the methods provided herein, a FLT3 agonist is not administered to a subject or human patient. In some embodiments, the FLT3 agonist is selected from GS-3583, CDX-301, TAK-605, ONCR-177, Alb-Ftl3L, and SYM-027. In some embodiments, the FLT3 agonist is GS-3583.

[0345] In some embodiments, provided herein are methods for treating, alleviating, reducing, preventing, or delaying recurrence or metastasis of urothelial carcinoma, comprising co-administering to a subject an effective amount of: (a) a TROP-2-targeting antibody-drug conjugate (ADC) comprising an anti-TROP-2 antibody (anti-TROP-2 ADC); (b) sepalizumab; and optionally, (c) dunalimumab. In some embodiments, the anti-TROP-2 ADC comprises an anticancer agent payload. In some embodiments, the anticancer agent payload is selected from a microtubule inhibitor, a DNA cleavage agent, and a topoisomerase I inhibitor. In some embodiments, the anti-TROP-2 ADC comprises a topoisomerase I inhibitor. In some embodiments, the topoisomerase I inhibitor is selected from irinotecan, topotecan, and SN-38. In some embodiments, the anti-TROP-2 ADC has the structural formula mAb-CL2A-SN-38, which is represented by the following formula:

[0346]

[0347] (described, e.g., in U.S. Patent No. 7,999,083). In some embodiments, the anti-TROP-2 ADC comprises sacilotuzumab (hRS7; described, e.g., in WO2003074566). Figure 3 and Figure 4In some embodiments, the anti-TROP-2 ADC is selected from gosatuzumab, dedabrafenib (DS-1062), ESG-401, SKB-264, DAC-02, and BAT-8003. In some embodiments, the anti-TROP-2 ADC is gosatuzumab. In some embodiments, the anti-TROP-2 ADC comprises a microtubule inhibitor. In some embodiments, the microtubule inhibitor is selected from auristatins, taxanes, vinca alkaloids, epothilones, and maytansines. In some embodiments, the auristatin is selected from monomethyl auristatin E (MMAE) and monomethyl auristatin F (MMAF). In some embodiments, the maytansine alkaloid is selected from maytansine (DM1) and raftansine (DM4). In some embodiments, the anticancer agent payload is selected from an anthracycline (e.g., doxorubicin, daunorubicin, epirubicin, idarubicin), a pyrrolobenzodiazepine (PBD) or a dimer thereof, the DNA crosslinker SC-DR002 (D6.5), a duocarmycin, a duocarmycin (A, B1, B2, C1, C2, D, SA, CC-1065), tubulysin B, and analogs thereof. In some embodiments, the method further comprises administering dunalimab. In some embodiments, the method further comprises co-administering an additional therapeutic agent or treatment modality. In some embodiments, the additional therapeutic agent or treatment modality comprises one, two, three, or four additional therapeutic agents and / or treatment modalities. In some embodiments, the cancer is (i) unresectable locally advanced cancer, (ii) metastatic cancer, or (iii) muscle-invasive cancer. In some embodiments, the cancer has progressed after at least one prior anticancer therapy. In some embodiments, the subject is treatment-naive. In some embodiments, the subject is treatment-naive in the metastatic or unresectable locally advanced setting (e.g., the subject has not received treatment for mUC and unresectable locally advanced UC). In some embodiments, the human patient is cisplatin-ineligible and has not received treatment in the metastatic or unresectable locally advanced setting. In some embodiments, the treatment-naive subject has not received prior anticancer therapy for (i) unresectable locally advanced cancer, (ii) metastatic cancer, or (iii) muscle-invasive cancer. In some embodiments, the subject has received one or more anticancer therapies prior to administration of the combination of ADC, sepalimumab, and optionally, dunalizumab. In some embodiments, the subject is not treatment-naive. In some embodiments, the subject has received one or more prior anticancer therapies for (i) unresectable locally advanced cancer, (ii) metastatic cancer, or (iii) muscle-invasive cancer. In some embodiments, the subject has received one or more anticancer therapies prior to administration of the combination of ADC, sepalimumab, and optionally, dunalizumab.In some embodiments, the cancer is resistant or refractory to one or more anticancer therapies. In some embodiments, the anticancer therapy is selected from surgery, radiation therapy, chemotherapy, and checkpoint inhibitor therapy. In some embodiments, the combination of an ADC, sepalizumab, and optionally dunalizumab is administered in a neoadjuvant setting (e.g., in preparation for surgery or radiation therapy). In some embodiments, the combination of an ADC, sepalizumab, and optionally dunalizumab is administered in an adjuvant setting (e.g., after primary treatment such as surgery or radiation therapy). In some embodiments, the combination of an ADC, sepalizumab, and optionally dunalizumab is administered in a treatment setting (e.g., as primary therapy). In some embodiments, the combination of an ADC, sepalizumab, and optionally dunalizumab is administered in a maintenance setting. In some embodiments, the subject receives one or more doses of an ADC. In some embodiments, the subject receives one or more doses of sepalizumab. In some embodiments, the subject receives one or more doses of dunalizumab. In some embodiments, the ADC and sepalizumab are administered simultaneously. In some embodiments, the ADC and sepalimab are administered sequentially. In some embodiments, the ADC and dunalizumab are administered simultaneously. In some embodiments, the ADC and dunalizumab are administered sequentially. In some embodiments, sepalimab and dunalizumab are administered simultaneously. In some embodiments, sepalimab and dunalizumab are administered sequentially. In some embodiments, the subject is human. In some embodiments, the subject does not meet the criteria for cisplatin. In some embodiments, the ADC is administered in one or more doses ranging from 8 mg / kg to 10 mg / kg. In some embodiments, the ADC is administered in one or more doses of 8 mg / kg or 10 mg / kg. In some embodiments, the ADC is administered in one or more doses of 10 mg / kg. In some embodiments, the ADC is administered intravenously. In some embodiments, the ADC is administered on days 1 and 8 of a 21-day cycle. In some embodiments, sepalimab is administered in one or more doses ranging from 300 mg to 400 mg. In some embodiments, sepalimab is administered in a dose of 360 mg. In some embodiments, sepalizumab is administered intravenously. In some embodiments, sepalizumab is administered on day 1 of a 21-day cycle. In some embodiments, dunalizumab is administered in one or more doses ranging from 800 mg to 1600 mg. In some embodiments, dunalizumab is administered in a dose of 1200 mg. In some embodiments, dunalizumab is administered intravenously. In some embodiments, dunalizumab is administered on day 1 of a 21-day cycle. In some embodiments of the methods provided herein, an anti-CD47 antibody is not co-administered to the subject or human patient.In some embodiments, the anti-CD47 antibody is selected from mololimab, leszolimab, leterlimab, lefalimab, 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 anti-CD47 antibody is magrolimab. In some embodiments of the methods provided herein, an MCL1 inhibitor is not co-administered to the subject or human patient. In some embodiments, the MCL1 inhibitor is selected from GS-9716, AMG-176, AMG-397, S-64315, AZD-5991, 483-LM, A-1210477, UMI-77, and JKY-5-037. In some embodiments, the MCL1 inhibitor is GS-9716. In some embodiments of the methods provided herein, a FLT3 agonist is not administered to a subject or human patient. In some embodiments, the FLT3 agonist is selected from GS-3583, CDX-301, TAK-605, ONCR-177, Alb-Ftl3L, and SYM-027. In some embodiments, the FLT3 agonist is GS-3583.

[0348] In some embodiments, provided herein are methods for treating urothelial carcinoma comprising co-administering to a subject an effective amount of: (a) a TROP-2 targeting antibody-drug conjugate (ADC) comprising an anti-TROP-2 antibody (anti-TROP-2 ADC); (b) sepalizumab; and optionally, (c) dunalimab. In some embodiments, the anti-TROP-2 ADC comprises an anticancer agent payload. In some embodiments, the anticancer agent payload is selected from a microtubule inhibitor, a DNA cleavage agent, and a topoisomerase I inhibitor. In some embodiments, the anti-TROP-2 ADC comprises a topoisomerase I inhibitor. In some embodiments, the topoisomerase I inhibitor is selected from irinotecan, topotecan, and SN-38. In some embodiments, the anti-TROP-2 ADC has the structural formula mAb-CL2A-SN-38, the structure of which is represented by the following formula:

[0349]

