Combination antibody therapy for treating colorectal cancer

Abstract

Provided is a method of treating colorectal cancer in a subject, comprising co-administering to the subject effective amounts of (a) an agent that inhibits binding between CD47 and SIRPα (e.g., magrolimab) and (b) an agent that inhibits binding between vascular endothelial growth factor A (VEGFA) and one or more VEGFA cognate receptors (e.g., bevacizumab), optionally further comprising a chemotherapy regimen (e.g., FOLFIRI).

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit under 35 U.S.C. §119(e) to U.S. Provisional Application No. 63 / 327,584, filed April 5, 2022, which is incorporated by reference herein in its entirety for all purposes.

[0002] Sequence Listing This application contains a Sequence Listing that has been submitted electronically in XML file format, which is incorporated herein by reference in its entirety. The XML copy created on January 14, 2023 is named 1433-WO-PCT_SL.xml and is 444,843 bytes in size. [Background technology]

[0003] Metastatic colorectal adenocarcinoma ranks as the second most lethal cancer and the third most prevalent malignancy worldwide. In 2018, 1.8 million new cases and 881,000 deaths were reported, accounting for nearly 10% of new cancer cases and deaths worldwide (Bray, et al., CA Cancer J Clin (2018) 68 (6): 394-424). The number of new cases is expected to increase to nearly 2.5 million in 2035 (Dekker, et al., Lancet (2019) 394 (10207): 1467-80). In the United States, metastatic colorectal cancer (mCRC) is the second leading cause of cancer death (Siegel, et al., CA Cancer J Clin (2018) 68 (1): 7-30). In 2020, 148,000 new diagnoses and 53,200 deaths were reported, including 17,930 cases and 3,640 deaths in individuals under 50 years of age. The 5-year survival rate is approximately 15% (Surveillance Epidemiology and End Results (SEER) 2021; https: / / seer.cancer.gov). Although screening strategies and new treatment modalities have been initiated to reduce overall CRC mortality, the development of progressive metastatic disease remains associated with poor long-term survival. Recent data demonstrate a continuous decline in incidence and mortality in patients at least 65 years of age, but an inverse increase in patients under 65 years of age. The etiology of this phenomenon has yet to be determined, and differences in genetics may be a contributing factor.

[0004] Colorectal cancer is a heterogeneous disease complicated by the common occurrence of several molecular alterations involving the epidermal growth factor receptor (EGFR) pathway, including mutations in Kirsten rat sarcoma (KRAS), neuroblastoma RAS viral oncogene homolog (NRAS), and v-raf murine sarcoma viral oncogene homolog B1 (BRAF[V600E]), as well as in the human epidermal growth factor receptor 2 (HER2) and MET receptor. Other molecular alterations include DNA damage repair mechanisms and rare kinase fusions. Furthermore, tumor lateralization is associated with distinct clinical and biological features. Right-sided CRC is more common in women and is associated with Lynch syndrome, mitogen-activated protein kinase (MAPK) signaling, high microsatellite instability (MSI-H), mismatch repair gene deficiencies, CpG island methylation, and KRAS and BRAF mutations. Left-sided CRC is more common in men and is associated with familial adenomatous polyposis polyposis syndrome, wingless-related integration sites (Wnt) and EGFR signaling, chromosomal instability, v-erb-b2 erythroblastic leukemia viral oncogene homolog 1 (ERBB1) and ERBB2 amplification, adenomatous polyposis coli (APC), p53, and NRAS mutations. These alterations represent oncogenic drivers that may coexist in the same tumor with other primary and acquired alterations through the process of clonal selection.