[0350] (described, e.g., in U.S. Patent No. 7,999,083). In some embodiments, the anti-TROP-2 ADC comprises sacilotuzumab (hRS7; described, e.g., in WO2003074566). Figure 3 and Figure 4In some embodiments, the anti-TROP-2 ADC is selected from gosatuzumab, dedabrafenib (DS-1062), ESG-401, SKB-264, DAC-02, and BAT-8003. In some embodiments, the anti-TROP-2 ADC is gosatuzumab. In some embodiments, the anti-TROP-2 ADC comprises a microtubule inhibitor. In some embodiments, the microtubule inhibitor is selected from auristatins, taxanes, vinca alkaloids, epothilones, and maytansines. In some embodiments, the auristatin is selected from monomethyl auristatin E (MMAE) and monomethyl auristatin F (MMAF). In some embodiments, the maytansine alkaloid is selected from maytansine (DM1) and raftansine (DM4). In some embodiments, the anticancer agent payload is selected from an anthracycline (e.g., doxorubicin, daunorubicin, epirubicin, idarubicin), a pyrrolobenzodiazepine (PBD) or a dimer thereof, the DNA crosslinker SC-DR002 (D6.5), a duocarmycin, a duocarmycin (A, B1, B2, C1, C2, D, SA, CC-1065), tubulysin B, and analogs thereof. In some embodiments, the method further comprises administering dunalimab. In some embodiments, the method further comprises co-administering an additional therapeutic agent or treatment modality. In some embodiments, the additional therapeutic agent or treatment modality comprises one, two, three, or four additional therapeutic agents and / or treatment modalities. In some embodiments, the cancer is (i) unresectable locally advanced cancer, (ii) metastatic cancer, or (iii) muscle-invasive cancer. In some embodiments, the cancer has progressed after at least one prior anticancer therapy. In some embodiments, the subject is treatment-naive. In some embodiments, the subject is treatment-naive in the metastatic or unresectable locally advanced setting (e.g., the subject has not received treatment for mUC and unresectable locally advanced UC). In some embodiments, the human patient is cisplatin-ineligible and has not received treatment in the metastatic or unresectable locally advanced setting. In some embodiments, the treatment-naive subject has not received prior anticancer therapy for (i) unresectable locally advanced cancer, (ii) metastatic cancer, or (iii) muscle-invasive cancer. In some embodiments, the subject has received one or more anticancer therapies prior to administration of the combination of ADC, sepalimumab, and optionally, dunalizumab. In some embodiments, the subject is not treatment-naive. In some embodiments, the subject has received one or more prior anticancer therapies for (i) unresectable locally advanced cancer, (ii) metastatic cancer, or (iii) muscle-invasive cancer. In some embodiments, the subject has received one or more anticancer therapies prior to administration of the combination of ADC, sepalimumab, and optionally, dunalizumab.In some embodiments, the cancer is resistant or refractory to one or more anticancer therapies. In some embodiments, the anticancer therapy is selected from surgery, radiation therapy, chemotherapy, and checkpoint inhibitor therapy. In some embodiments, the combination of an ADC, sepalizumab, and optionally dunalizumab is administered in a neoadjuvant setting (e.g., in preparation for surgery or radiation therapy). In some embodiments, the combination of an ADC, sepalizumab, and optionally dunalizumab is administered in an adjuvant setting (e.g., after primary treatment such as surgery or radiation therapy). In some embodiments, the combination of an ADC, sepalizumab, and optionally dunalizumab is administered in a treatment setting (e.g., as primary therapy). In some embodiments, the combination of an ADC, sepalizumab, and optionally dunalizumab is administered in a maintenance setting. In some embodiments, the subject receives one or more doses of an ADC. In some embodiments, the subject receives one or more doses of sepalizumab. In some embodiments, the subject receives one or more doses of dunalizumab. In some embodiments, the ADC and sepalizumab are administered simultaneously. In some embodiments, the ADC and sepalimab are administered sequentially. In some embodiments, the ADC and dunalizumab are administered simultaneously. In some embodiments, the ADC and dunalizumab are administered sequentially. In some embodiments, sepalimab and dunalizumab are administered simultaneously. In some embodiments, sepalimab and dunalizumab are administered sequentially. In some embodiments, the subject is human. In some embodiments, the subject does not meet the criteria for cisplatin. In some embodiments, the ADC is administered in one or more doses ranging from 8 mg / kg to 10 mg / kg. In some embodiments, the ADC is administered in one or more doses of 8 mg / kg or 10 mg / kg. In some embodiments, the ADC is administered in one or more doses of 10 mg / kg. In some embodiments, the ADC is administered intravenously. In some embodiments, the ADC is administered on days 1 and 8 of a 21-day cycle. In some embodiments, sepalimab is administered in one or more doses ranging from 300 mg to 400 mg. In some embodiments, sepalimab is administered in a dose of 360 mg. In some embodiments, sepalizumab is administered intravenously. In some embodiments, sepalizumab is administered on day 1 of a 21-day cycle. In some embodiments, dunalizumab is administered in one or more doses ranging from 800 mg to 1600 mg. In some embodiments, dunalizumab is administered in a dose of 1200 mg. In some embodiments, dunalizumab is administered intravenously. In some embodiments, dunalizumab is administered on day 1 of a 21-day cycle. In some embodiments of the methods provided herein, an anti-CD47 antibody is not co-administered to the subject or human patient.In some embodiments, the anti-CD47 antibody is selected from mololimab, leszolimab, leterlimab, lefalimab, 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 anti-CD47 antibody is magrolimab. In some embodiments of the methods provided herein, an MCL1 inhibitor is not co-administered to the subject or human patient. In some embodiments, the MCL1 inhibitor is selected from GS-9716, AMG-176, AMG-397, S-64315, AZD-5991, 483-LM, A-1210477, UMI-77, and JKY-5-037. In some embodiments, the MCL1 inhibitor is GS-9716. In some embodiments of the methods provided herein, a FLT3 agonist is not administered to a subject or human patient. In some embodiments, the FLT3 agonist is selected from GS-3583, CDX-301, TAK-605, ONCR-177, Alb-Ftl3L, and SYM-027. In some embodiments, the FLT3 agonist is GS-3583.

[0351] In some embodiments, provided herein are methods for treating, alleviating, reducing, preventing, or delaying recurrence or metastasis of urothelial carcinoma, comprising co-administering to a subject an effective amount of: (a) a TROP-2-targeting antibody-drug conjugate (ADC) comprising an anti-TROP-2 antibody (anti-TROP-2 ADC); (b) an anti-PD-(L)1 antibody; and optionally, (c) dunalimab. In some embodiments, the anti-TROP-2 ADC comprises an anticancer agent payload. In some embodiments, the anticancer agent payload is selected from a microtubule inhibitor, a DNA cleavage agent, and a topoisomerase I inhibitor. In some embodiments, the anti-TROP-2 ADC comprises a topoisomerase I inhibitor. In some embodiments, the topoisomerase I inhibitor is selected from irinotecan, topotecan, and SN-38. In some embodiments, the anti-TROP-2 ADC has the structural formula mAb-CL2A-SN-38, which is represented by the following formula:

[0352]

[0353] (described, e.g., in U.S. Patent No. 7,999,083). In some embodiments, the anti-TROP-2 ADC comprises sacilotuzumab (hRS7; described, e.g., in WO2003074566). Figure 3 and Figure 4In some embodiments, the anti-TROP-2 ADC is selected from gosatuzumab, dedabrafenib (DS-1062), ESG-401, SKB-264, DAC-02, and BAT-8003. In some embodiments, the anti-TROP-2 ADC is gosatuzumab. In some embodiments, the anti-TROP-2 ADC comprises a microtubule inhibitor. In some embodiments, the microtubule inhibitor is selected from auristatins, taxanes, vinca alkaloids, epothilones, and maytansines. In some embodiments, the auristatin is selected from monomethyl auristatin E (MMAE) and monomethyl auristatin F (MMAF). In some embodiments, the maytansine alkaloid is selected from maytansine (DM1) and raftansine (DM4). In some embodiments, the anticancer agent payload is selected from anthracyclines (e.g., doxorubicin, daunorubicin, epirubicin, idarubicin), pyrrolobenzodiazepine (PBD) or dimers thereof, DNA cross-linker SC-DR002 (D6.5), duocarmycin, duocarmycins (A, B1, B2, C1, C2, D, SA, CC-1065), tubulysin B, and analogs thereof. In some embodiments, the anti-PD-(L)1 antibody is pembrolizumab, nivolumab, cemiprilimab, pidilizumab, spartalizumab, atezolizumab, avelumab, durvalumab, cocilimab, sazanlimab, tislelizumab, rivalizumab, batilizumab, toripalimab, sitrilimab, genoluzumab, palolizumab, lodalizumab, camrelizumab, budigalimab, avelumab, dotalimumab, envolimab, sintilimab, or sepalizumab. In some embodiments, the anti-PD-(L)1 antibody is sepalizumab. In some embodiments, the anti-PD-(L)1 antibody is durvalumab. In some embodiments, the anti-PD-(L)1 antibody is an Fc-silent antibody. In some embodiments, the anti-PD-(L)1 antibody is an Fc-enabled antibody. In some embodiments, the method further comprises administering dunarizumab. In some embodiments, the method further comprises co-administering an additional therapeutic agent or treatment modality. In some embodiments, the additional therapeutic agent or treatment modality comprises one, two, three, or four additional therapeutic agents and / or treatment modalities. In some embodiments, the cancer is (i) unresectable locally advanced cancer, (ii) metastatic cancer, or (iii) muscle-invasive cancer. In some embodiments, the cancer has progressed after at least one prior anticancer therapy. In some embodiments, the subject is treatment naive. In some embodiments, the subject has not received treatment in the metastatic or unresectable locally advanced setting (e.g., the subject has not received treatment for mUC and unresectable locally advanced UC).In some embodiments, in a metastatic or unresectable locally advanced setting, the human patient does not meet the cisplatin criteria and has not received treatment. In some embodiments, the untreated subject has not received previous anticancer therapy for (i) unresectable locally advanced cancer, (ii) metastatic cancer, or (iii) muscle-invasive cancer. In some embodiments, the subject has received one or more anticancer therapies before administering the combination of ADC, anti-PD-(L)1 antibody, and optionally dunalimab. In some embodiments, the subject is not untreated. In some embodiments, the subject has received one or more previous anticancer therapies for (i) unresectable locally advanced cancer, (ii) metastatic cancer, or (iii) muscle-invasive cancer. In some embodiments, the subject has received one or more anticancer therapies before administering the combination of ADC, anti-PD-(L)1 antibody, and optionally dunalimab. In some embodiments, the cancer is resistant to one or more anticancer therapies, or is refractory to one or more anticancer therapies. In some embodiments, the anticancer therapy is selected from surgery, radiotherapy, chemotherapy, and checkpoint inhibitor therapy. In some embodiments, the combination of an ADC, an anti-PD-(L)1 antibody, and optionally dunalizumab is administered in a neoadjuvant setting (e.g., in preparation for surgery or radiation therapy). In some embodiments, the combination of an ADC, an anti-PD-(L)1 antibody, and optionally dunalizumab is administered in an adjuvant setting (e.g., following primary treatment such as surgery or radiation therapy). In some embodiments, the combination of an ADC, an anti-PD-(L)1 antibody, and optionally dunalizumab is administered in a therapeutic setting (e.g., as primary therapy). In some embodiments, the combination of an ADC, an anti-PD-(L)1 antibody, and optionally dunalizumab is administered in a maintenance setting. In some embodiments, the subject receives one or more doses of the ADC. In some embodiments, the subject receives one or more doses of the anti-PD-(L)1 antibody. In some embodiments, the subject receives one or more doses of dunalizumab. In some embodiments, the ADC and anti-PD-(L)1 antibody are administered simultaneously. In some embodiments, the ADC and anti-PD-(L)1 antibody are administered sequentially. In some embodiments, the ADC and dunalizumab are administered simultaneously. In some embodiments, the ADC and dunalimab are administered sequentially. In some embodiments, the anti-PD-(L)1 antibody and dunalimab are administered simultaneously. In some embodiments, the anti-PD-(L)1 antibody and dunalimab are administered sequentially. In some embodiments, the subject is a human. In some embodiments, the subject does not meet the criteria for cisplatin. In some embodiments, the ADC is administered in one or more doses ranging from 8 mg / kg to 10 mg / kg. In some embodiments, the ADC is administered in one or more doses of 8 mg / kg or 10 mg / kg.In some embodiments, the ADC is administered at one or more doses of 10 mg / kg. In some embodiments, the ADC is administered intravenously. In some embodiments, the ADC is administered on days 1 and 8 of a 21-day cycle. In some embodiments, the anti-PD-(L)1 antibody is administered at one or more doses ranging from 300 mg to 400 mg. In some embodiments, the anti-PD-(L)1 antibody is administered at a dose of 360 mg. In some embodiments, the anti-PD-(L)1 antibody is administered intravenously. In some embodiments, the anti-PD-(L)1 antibody is administered on day 1 of a 21-day cycle. In some embodiments, dunalizumab is administered at one or more doses ranging from 800 mg to 1600 mg. In some embodiments, dunalizumab is administered at a dose of 1200 mg. In some embodiments, dunalizumab is administered intravenously. In some embodiments, dunalizumab is administered on day 1 of a 21-day cycle. In some embodiments of the methods provided herein, an anti-CD47 antibody is not co-administered to the subject or human patient. In some embodiments, the anti-CD47 antibody is selected from mololimab, leszolimab, leterlimab, lefalimab, 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 anti-CD47 antibody is magrolimab. In some embodiments of the methods provided herein, an MCL1 inhibitor is not co-administered to the subject or human patient. In some embodiments, the MCL1 inhibitor is selected from GS-9716, AMG-176, AMG-397, S-64315, AZD-5991, 483-LM, A-1210477, UMI-77, and JKY-5-037. In some embodiments, the MCL1 inhibitor is GS-9716. In some embodiments of the methods provided herein, a FLT3 agonist is not administered to a subject or human patient. In some embodiments, the FLT3 agonist is selected from GS-3583, CDX-301, TAK-605, ONCR-177, Alb-Ftl3L, and SYM-027. In some embodiments, the FLT3 agonist is GS-3583.

[0354] In some embodiments, provided herein are methods for treating urothelial carcinoma comprising co-administering to a subject an effective amount of: (a) a TROP-2-targeting antibody-drug conjugate (ADC) comprising an anti-TROP-2 antibody (anti-TROP-2 ADC); (b) an anti-PD-(L)1 antibody; and optionally, (c) dunalimab. In some embodiments, the anti-TROP-2 ADC comprises an anticancer agent payload. In some embodiments, the anticancer agent payload is selected from a microtubule inhibitor, a DNA cleavage agent, and a topoisomerase I inhibitor. In some embodiments, the anti-TROP-2 ADC comprises a topoisomerase I inhibitor. In some embodiments, the topoisomerase I inhibitor is selected from irinotecan, topotecan, and SN-38. In some embodiments, the anti-TROP-2 ADC has the structural formula mAb-CL2A-SN-38, which is represented by the following formula:

[0355]

[0356] (described, e.g., in U.S. Patent No. 7,999,083). In some embodiments, the anti-TROP-2 ADC comprises sacilotuzumab (hRS7; described, e.g., in WO2003074566). Figure 3 and Figure 4In some embodiments, the anti-TROP-2 ADC is selected from gosatuzumab, dedabrafenib (DS-1062), ESG-401, SKB-264, DAC-02, and BAT-8003. In some embodiments, the anti-TROP-2 ADC is gosatuzumab. In some embodiments, the anti-TROP-2 ADC comprises a microtubule inhibitor. In some embodiments, the microtubule inhibitor is selected from auristatins, taxanes, vinca alkaloids, epothilones, and maytansines. In some embodiments, the auristatin is selected from monomethyl auristatin E (MMAE) and monomethyl auristatin F (MMAF). In some embodiments, the maytansine alkaloid is selected from maytansine (DM1) and raftansine (DM4). In some embodiments, the anticancer agent payload is selected from anthracyclines (e.g., doxorubicin, daunorubicin, epirubicin, idarubicin), pyrrolobenzodiazepine (PBD) or dimers thereof, DNA cross-linker SC-DR002 (D6.5), duocarmycin, duocarmycins (A, B1, B2, C1, C2, D, SA, CC-1065), tubulysin B, and analogs thereof. In some embodiments, the anti-PD-(L)1 antibody is pembrolizumab, nivolumab, cemiprilimab, pidilizumab, spartalizumab, atezolizumab, avelumab, durvalumab, cocilimab, sazanlimab, tislelizumab, rivalizumab, batilizumab, toripalimab, sitrilimab, genoluzumab, palolizumab, lodalizumab, camrelizumab, budigalimab, avelumab, dotalimumab, envolimab, sintilimab, or sepalizumab. In some embodiments, the anti-PD-(L)1 antibody is sepalizumab. In some embodiments, the anti-PD-(L)1 antibody is durvalumab. In some embodiments, the anti-PD-(L)1 antibody is an Fc-silent antibody. In some embodiments, the anti-PD-(L)1 antibody is an Fc-enabled antibody. In some embodiments, the method further comprises administering dunarizumab. In some embodiments, the method further comprises co-administering an additional therapeutic agent or treatment modality. In some embodiments, the additional therapeutic agent or treatment modality comprises one, two, three, or four additional therapeutic agents and / or treatment modalities. In some embodiments, the cancer is (i) unresectable locally advanced cancer, (ii) metastatic cancer, or (iii) muscle-invasive cancer. In some embodiments, the cancer has progressed after at least one prior anticancer therapy. In some embodiments, the subject is treatment naive. In some embodiments, the subject has not received treatment in the metastatic or unresectable locally advanced setting (e.g., the subject has not received treatment for mUC and unresectable locally advanced UC).In some embodiments, in a metastatic or unresectable locally advanced setting, the human patient does not meet the cisplatin criteria and has not received treatment. In some embodiments, the untreated subject has not received previous anticancer therapy for (i) unresectable locally advanced cancer, (ii) metastatic cancer, or (iii) muscle-invasive cancer. In some embodiments, the subject has received one or more anticancer therapies before administering the combination of ADC, anti-PD-(L)1 antibody, and optionally dunalimab. In some embodiments, the subject is not untreated. In some embodiments, the subject has received one or more previous anticancer therapies for (i) unresectable locally advanced cancer, (ii) metastatic cancer, or (iii) muscle-invasive cancer. In some embodiments, the subject has received one or more anticancer therapies before administering the combination of ADC, anti-PD-(L)1 antibody, and optionally dunalimab. In some embodiments, the cancer is resistant to one or more anticancer therapies, or is refractory to one or more anticancer therapies. In some embodiments, the anticancer therapy is selected from surgery, radiotherapy, chemotherapy, and checkpoint inhibitor therapy. In some embodiments, the combination of an ADC, an anti-PD-(L)1 antibody, and optionally dunalizumab is administered in a neoadjuvant setting (e.g., in preparation for surgery or radiation therapy). In some embodiments, the combination of an ADC, an anti-PD-(L)1 antibody, and optionally dunalizumab is administered in an adjuvant setting (e.g., following primary treatment such as surgery or radiation therapy). In some embodiments, the combination of an ADC, an anti-PD-(L)1 antibody, and optionally dunalizumab is administered in a therapeutic setting (e.g., as primary therapy). In some embodiments, the combination of an ADC, an anti-PD-(L)1 antibody, and optionally dunalizumab is administered in a maintenance setting. In some embodiments, the subject receives one or more doses of the ADC. In some embodiments, the subject receives one or more doses of the anti-PD-(L)1 antibody. In some embodiments, the subject receives one or more doses of dunalizumab. In some embodiments, the ADC and anti-PD-(L)1 antibody are administered simultaneously. In some embodiments, the ADC and anti-PD-(L)1 antibody are administered sequentially. In some embodiments, the ADC and dunalizumab are administered simultaneously. In some embodiments, the ADC and dunalimab are administered sequentially. In some embodiments, the anti-PD-(L)1 antibody and dunalimab are administered simultaneously. In some embodiments, the anti-PD-(L)1 antibody and dunalimab are administered sequentially. In some embodiments, the subject is a human. In some embodiments, the subject does not meet the criteria for cisplatin. In some embodiments, the ADC is administered in one or more doses ranging from 8 mg / kg to 10 mg / kg. In some embodiments, the ADC is administered in one or more doses of 8 mg / kg or 10 mg / kg.In some embodiments, the ADC is administered at one or more doses of 10 mg / kg. In some embodiments, the ADC is administered intravenously. In some embodiments, the ADC is administered on days 1 and 8 of a 21-day cycle. In some embodiments, the anti-PD-(L)1 antibody is administered at one or more doses ranging from 300 mg to 400 mg. In some embodiments, the anti-PD-(L)1 antibody is administered at a dose of 360 mg. In some embodiments, the anti-PD-(L)1 antibody is administered intravenously. In some embodiments, the anti-PD-(L)1 antibody is administered on day 1 of a 21-day cycle. In some embodiments, dunalizumab is administered at one or more doses ranging from 800 mg to 1600 mg. In some embodiments, dunalizumab is administered at a dose of 1200 mg. In some embodiments, dunalizumab is administered intravenously. In some embodiments, dunalizumab is administered on day 1 of a 21-day cycle. In some embodiments of the methods provided herein, an anti-CD47 antibody is not co-administered to the subject or human patient. In some embodiments, the anti-CD47 antibody is selected from mololimab, leszolimab, leterlimab, lefalimab, 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 anti-CD47 antibody is magrolimab. In some embodiments of the methods provided herein, an MCL1 inhibitor is not co-administered to the subject or human patient. In some embodiments, the MCL1 inhibitor is selected from GS-9716, AMG-176, AMG-397, S-64315, AZD-5991, 483-LM, A-1210477, UMI-77, and JKY-5-037. In some embodiments, the MCL1 inhibitor is GS-9716. In some embodiments of the methods provided herein, a FLT3 agonist is not administered to a subject or human patient. In some embodiments, the FLT3 agonist is selected from GS-3583, CDX-301, TAK-605, ONCR-177, Alb-Ftl3L, and SYM-027. In some embodiments, the FLT3 agonist is GS-3583.

[0357] In some embodiments, provided herein are methods for treating, alleviating, reducing, preventing, or delaying tumor antigen positive (TA +) a method for treating recurrence or metastasis of cancer, comprising co-administering to a subject an effective amount of the following: a) a tumor antigen-targeting antibody-drug conjugate (ADC) comprising a topoisomerase I inhibitor (TopI ADC); b) an anti-PD-(L)1 antibody; and optionally, c) an anti-TIGIT antibody. In some embodiments, the topoisomerase I inhibitor is a camptothecin. In some embodiments, the camptothecin is selected from irinotecan, topotecan, belotecan, and an exatecan derivative. In some embodiments, the exatecan derivative is selected from Dxd or SN38. In some embodiments, the topoisomerase I inhibitor is selected from irinotecan, topotecan, and SN-38. In some embodiments, the TopI ADC has the structural formula mAb-CL2A-SN-38, which is represented by the following formula:

[0358]

[0359] (Described, e.g., in U.S. Patent No. 7,999,083). In some embodiments, the TopI ADC comprises an antibody that binds to a tumor antigen. In some embodiments, the tumor antigen is 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, insulin-like growth factor (ILGF), IFN-a, IFN-b, IL-g, IL-2R, IL-4R, IL-6R, IL-13R, IL-15R, IL-17R, IL-18R, IL-2, IL-6, IL-8, IL-12, IL-15, IL-17, IL-18, IL-25, IP-10, IGF-1R, Ia, HM1.24, gangliosides, HCG, HLA-DR, HLA-G, CD66a-d, MAGE, mCRP, MCP-1, MIP-1A, MIP-1B, macrophage migration inhibitory factor ( MIF), MUC1, MUC2, MUC3, MUC4, MUC5, placental growth factor (P1GF), PSA (prostate-specific antigen), PSMA, PSMA dimer, PAM4 antigen, NCA-95, NCA-90, A3, A33, Ep-CAM, KS-1, Le(y), mesothelin, S100, tenascin, TAC, Tn antigen, Thomas-Friedenreich antigen, tumor necrosis antigen, tumor angiogenesis antigen, TNF-a, TRAIL 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 comprises an antibody selected from the group consisting of gemtuzumab, brentuximab, berantuzumab, camizumab, trastuzumab, inotuzumab, gebatumumab, anetuzumab, milvitutuzumab, dexuzumab, vadatuximab, labetuzumab, laditutuzumab, lantuximab, paltratuzumab, rifatuzumab, indostatuzumab, polotuzumab, pinatuzumab, cotuximab, eupilitutuzumab, indalatuximab, milatuzumab, lovatuzumab, enroku, tesotuzumab, tesituximab, decitumomab, teritutuzumab, and antigen-binding fragments thereof. In some embodiments, the TopI ADC comprises an antibody selected from the group consisting of: hLL1 (anti-CD74), hLL2 (anti-CD22), hRFB4 (anti-CD22), hPAM4 (anti-MUC5ac), hMN-3 (anti-NOTCH3), hMN-14 (labetuzumab; anti-CEACAM5); hMN15 (anti-CEACAM6) hA19 (anti-CD19), hA20 (anti-CD22), hMu-9 (anti-CSAp), hL243 (anti-HLA-DR), hImmu-31 (anti-AFP), and antigen-binding fragments thereof. In some embodiments, the anti-PD-(L)1 antibody is pembrolizumab, nivolumab, cemiprilimab, pidilizumab, spartalizumab, atezolizumab, avelumab, durvalumab, cocilimab, sazanlimab, tislelizumab, rivalizumab, batilizumab, toripalimab, sitrilimab, genoluzumab, palolizumab, lodalizumab, camrelizumab, budigalimab, avelumab, dotalimumab, envolimab, sintilimab, or sepalizumab. In some embodiments, the anti-PD-(L)1 antibody is sepalizumab. In some embodiments, the anti-PD-(L)1 antibody is durvalumab. In some embodiments, the anti-PD-(L)1 antibody is an Fc-silent antibody. In some embodiments, the anti-PD-(L)1 antibody is an Fc-enabled antibody. In some embodiments, any of the methods disclosed herein further comprise administering an anti-TIGIT antibody. In some embodiments, the anti-TIGIT antibody is AB308, AGEN-1307 (AGEN-1327), AGEN-1777, AK127, BMS-986207, dunalimab, EOS-448, eitinib, JS006, M6223, osperlimab, rapasumab, SEA-TGT (SGN-TGT), tisleliumab, or vembralizumab. In some embodiments, the anti-TIGIT antibody is dunalimab. In some embodiments, the anti-TIGIT antibody is M6223.In some embodiments, the anti-PD-(L)1 antibody and the anti-TIGIT antibody are a) sepalizumab and dunalizumab, b) sepalizumab and AB308, c) atezolizumab and tislelizumab, d) pembrolizumab and vembrolizumab, e) pembrolizumab and dunalizumab, f) pembrolizumab and AB308, g) MK-7684A (pembrolizumab / vembrolizumab co-formulation), h) durvalumab and dunalizumab, i) sepalizumab and rapasumab, or j) pembrolizumab and rapasumab. In some embodiments, the anti-PD-(L)1 antibody and the anti-TIGIT antibody are sepalizumab and dunalizumab. In some embodiments, the anti-PD-(L)1 antibody and the anti-TIGIT antibody are sepalizumab and dunalizumab. In some embodiments, the anti-PD-(L)1 antibody and the anti-TIGIT antibody are sepalizumab and rapasumab. In some embodiments, the anti-PD-(L)1 antibody and the anti-TIGIT antibody are durvalumab and dunalimab. In some embodiments, the method further comprises co-administering an additional therapeutic agent or treatment modality. In some embodiments, the additional therapeutic agent or treatment modality comprises one, two, three, or four additional therapeutic agents and / or treatment modalities. In some embodiments, the cancer is a solid epithelial cancer. In some embodiments, the solid epithelial cancer is selected from breast cancer (e.g., triple-negative breast cancer (TNBC), HR. + / Her2 - Breast cancer or HR + / Her2 低In some embodiments, the bladder cancer is urothelial carcinoma (UC). In some embodiments, the bladder cancer is (i) unresectable locally advanced bladder cancer, (ii) metastatic bladder cancer, or (iii) muscle-invasive bladder cancer. In some embodiments, the urothelial carcinoma is (i) unresectable locally advanced bladder cancer, (ii) metastatic bladder cancer, or (iii) muscle-invasive bladder cancer. In some embodiments, the lung cancer is non-small cell lung cancer (NSCLC). In some embodiments, the lung cancer is (i) advanced lung cancer or (ii) metastatic lung cancer. In some embodiments, the lung cancer is (i) advanced NSCLC or (ii) metastatic NSCLC. In some embodiments, the NSCLC is squamous NSCLC. In some embodiments, the NSCLC is non-squamous NSCLC. In some embodiments, the metastatic NSCLC is metastatic squamous NSCLC. In some embodiments, the metastatic NSCLC is metastatic non-squamous NSCLC. In some embodiments, the NSCLC is NSCLC without EGFR, ALK, or other actionable genomic alterations. In some embodiments, the cancer is (i) unresectable locally advanced cancer, (ii) metastatic cancer, or (iii) muscle-invasive cancer. In some embodiments, the cancer is (i) advanced cancer, or (ii) metastatic cancer. In some embodiments, the cancer has progressed after at least one prior anticancer therapy. In some embodiments, the subject is treatment-naive. In some embodiments, the subject is treatment-naive in the metastatic or unresectable locally advanced setting (e.g., the subject has not received treatment for mUC and unresectable locally advanced UC). In some embodiments, the subject is treatment-naive in the metastatic or advanced setting (e.g., the subject has not received treatment for metastatic and advanced lung cancer and NSCLC). In some embodiments, the human patient is cisplatin-ineligible and has not received treatment in the metastatic or unresectable locally advanced setting. In some embodiments, the treatment-naive subject has not received prior anticancer therapy for (i) unresectable locally advanced cancer, (ii) metastatic cancer, or (iii) muscle-invasive cancer. In some embodiments, the treatment-naive subject has not received prior anticancer therapy for (i) advanced cancer or (ii) metastatic cancer. In some embodiments, the subject has received one or more anticancer therapies prior to administration of the combination of ADC, anti-PD-(L)1 antibody, and optionally, anti-TIGIT antibody. In some embodiments, the subject is not treatment-naive.In some embodiments, the subject has received one or more prior anticancer therapies for (i) unresectable locally advanced cancer, (ii) metastatic cancer, or (iii) muscle-invasive cancer. In some embodiments, the subject has received one or more prior anticancer therapies for (i) advanced cancer or (ii) metastatic cancer. In some embodiments, the subject has received one or more prior anticancer therapies prior to administration of the combination of an ADC, an anti-PD-(L)1 antibody, and optionally an anti-TIGIT antibody. In some embodiments, the cancer is resistant to or refractory to one or more anticancer therapies. In some embodiments, the anticancer therapy is selected from surgery, radiation therapy, chemotherapy, and checkpoint inhibitor therapy. In some embodiments, the combination of an ADC, an anti-PD-(L)1 antibody, and optionally an anti-TIGIT antibody is administered in a neoadjuvant setting (e.g., in preparation for surgery or radiation therapy). In some embodiments, the combination of an ADC, an anti-PD-(L)1 antibody, and optionally an anti-TIGIT antibody is administered in an adjuvant setting (e.g., after primary treatment such as surgery or radiation therapy). In some embodiments, the combination of an ADC, an anti-PD-(L)1 antibody, and optionally an anti-TIGIT antibody is administered in a therapeutic setting (e.g., as a primary therapy). In some embodiments, the combination of an ADC, an anti-PD-(L)1 antibody, and optionally an anti-TIGIT antibody is administered in a maintenance setting. In some embodiments, the subject receives one or more doses of an ADC. In some embodiments, the subject receives one or more doses of an anti-PD-(L)1 antibody. In some embodiments, the subject receives one or more doses of an anti-TIGIT antibody. In some embodiments, the ADC and anti-PD-(L)1 antibody are administered simultaneously. In some embodiments, the ADC and anti-PD-(L)1 antibody are administered sequentially. In some embodiments, the ADC and anti-TIGIT antibody are administered simultaneously. In some embodiments, the ADC and anti-TIGIT antibody are administered sequentially. In some embodiments, the anti-PD-(L)1 antibody and anti-TIGIT antibody are administered simultaneously. In some embodiments, the anti-PD-(L)1 antibody and anti-TIGIT antibody are administered sequentially. In some embodiments, the subject is human. In some embodiments, the subject does not meet criteria for cisplatin. In some embodiments, the ADC is administered in one or more doses ranging from 8 mg / kg to 10 mg / kg. In some embodiments, the ADC is administered in one or more doses of 8 mg / kg or 10 mg / kg. In some embodiments, the ADC is administered in one or more doses of 10 mg / kg. In some embodiments, the ADC is administered intravenously. In some embodiments, the ADC is administered on days 1 and 8 of a 21-day cycle. In some embodiments, the anti-PD-(L)1 antibody is administered in one or more doses ranging from 300 mg to 400 mg.In some embodiments, the anti-PD-(L)1 antibody is administered at a dose of 360 mg. In some embodiments, the anti-PD-(L)1 antibody is administered intravenously. In some embodiments, the anti-PD-(L)1 antibody is administered on day 1 of a 21-day cycle. In some embodiments, the anti-TIGIT antibody is administered at one or more doses ranging from 800 mg to 1600 mg. In some embodiments, the anti-TIGIT antibody is administered at a dose of 1200 mg. In some embodiments, the anti-TIGIT antibody is administered intravenously. In some embodiments, the anti-TIGIT antibody is administered on day 1 of a 21-day cycle. In some embodiments of the methods provided herein, an anti-CD47 antibody is not co-administered to the subject or human patient. In some embodiments, the anti-CD47 antibody is selected from mololimab, leszolimab, leterlimab, lefalimab, 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 anti-CD47 antibody is magrolimab. In some embodiments of the methods provided herein, an MCL1 inhibitor is not co-administered to the subject or human patient. In some embodiments, the MCL1 inhibitor is selected from GS-9716, AMG-176, AMG-397, S-64315, AZD-5991, 483-LM, A-1210477, UMI-77, and JKY-5-037. In some embodiments, the MCL1 inhibitor is GS-9716. In some embodiments of the methods provided herein, a FLT3 agonist is not administered to a subject or human patient. In some embodiments, the FLT3 agonist is selected from GS-3583, CDX-301, TAK-605, ONCR-177, Alb-Ftl3L, and SYM-027. In some embodiments, the FLT3 agonist is GS-3583.

[0360] In some embodiments, the methods provided herein are used to treat tumor antigen positive (TA +) cancer, comprising co-administering to a subject an effective amount of: a) a tumor antigen-targeting antibody-drug conjugate (ADC) comprising a topoisomerase I inhibitor (TopI ADC); b) an anti-PD-(L)1 antibody; and optionally, c) an anti-TIGIT antibody. In some embodiments, the topoisomerase I inhibitor is a camptothecin. In some embodiments, the camptothecin is selected from irinotecan, topotecan, belotecan, and an exatecan derivative. In some embodiments, the exatecan derivative is selected from Dxd or SN38. In some embodiments, the topoisomerase I inhibitor is selected from irinotecan, topotecan, and SN-38. In some embodiments, the TopI ADC has the structural formula mAb-CL2A-SN-38, which is represented by the following formula:

[0361]

[0362] (Described, e.g., in U.S. Patent No. 7,999,083). In some embodiments, the TopI ADC comprises an antibody that binds to a tumor antigen. In some embodiments, the tumor antigen is 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, insulin-like growth factor (ILGF), IFN-a, IFN-b, IL-g, IL-2R, IL-4R, IL-6R, IL-13R, IL-15R, IL-17R, IL-18R, IL-2, IL-6, IL-8, IL-12, IL-15, IL-17, IL-18, IL-25, IP-10, IGF-1R, Ia, HM1.24, gangliosides, HCG, HLA-DR, HLA-G, CD66a-d, MAGE, mCRP, MCP-1, MIP-1A, MIP-1B, macrophage migration inhibitory factor ( MIF), MUC1, MUC2, MUC3, MUC4, MUC5, placental growth factor (P1GF), PSA (prostate-specific antigen), PSMA, PSMA dimer, PAM4 antigen, NCA-95, NCA-90, A3, A33, Ep-CAM, KS-1, Le(y), mesothelin, S100, tenascin, TAC, Tn antigen, Thomas-Friedenreich antigen, tumor necrosis antigen, tumor angiogenesis antigen, TNF-a, TRAIL 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 comprises an antibody selected from the group consisting of gemtuzumab, brentuximab, berantuzumab, camizumab, trastuzumab, inotuzumab, gebatumumab, anetuzumab, milvitutuzumab, dexuzumab, vadatuximab, labetuzumab, laditutuzumab, lantuximab, paltratuzumab, rifatuzumab, indostatuzumab, polotuzumab, pinatuzumab, cotuximab, eupilitutuzumab, indalatuximab, milatuzumab, lovatuzumab, enroku, tesotuzumab, tesituximab, decitumomab, teritutuzumab, and antigen-binding fragments thereof. In some embodiments, the TopI ADC comprises an antibody selected from the group consisting of: hLL1 (anti-CD74), hLL2 (anti-CD22), hRFB4 (anti-CD22), hPAM4 (anti-MUC5ac), hMN-3 (anti-NOTCH3), hMN-14 (labetuzumab; anti-CEACAM5); hMN15 (anti-CEACAM6) hA19 (anti-CD19), hA20 (anti-CD22), hMu-9 (anti-CSAp), hL243 (anti-HLA-DR), hImmu-31 (anti-AFP), and antigen-binding fragments thereof. In some embodiments, the anti-PD-(L)1 antibody is pembrolizumab, nivolumab, cemiprilimab, pidilizumab, spartalizumab, atezolizumab, avelumab, durvalumab, cocilimab, sazanlimab, tislelizumab, rivalizumab, batilizumab, toripalimab, sitrilimab, genoluzumab, palolizumab, lodalizumab, camrelizumab, budigalimab, avelumab, dotalimumab, envolimab, sintilimab, or sepalizumab. In some embodiments, the anti-PD-(L)1 antibody is sepalizumab. In some embodiments, the anti-PD-(L)1 antibody is durvalumab. In some embodiments, the anti-PD-(L)1 antibody is an Fc-silent antibody. In some embodiments, the anti-PD-(L)1 antibody is an Fc-enabled antibody. In some embodiments, any of the methods disclosed herein further comprise administering an anti-TIGIT antibody. In some embodiments, the anti-TIGIT antibody is AB308, AGEN-1307 (AGEN-1327), AGEN-1777, AK127, BMS-986207, dunalimab, EOS-448, eitinib, JS006, M6223, osperlimab, rapasumab, SEA-TGT (SGN-TGT), tisleliumab, or vembralizumab. In some embodiments, the anti-TIGIT antibody is dunalimab. In some embodiments, the anti-TIGIT antibody is M6223.In some embodiments, the anti-PD-(L)1 antibody and the anti-TIGIT antibody are a) sepalizumab and dunalizumab, b) sepalizumab and AB308, c) atezolizumab and tislelizumab, d) pembrolizumab and vembrolizumab, e) pembrolizumab and dunalizumab, f) pembrolizumab and AB308, g) MK-7684A (pembrolizumab / vembrolizumab co-formulation), h) durvalumab and dunalizumab, i) sepalizumab and rapasumab, or j) pembrolizumab and rapasumab. In some embodiments, the anti-PD-(L)1 antibody and the anti-TIGIT antibody are sepalizumab and dunalizumab. In some embodiments, the anti-PD-(L)1 antibody and the anti-TIGIT antibody are sepalizumab and dunalizumab. In some embodiments, the anti-PD-(L)1 antibody and the anti-TIGIT antibody are sepalizumab and rapasumab. In some embodiments, the anti-PD-(L)1 antibody and the anti-TIGIT antibody are durvalumab and dunalimab. In some embodiments, the method further comprises co-administering an additional therapeutic agent or treatment modality. In some embodiments, the additional therapeutic agent or treatment modality comprises one, two, three, or four additional therapeutic agents and / or treatment modalities. In some embodiments, the cancer is a solid epithelial cancer. In some embodiments, the solid epithelial cancer is selected from breast cancer (e.g., triple-negative breast cancer (TNBC), HR. + / Her2 - Breast cancer or HR + / Her2 低In some embodiments, the bladder cancer is urothelial carcinoma (UC). In some embodiments, the bladder cancer is (i) unresectable locally advanced bladder cancer, (ii) metastatic bladder cancer, or (iii) muscle-invasive bladder cancer. In some embodiments, the urothelial carcinoma is (i) unresectable locally advanced bladder cancer, (ii) metastatic bladder cancer, or (iii) muscle-invasive bladder cancer. In some embodiments, the lung cancer is non-small cell lung cancer (NSCLC). In some embodiments, the lung cancer is (i) advanced lung cancer or (ii) metastatic lung cancer. In some embodiments, the lung cancer is (i) advanced NSCLC or (ii) metastatic NSCLC. In some embodiments, the NSCLC is squamous NSCLC. In some embodiments, the NSCLC is non-squamous NSCLC. In some embodiments, the metastatic NSCLC is metastatic squamous NSCLC. In some embodiments, the metastatic NSCLC is metastatic non-squamous NSCLC. In some embodiments, the NSCLC is NSCLC without EGFR, ALK, or other actionable genomic alterations. In some embodiments, the cancer is (i) unresectable locally advanced cancer, (ii) metastatic cancer, or (iii) muscle-invasive cancer. In some embodiments, the cancer is (i) advanced cancer, or (ii) metastatic cancer. In some embodiments, the cancer has progressed after at least one prior anticancer therapy. In some embodiments, the subject is treatment-naive. In some embodiments, the subject has not received treatment in the metastatic or unresectable locally advanced setting (e.g., the subject has not received treatment for mUC and unresectable locally advanced UC). In some embodiments, the subject has not received treatment in the metastatic or unresectable locally advanced setting (e.g., the subject has not received treatment for metastatic and advanced lung cancer and NSCLC). In some embodiments, the human patient does not meet the criteria for cisplatin and has not received treatment in the metastatic or unresectable locally advanced setting. In some embodiments, the untreated subject has not received prior anticancer therapy for (i) unresectable locally advanced cancer, (ii) metastatic cancer, or (iii) muscle-invasive cancer. In some embodiments, the untreated subject has not received prior anticancer therapy for (i) advanced cancer or (ii) metastatic cancer. In some embodiments, the subject has received one or more anticancer therapies prior to administering the combination of ADC, anti-PD-(L)1 antibody, and optionally an anti-TIGIT antibody. In some embodiments, the subject is not untreated.In some embodiments, the subject has received one or more prior anticancer therapies for (i) unresectable locally advanced cancer, (ii) metastatic cancer, or (iii) muscle-invasive cancer. In some embodiments, the subject has received one or more prior anticancer therapies for (i) advanced cancer or (ii) metastatic cancer. In some embodiments, the subject has received one or more prior anticancer therapies prior to administration of the combination of an ADC, an anti-PD-(L)1 antibody, and optionally an anti-TIGIT antibody. In some embodiments, the cancer is resistant to or refractory to one or more anticancer therapies. In some embodiments, the anticancer therapy is selected from surgery, radiation therapy, chemotherapy, and checkpoint inhibitor therapy. In some embodiments, the combination of an ADC, an anti-PD-(L)1 antibody, and optionally an anti-TIGIT antibody is administered in a neoadjuvant setting (e.g., in preparation for surgery or radiation therapy). In some embodiments, the combination of an ADC, an anti-PD-(L)1 antibody, and optionally an anti-TIGIT antibody is administered in an adjuvant setting (e.g., after primary treatment such as surgery or radiation therapy). In some embodiments, the combination of an ADC, an anti-PD-(L)1 antibody, and optionally an anti-TIGIT antibody is administered in a therapeutic setting (e.g., as a primary therapy). In some embodiments, the combination of an ADC, an anti-PD-(L)1 antibody, and optionally an anti-TIGIT antibody is administered in a maintenance setting. In some embodiments, the subject receives one or more doses of an ADC. In some embodiments, the subject receives one or more doses of an anti-PD-(L)1 antibody. In some embodiments, the subject receives one or more doses of an anti-TIGIT antibody. In some embodiments, the ADC and anti-PD-(L)1 antibody are administered simultaneously. In some embodiments, the ADC and anti-PD-(L)1 antibody are administered sequentially. In some embodiments, the ADC and anti-TIGIT antibody are administered simultaneously. In some embodiments, the ADC and anti-TIGIT antibody are administered sequentially. In some embodiments, the anti-PD-(L)1 antibody and anti-TIGIT antibody are administered simultaneously. In some embodiments, the anti-PD-(L)1 antibody and anti-TIGIT antibody are administered sequentially. In some embodiments, the subject is human. In some embodiments, the subject does not meet criteria for cisplatin. In some embodiments, the ADC is administered in one or more doses ranging from 8 mg / kg to 10 mg / kg. In some embodiments, the ADC is administered in one or more doses of 8 mg / kg or 10 mg / kg. In some embodiments, the ADC is administered in one or more doses of 10 mg / kg. In some embodiments, the ADC is administered intravenously. In some embodiments, the ADC is administered on days 1 and 8 of a 21-day cycle. In some embodiments, the anti-PD-(L)1 antibody is administered in one or more doses ranging from 300 mg to 400 mg.In some embodiments, the anti-PD-(L)1 antibody is administered at a dose of 360 mg. In some embodiments, the anti-PD-(L)1 antibody is administered intravenously. In some embodiments, the anti-PD-(L)1 antibody is administered on day 1 of a 21-day cycle. In some embodiments, the anti-TIGIT antibody is administered at one or more doses ranging from 800 mg to 1600 mg. In some embodiments, the anti-TIGIT antibody is administered at a dose of 1200 mg. In some embodiments, the anti-TIGIT antibody is administered intravenously. In some embodiments, the anti-TIGIT antibody is administered on day 1 of a 21-day cycle. In some embodiments of the methods provided herein, an anti-CD47 antibody is not co-administered to the subject or human patient. In some embodiments, the anti-CD47 antibody is selected from mololimab, leszolimab, leterlimab, lefalimab, 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 anti-CD47 antibody is magrolimab. In some embodiments of the methods provided herein, an MCL1 inhibitor is not co-administered to the subject or human patient. In some embodiments, the MCL1 inhibitor is selected from GS-9716, AMG-176, AMG-397, S-64315, AZD-5991, 483-LM, A-1210477, UMI-77, and JKY-5-037. In some embodiments, the MCL1 inhibitor is GS-9716. In some embodiments of the methods provided herein, a FLT3 agonist is not administered to a subject or human patient. In some embodiments, the FLT3 agonist is selected from GS-3583, CDX-301, TAK-605, ONCR-177, Alb-Ftl3L, and SYM-027. In some embodiments, the FLT3 agonist is GS-3583.

[0363] In some embodiments, provided herein are methods for treating, alleviating, reducing, preventing, or delaying the recurrence or metastasis of urothelial carcinoma (UC), comprising co-administering to a subject an effective amount of: a) a tumor antigen-targeting antibody-drug conjugate (ADC) comprising a topoisomerase I inhibitor (TopI ADC); b) an anti-PD-(L)1 antibody; and optionally, c) an anti-TIGIT antibody. In some embodiments, the topoisomerase I inhibitor is a camptothecin. In some embodiments, the camptothecin is selected from irinotecan, topotecan, belotecan, and an exatecan derivative. In some embodiments, the exatecan derivative is selected from Dxd or SN38. In some embodiments, the topoisomerase I inhibitor is selected from irinotecan, topotecan, and SN-38. In some embodiments, the TopI ADC has the structural formula mAb-CL2A-SN-38, which is represented by the following formula:

[0364]

[0365] (Described, e.g., in U.S. Patent No. 7,999,083). In some embodiments, the TopI ADC comprises an antibody that binds to a tumor antigen. In some embodiments, the tumor antigen is 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, insulin-like growth factor (ILGF), IFN-a, IFN-b, IL-g, IL-2R, IL-4R, IL-6R, IL-13R, IL-15R, IL-17R, IL-18R, IL-2, IL-6, IL-8, IL-12, IL-15, IL-17, IL-18, IL-25, IP-10, IGF-1R, Ia, HM1.24, gangliosides, HCG, HLA-DR, HLA-G, CD66a-d, MAGE, mCRP, MCP-1, MIP-1A, MIP-1B, macrophage migration inhibitory factor ( MIF), MUC1, MUC2, MUC3, MUC4, MUC5, placental growth factor (P1GF), PSA (prostate-specific antigen), PSMA, PSMA dimer, PAM4 antigen, NCA-95, NCA-90, A3, A33, Ep-CAM, KS-1, Le(y), mesothelin, S100, tenascin, TAC, Tn antigen, Thomas-Friedenreich antigen, tumor necrosis antigen, tumor angiogenesis antigen, TNF-a, TRAIL 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 comprises an antibody selected from the group consisting of gemtuzumab, brentuximab, berantuzumab, camizumab, trastuzumab, inotuzumab, gebatumumab, anetuzumab, milvitutuzumab, dexuzumab, vadatuximab, labetuzumab, laditutuzumab, lantuximab, paltratuzumab, rifatuzumab, indostatuzumab, polotuzumab, pinatuzumab, cotuximab, eupilitutuzumab, indalatuximab, milatuzumab, lovatuzumab, enroku, tesotuzumab, tesituximab, decitumomab, teritutuzumab, and antigen-binding fragments thereof. In some embodiments, the TopI ADC comprises an antibody selected from the group consisting of: hLL1 (anti-CD74), hLL2 (anti-CD22), hRFB4 (anti-CD22), hPAM4 (anti-MUC5ac), hMN-3 (anti-NOTCH3), hMN-14 (labetuzumab; anti-CEACAM5); hMN15 (anti-CEACAM6) hA19 (anti-CD19), hA20 (anti-CD22), hMu-9 (anti-CSAp), hL243 (anti-HLA-DR), hImmu-31 (anti-AFP), and antigen-binding fragments thereof. In some embodiments, the anti-PD-(L)1 antibody is pembrolizumab, nivolumab, cemiprilimab, pidilizumab, spartalizumab, atezolizumab, avelumab, durvalumab, cocilimab, sazanlimab, tislelizumab, rivalizumab, batilizumab, toripalimab, sitrilimab, genoluzumab, palolizumab, lodalizumab, camrelizumab, budigalimab, avelumab, dotalimumab, envolimab, sintilimab, or sepalizumab. In some embodiments, the anti-PD-(L)1 antibody is sepalizumab. In some embodiments, the anti-PD-(L)1 antibody is durvalumab. In some embodiments, the anti-PD-(L)1 antibody is an Fc-silent antibody. In some embodiments, the anti-PD-(L)1 antibody is an Fc-enabled antibody. In some embodiments, any of the methods disclosed herein further comprise administering an anti-TIGIT antibody. In some embodiments, the anti-TIGIT antibody is AB308, AGEN-1307 (AGEN-1327), AGEN-1777, AK127, BMS-986207, dunalimab, EOS-448, eitinib, JS006, M6223, osperlimab, rapasumab, SEA-TGT (SGN-TGT), tisleliumab, or vembralizumab. In some embodiments, the anti-TIGIT antibody is dunalimab. In some embodiments, the anti-TIGIT antibody is M6223.In some embodiments, the anti-PD-(L)1 antibody and the anti-TIGIT antibody are a) sepalizumab and dunalizumab, b) sepalizumab and AB308, c) atezolizumab and tislelizumab, d) pembrolizumab and vembrolizumab, e) pembrolizumab and dunalizumab, f) pembrolizumab and AB308, g) MK-7684A (pembrolizumab / vembrolizumab co-formulation), h) durvalumab and dunalizumab, i) sepalizumab and rapasumab, or j) pembrolizumab and rapasumab. In some embodiments, the anti-PD-(L)1 antibody and the anti-TIGIT antibody are sepalizumab and dunalizumab. In some embodiments, the anti-PD-(L)1 antibody and the anti-TIGIT antibody are sepalizumab and dunalizumab. In some embodiments, the anti-PD-(L)1 antibody and the anti-TIGIT antibody are sepalizumab and rapasumab. In some embodiments, the anti-PD-(L)1 antibody and the anti-TIGIT antibody are durvalumab and dunalimab. In some embodiments, the method further comprises co-administering an additional therapeutic agent or treatment modality. In some embodiments, the additional therapeutic agent or treatment modality comprises one, two, three, or four additional therapeutic agents and / or treatment modalities. In some embodiments, the cancer is a solid epithelial cancer. In some embodiments, the solid epithelial cancer is selected from breast cancer (e.g., triple-negative breast cancer (TNBC), HR. + / Her2 - Breast cancer or HR + / Her2 低In some embodiments, the bladder cancer is urothelial carcinoma (UC). In some embodiments, the bladder cancer is (i) unresectable locally advanced bladder cancer, (ii) metastatic bladder cancer, or (iii) muscle-invasive bladder cancer. In some embodiments, the urothelial carcinoma is (i) unresectable locally advanced bladder cancer, (ii) metastatic bladder cancer, or (iii) muscle-invasive bladder cancer. In some embodiments, the lung cancer is non-small cell lung cancer (NSCLC). In some embodiments, the lung cancer is (i) advanced lung cancer or (ii) metastatic lung cancer. In some embodiments, the lung cancer is (i) advanced NSCLC or (ii) metastatic NSCLC. In some embodiments, the NSCLC is squamous NSCLC. In some embodiments, the NSCLC is non-squamous NSCLC. In some embodiments, the metastatic NSCLC is metastatic squamous NSCLC. In some embodiments, the metastatic NSCLC is metastatic non-squamous NSCLC. In some embodiments, the NSCLC is NSCLC without EGFR, ALK, or other actionable genomic alterations. In some embodiments, the cancer is (i) unresectable locally advanced cancer, (ii) metastatic cancer, or (iii) muscle-invasive cancer. In some embodiments, the cancer is (i) advanced cancer, or (ii) metastatic cancer. In some embodiments, the cancer has progressed after at least one prior anticancer therapy. In some embodiments, the subject is treatment-naive. In some embodiments, the subject has not received treatment in the metastatic or unresectable locally advanced setting (e.g., the subject has not received treatment for mUC and unresectable locally advanced UC). In some embodiments, the subject has not received treatment in the metastatic or unresectable locally advanced setting (e.g., the subject has not received treatment for metastatic and advanced lung cancer and NSCLC). In some embodiments, the human patient does not meet the criteria for cisplatin and has not received treatment in the metastatic or unresectable locally advanced setting. In some embodiments, the untreated subject has not received prior anticancer therapy for (i) unresectable locally advanced cancer, (ii) metastatic cancer, or (iii) muscle-invasive cancer. In some embodiments, the untreated subject has not received prior anticancer therapy for (i) advanced cancer or (ii) metastatic cancer. In some embodiments, the subject has received one or more anticancer therapies prior to administering the combination of ADC, anti-PD-(L)1 antibody, and optionally an anti-TIGIT antibody. In some embodiments, the subject is not untreated.In some embodiments, the subject has received one or more prior anticancer therapies for (i) unresectable locally advanced cancer, (ii) metastatic cancer, or (iii) muscle-invasive cancer. In some embodiments, the subject has received one or more prior anticancer therapies for (i) advanced cancer or (ii) metastatic cancer. In some embodiments, the subject has received one or more prior anticancer therapies prior to administration of the combination of an ADC, an anti-PD-(L)1 antibody, and optionally an anti-TIGIT antibody. In some embodiments, the cancer is resistant to or refractory to one or more anticancer therapies. In some embodiments, the anticancer therapy is selected from surgery, radiation therapy, chemotherapy, and checkpoint inhibitor therapy. In some embodiments, the combination of an ADC, an anti-PD-(L)1 antibody, and optionally an anti-TIGIT antibody is administered in a neoadjuvant setting (e.g., in preparation for surgery or radiation therapy). In some embodiments, the combination of an ADC, an anti-PD-(L)1 antibody, and optionally an anti-TIGIT antibody is administered in an adjuvant setting (e.g., after primary treatment such as surgery or radiation therapy). In some embodiments, the combination of an ADC, an anti-PD-(L)1 antibody, and optionally an anti-TIGIT antibody is administered in a therapeutic setting (e.g., as a primary therapy). In some embodiments, the combination of an ADC, an anti-PD-(L)1 antibody, and optionally an anti-TIGIT antibody is administered in a maintenance setting. In some embodiments, the subject receives one or more doses of an ADC. In some embodiments, the subject receives one or more doses of an anti-PD-(L)1 antibody. In some embodiments, the subject receives one or more doses of an anti-TIGIT antibody. In some embodiments, the ADC and anti-PD-(L)1 antibody are administered simultaneously. In some embodiments, the ADC and anti-PD-(L)1 antibody are administered sequentially. In some embodiments, the ADC and anti-TIGIT antibody are administered simultaneously. In some embodiments, the ADC and anti-TIGIT antibody are administered sequentially. In some embodiments, the anti-PD-(L)1 antibody and anti-TIGIT antibody are administered simultaneously. In some embodiments, the anti-PD-(L)1 antibody and anti-TIGIT antibody are administered sequentially. In some embodiments, the subject is human. In some embodiments, the subject does not meet criteria for cisplatin. In some embodiments, the ADC is administered in one or more doses ranging from 8 mg / kg to 10 mg / kg. In some embodiments, the ADC is administered in one or more doses of 8 mg / kg or 10 mg / kg. In some embodiments, the ADC is administered in one or more doses of 10 mg / kg. In some embodiments, the ADC is administered intravenously. In some embodiments, the ADC is administered on days 1 and 8 of a 21-day cycle. In some embodiments, the anti-PD-(L)1 antibody is administered in one or more doses ranging from 300 mg to 400 mg.In some embodiments, the anti-PD-(L)1 antibody is administered at a dose of 360 mg. In some embodiments, the anti-PD-(L)1 antibody is administered intravenously. In some embodiments, the anti-PD-(L)1 antibody is administered on day 1 of a 21-day cycle. In some embodiments, the anti-TIGIT antibody is administered at one or more doses ranging from 800 mg to 1600 mg. In some embodiments, the anti-TIGIT antibody is administered at a dose of 1200 mg. In some embodiments, the anti-TIGIT antibody is administered intravenously. In some embodiments, the anti-TIGIT antibody is administered on day 1 of a 21-day cycle. In some embodiments of the methods provided herein, an anti-CD47 antibody is not co-administered to the subject or human patient. In some embodiments, the anti-CD47 antibody is selected from mololimab, leszolimab, leterlimab, lefalimab, 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 anti-CD47 antibody is magrolimab. In some embodiments of the methods provided herein, an MCL1 inhibitor is not co-administered to the subject or human patient. In some embodiments, the MCL1 inhibitor is selected from GS-9716, AMG-176, AMG-397, S-64315, AZD-5991, 483-LM, A-1210477, UMI-77, and JKY-5-037. In some embodiments, the MCL1 inhibitor is GS-9716. In some embodiments of the methods provided herein, a FLT3 agonist is not administered to a subject or human patient. In some embodiments, the FLT3 agonist is selected from GS-3583, CDX-301, TAK-605, ONCR-177, Alb-Ftl3L, and SYM-027. In some embodiments, the FLT3 agonist is GS-3583.

[0366] In some embodiments, the methods provided herein are used to treat urothelial carcinoma, comprising co-administering to a subject an effective amount of: a) a tumor antigen-targeting antibody-drug conjugate (ADC) comprising a topoisomerase I inhibitor (TopI ADC); b) an anti-PD-(L)1 antibody; and optionally, c) an anti-TIGIT antibody. In some embodiments, the topoisomerase I inhibitor is a camptothecin. In some embodiments, the camptothecin is selected from irinotecan, topotecan, belotecan, and an exatecan derivative. In some embodiments, the exatecan derivative is selected from Dxd or SN38. In some embodiments, the topoisomerase I inhibitor is selected from irinotecan, topotecan, and SN-38. In some embodiments, the TopI ADC has the structural formula mAb-CL2A-SN-38, which is represented by the following formula:

[0367]

[0368] (Described, e.g., in U.S. Patent No. 7,999,083). In some embodiments, the TopI ADC comprises an antibody that binds to a tumor antigen. In some embodiments, the tumor antigen is 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, insulin-like growth factor (ILGF), IFN-a, IFN-b, IL-g, IL-2R, IL-4R, IL-6R, IL-13R, IL-15R, IL-17R, IL-18R, IL-2, IL-6, IL-8, IL-12, IL-15, IL-17, IL-18, IL-25, IP-10, IGF-1R, Ia, HM1.24, gangliosides, HCG, HLA-DR, HLA-G, CD66a-d, MAGE, mCRP, MCP-1, MIP-1A, MIP-1B, macrophage migration inhibitory factor ( MIF), MUC1, MUC2, MUC3, MUC4, MUC5, placental growth factor (P1GF), PSA (prostate-specific antigen), PSMA, PSMA dimer, PAM4 antigen, NCA-95, NCA-90, A3, A33, Ep-CAM, KS-1, Le(y), mesothelin, S100, tenascin, TAC, Tn antigen, Thomas-Friedenreich antigen, tumor necrosis antigen, tumor angiogenesis antigen, TNF-a, TRAIL 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 comprises an antibody selected from the group consisting of gemtuzumab, brentuximab, berantuzumab, camizumab, trastuzumab, inotuzumab, gebatumumab, anetuzumab, milvitutuzumab, dexuzumab, vadatuximab, labetuzumab, laditutuzumab, lantuximab, paltratuzumab, rifatuzumab, indosta...

Claims

1. A method for treating, alleviating, reducing, preventing or delaying the recurrence or metastasis of urothelial carcinoma, comprising co-administering an effective amount of the following substances to a human patient who does not meet the criteria for cisplatin: a) gosartuzumab; and b) Sepalimab.

2. A kit for use as a medicine, wherein the kit comprises a) gosartuzumab; and b) Sepalimab.

3. A kit for treating, alleviating, reducing, preventing or delaying the recurrence or metastasis of urothelial carcinoma, wherein the kit comprises a) gosartuzumab; and b) Sepalimab.

4. The method of claim 1 or the kit of claim 2 or 3, wherein gosartuzumab is administered in one or more doses in the range of 8 mg / kg to 10 mg / kg.

5. The method or kit of claim 4, wherein gosartuzumab is administered in one or more doses of 10 mg / kg.

6. The method or kit of any one of claims 1 to 5, wherein gosartuzumab is administered intravenously.

7. The method or kit of any one of claims 1 to 6, wherein gosartuzumab is administered on days 1 and 8 of a 21 day cycle.

8. The method or kit of any one of claims 1 to 7, wherein sepalimumab is administered in one or more doses ranging from 300 mg to 400 mg.

9. The method or kit of claim 8, wherein sepalimumab is administered at a dose of 360 mg.

10. The method or kit of any one of claims 1 to 9, wherein sepalimumab is administered intravenously.

11. The method or kit of any one of claims 1 to 10, wherein sepalimumab is administered on day 1 of a 21 day cycle.

12. The method or kit of any one of claims 1 to 11, wherein gosartuzumab is administered at a dose of 10 mg / kg on day 1 and day 8 of a 21-day cycle; and sepalizumab is administered at a dose of 360 mg on day 1 of the 21-day cycle.

13. A method for treating, alleviating, reducing, preventing or delaying the recurrence or metastasis of urothelial carcinoma, comprising co-administering an effective amount of the following to a human patient who is not compliant with cisplatin: a) Gosartuzumab; b) sepalizumab; and c) Dunalitumab.

14. A kit for use as a medicine, wherein the kit comprises a) Gosartuzumab; b) sepalizumab; and c) Dunalitumab.

15. A kit for treating, alleviating, reducing, preventing or delaying the recurrence or metastasis of urothelial carcinoma, wherein the kit comprises a) Gosartuzumab; b) sepalizumab; and c) Dunalitumab.

16. The method of claim 13 or the kit of claim 14 or 15, wherein gosartuzumab is administered in one or more doses in the range of 8 mg / kg to 10 mg / kg.

17. The method or kit of claim 16, wherein gosartuzumab is administered in one or more doses of 10 mg / kg.

18. The method or kit of any one of claims 13 to 17, wherein gosartuzumab is administered intravenously.

19. The method or kit of any one of claims 13 to 18, wherein gosartuzumab is administered on days 1 and 8 of a 21 day cycle.

20. The method or kit of any one of claims 13 to 19, wherein sepalimumab is administered in one or more doses ranging from 300 mg to 400 mg.

21. The method or kit of claim 20, wherein sepalimumab is administered at a dose of 360 mg.

22. The method or kit of any one of claims 13 to 21, wherein sepalimumab is administered intravenously.

23. The method or kit of any one of claims 13 to 22, wherein sepalimumab is administered on day 1 of a 21 day cycle.

24. The method or kit of any one of claims 13 to 23, wherein dunalimumab is administered in one or more doses ranging from 800 mg to 1600 mg.

25. The method or kit of claim 24, wherein dunalimab is administered at a dose of 1200 mg.

26. The method or kit of any one of claims 13 to 25, wherein dunalimab is administered intravenously.

27. The method or kit of any one of claims 13 to 26, wherein dunalimumab is administered on day 1 of a 21 day cycle.

28. The method or kit of any one of claims 13 to 27, wherein gosartuzumab is administered at a dose of 10 mg / kg on Day 1 and Day 8 of a 21-day cycle; sepalimumab is administered at a dose of 360 mg on Day 1 of the 21-day cycle, and dunalimumab is administered at a dose of 1200 mg on Day 1 of the 21-day cycle.

29. The method or kit of any one of claims 1 to 28, wherein no anti-CD47 antibody is administered to the subject or human patient.

30. The method or kit of claim 29, wherein the anti-CD47 antibody is selected from mololimab, leszolimab, leterlimab, lefalimab, 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.

31. The method or kit of claim 29, wherein the anti-CD47 antibody is mololimab.

32. A method for treating, alleviating, reducing, preventing or delaying the recurrence or metastasis of non-small cell lung cancer, comprising co-administering to a human patient an effective amount of: a) Gosartuzumab; b) sepalizumab; and c) Dunalitumab.

33. A kit for treating, alleviating, reducing, preventing or delaying the recurrence or metastasis of non-small cell lung cancer, wherein the kit comprises a) Gosartuzumab; b) sepalizumab; and c) Dunalitumab.

34. The method of claim 32 or the kit of claim 33, wherein gosartuzumab is administered in one or more doses in the range of 8 mg / kg to 10 mg / kg.

35. The method or kit of claim 34, wherein gosartuzumab is administered in one or more doses of 10 mg / kg.

36. The method or kit of any one of claims 32 to 34, wherein gosartuzumab is administered intravenously.

37. The method or kit of any one of claims 32 to 36, wherein gosartuzumab is administered on days 1 and 8 of a 21 day cycle.

38. The method or kit of any one of claims 32 to 37, wherein sepalimumab is administered in one or more doses ranging from 300 mg to 400 mg.

39. The method or kit of claim 38, wherein sepalimumab is administered at a dose of 360 mg.

40. The method or kit of any one of claims 32 to 39, wherein sepalimumab is administered intravenously.

41. The method or kit of any one of claims 32 to 40, wherein sepalimumab is administered on day 1 of a 21 day cycle.

42. The method or kit of any one of claims 32 to 41, wherein dunalimumab is administered in one or more doses ranging from 800 mg to 1600 mg.

43. The method or kit of claim 42, wherein dunalimab is administered at a dose of 1200 mg.

44. The method or kit of any one of claims 32 to 43, wherein dunalimumab is administered intravenously.

45. The method or kit of any one of claims 32 to 44, wherein dunalimumab is administered on day 1 of a 21 day cycle.

46. ​​The method or kit of any one of claims 32 to 45, wherein gosartuzumab is administered at a dose of 10 mg / kg on Day 1 and Day 8 of a 21 day cycle; sepalimumab is administered at a dose of 360 mg on Day 1 of the 21 day cycle, and dunalimumab is administered at a dose of 1200 mg on Day 1 of the 21 day cycle.

47. The method or kit of any one of claims 32 to 46, wherein no anti-CD47 antibody is administered to the subject or human patient.

48. The method or kit of claim 47, wherein the anti-CD47 antibody is selected from mololimab, leszolimab, leterlimab, lefalimab, 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.

49. The method or kit of claim 48, wherein the anti-CD47 antibody is mololimab.

50. The method or kit of any one of claims 32 to 49, wherein the NSCLC is (i) squamous NSCLC or (ii) non-squamous NSCLC.

51. The method or kit of any one of claims 32 to 50, wherein the NSCLC is devoid of EGFR, ALK and other actionable genomic alterations.

52. The method or kit of any one of claims 32 to 51, wherein the NSCLC is (i) metastatic NSCLC or (ii) advanced NSCLC.

53. A method for treating, alleviating, reducing, preventing or delaying the recurrence or metastasis of breast cancer, comprising co-administering an effective amount of the following to a human patient who is not compliant with cisplatin: a) gosartuzumab; and b) Sepalimab.

54. A kit for treating, alleviating, reducing, preventing or delaying the recurrence or metastasis of breast cancer, wherein the kit comprises a) gosartuzumab; and b) Sepalimab.

55. The method of claim 1 or the kit of claim 3, wherein gosartuzumab is administered in one or more doses within the range of 8 mg / kg to 10 mg / kg.

56. The method or kit of claim 4, wherein gosartuzumab is administered in one or more doses of 10 mg / kg.

57. The method or kit of any one of claims 1 to 5, wherein gosartuzumab is administered intravenously.

58. The method or kit of any one of claims 1 to 6, wherein gosartuzumab is administered on days 1 and 8 of a 21 day cycle.

59. The method or kit of any one of claims 1 to 7, wherein sepalimumab is administered in one or more doses ranging from 300 mg to 400 mg.

60. The method or kit of claim 8, wherein sepalimumab is administered at a dose of 360 mg.

61. The method or kit of any one of claims 1 to 9, wherein sepalimumab is administered intravenously.

62. The method or kit of any one of claims 1 to 10, wherein sepalimumab is administered on day 1 of a 21 day cycle.

63. The method or kit of any one of claims 1 to 11, wherein gosartuzumab is administered at a dose of 10 mg / kg on Day 1 and Day 8 of a 21-day cycle; and sepalimumab is administered at a dose of 360 mg on Day 1 of the 21-day cycle.

64. A method for treating, alleviating, reducing, preventing or delaying the recurrence or metastasis of breast cancer, comprising co-administering an effective amount of the following to a human patient who is not compliant with cisplatin: a) Gosartuzumab; b) sepalizumab; and c) Dunalitumab.

65. A kit for treating, alleviating, reducing, preventing or delaying the recurrence or metastasis of breast cancer, wherein the kit comprises a) Gosartuzumab; b) sepalizumab; and c) Dunalitumab.

66. The method of claim 13 or the kit of claim 15, wherein gosartuzumab is administered in one or more doses within the range of 8 mg / kg to 10 mg / kg.

67. The method or kit of claim 16, wherein gosartuzumab is administered in one or more doses of 10 mg / kg.

68. The method or kit of any one of claims 13 to 17, wherein gosartuzumab is administered intravenously.

69. The method or kit of any one of claims 13 to 18, wherein gosartuzumab is administered on days 1 and 8 of a 21 day cycle.

70. The method or kit of any one of claims 13 to 19, wherein sepalimumab is administered in one or more doses ranging from 300 mg to 400 mg.

71. The method or kit of claim 20, wherein sepalimumab is administered at a dose of 360 mg.

72. The method or kit of any one of claims 13 to 21, wherein sepalimumab is administered intravenously.

73. The method or kit of any one of claims 13 to 22, wherein sepalimumab is administered on day 1 of a 21 day cycle.

74. The method or kit of any one of claims 13 to 23, wherein dunalimumab is administered in one or more doses ranging from 800 mg to 1600 mg.

75. The method or kit of claim 24, wherein dunalimumab is administered at a dose of 1200 mg.

76. The method or kit of any one of claims 13 to 25, wherein dunalimumab is administered intravenously.

77. The method or kit of any one of claims 13 to 26, wherein dunalimumab is administered on day 1 of a 21 day cycle.

78. The method or kit of any one of claims 13 to 27, wherein gosartuzumab is administered at a dose of 10 mg / kg on Days 1 and 8 of a 21 day cycle; sepalimumab is administered at a dose of 360 mg on Day 1 of the 21 day cycle, and dunalimumab is administered at a dose of 1200 mg on Day 1 of the 21 day cycle.

79. The method or kit of any one of claims 1 to 28, wherein no anti-CD47 antibody is administered to the subject or human patient.

80. The method or kit of claim 29, wherein the anti-CD47 antibody is selected from mololimab, leszolimab, leterlimab, lefalimab, 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.

81. The method or kit of claim 29, wherein the anti-CD47 antibody is mololimab.

82. The method or kit of any one of claims 53 to 81, wherein the breast cancer is triple negative breast cancer, HR + / HER2 - Breast cancer, or HR + / HER2 低 Breast cancer.

83. The method or kit of any one of claims 53 to 82, wherein the breast cancer is metastatic.

84. The method or kit of any one of claims 53 to 83, wherein the breast cancer is resistant to or refractory to one or more anti-cancer therapies.

85. The method or kit of any one of claims 1 to 84, wherein no MCL1 inhibitor is administered to the subject or human patient.

86. The method or kit of claim 85, wherein the MCL1 inhibitor is selected from the group consisting of GS-9716, AMG-176, AMG-397, S-64315, AZD-5991, 483-LM, A-1210477, UMI-77, and JKY-5-037.

87. The method or kit of claim 85, wherein the MCL1 inhibitor is GS-9716.

88. The method or kit of any one of claims 1 to 87, wherein a FLT3 agonist is not administered to the subject or human patient.

89. The method or kit of claim 88, wherein the FLT3 agonist is selected from GS-3583, CDX-301, TAK-605, ONCR-177, Alb-Ftl3L, and SYM-027.

90. The method or kit of claim 88, wherein the FLT3 agonist is GS-3583.

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