[0005] There have been advances in therapy of CRC in targeted subgroups with specific mutational profiles. However, resistance to these targeted agents as well as standard chemotherapy based on specific molecular alterations have complicated treatment. Increasingly, enhanced knowledge of tumor biology is driving therapeutic decision-making. The optimal combination and sequencing of these agents continues to evolve. Known biologic drugs that are active against mCRC include agents targeting vascular endothelial growth factor (VEGF) and their receptors (VEGFR), EGFR, BRAF V600E, HER2, immunotherapy using immune checkpoint inhibitors, and tropomyosin receptor kinase (TRK) inhibitors. Biomarkers have been defined for agents targeting EGFR, HER2, TRK fusions, and patients who are candidates for immunotherapy, but not yet for other agents. Systemic chemotherapy in combination with anti-EGFR antibodies such as cetuximab and panitumumab has a markedly improved prognosis in KRAS wild-type patients (Lee, et al., Clin Colorectal Cancer (2015) 14(4):203-18). In addition, patients with MSI-H have demonstrated superior responses to checkpoint inhibitors, such as the anti-programmed cell death-1 (PD-1) agent pembrolizumab (Le, et al., N Engl J Med (2015) 372(26):2509-20; Overman, et al., Abstract 3501, American Society of Clinical Oncology (ASCO) Annual Meeting; 2016 03-07 June; Chicago, Illinois), although this represents only a subset of this tumor type (10%-15% at diagnosis). On the other hand, certain subsets of patients, such as those with KRAS mutations, which constitute more than 40% of CRCs (Vaughn, et al., Genes Chromosomes Cancer (2011) 50(5):307-12), do not respond to anti-EGFR antibody therapy (Allegra, et al., J Clin Oncol (2009) 27(12):2091-6). Patients with KRAS mutant mCRC have a poor prognosis but limited available therapies. For the majority of patients who are ineligible or unable to benefit from new targeted or immunotherapies, standard of care (SOC) double- or triple-drug chemotherapy-based regimens, which are associated with systemic toxicity, unsatisfactory response rates, unpredictable innate and acquired resistance, and low tumor-specific selectivity, are the only available treatment options. [Prior art documents] [Non-patent literature]

[0006] [Non-Patent Document 1] Bray, et al., CA Cancer J Clin(2018)68(6):394-424 [Non-Patent Document 2] Dekker, et al., Lancet (2019) 394(10207):1467-80

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Summary of the Invention

[0007] In one aspect, a method of treating previously treated progressive inoperable metastatic colorectal cancer in a subject is provided, comprising co-administering to the subject effective amounts of (a) an agent that inhibits binding between CD47 and SIRPα, and (b) an agent that inhibits binding between vascular endothelial growth factor A (VEGFA) and one or more VEGFA cognate receptors. In some embodiments, the one or more VEGFA cognate receptors are selected from fms-related receptor tyrosine kinase 1 (FLT1, also known as VEGFR1) and kinase insert domain receptor (KDR, also known as VEGFR2). In some embodiments, the agent that inhibits binding between CD47 and SIRPα comprises an antibody that binds CD47. In some embodiments, the antibody that binds CD47 is selected from magrolimab, lemzoparlimab, letaplimab, ligufalimab, AO-176, simridarlimab (IBI-322), gentulizumab, 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 agent that inhibits binding between CD47 and SIRPα comprises an antibody that binds SIRPα. In some embodiments, the antibody that binds SIRPα is selected from GS-0189 (also known as FSI-189), CC-95251, BI-765063, and APX-700. In some embodiments, the agent that inhibits binding between CD47 and SIRPα comprises a SIRPα-Fc fusion protein. In some embodiments, the SIRPα-Fc fusion protein is selected from evorpacept (ALX-148), timdarpacept, TTI-621, TTI-622, JMT601 (CPO107), and SL-172154.In some embodiments, the agent that inhibits binding between VEGFA and one or more VEGFA cognate receptors comprises an antibody that binds to VEGFA. In some embodiments, the antibody that binds to VEGFA is selected from bevacizumab, ranibizumab, brolucizumab, ivonescimab, sevacizumab, and faricimab. In some embodiments, the agent that inhibits binding between VEGFA and one or more VEGFA cognate receptors comprises an antibody that binds to VEGFR2. In some embodiments, the antibody that binds to VEGFR2 is ramucirumab. In some embodiments, the agent that inhibits binding between VEGFA and one or more VEGFA cognate receptors comprises a VEGFA-Fc fusion protein. In some embodiments, the VEGFA-Fc fusion protein is selected from conbercept and aflibercept. In some embodiments, the agent that inhibits binding between VEGFA and one or more VEGFA cognate receptors comprises a small molecule inhibitor. In some embodiments, the small molecule is selected from surufatinib, catequentinib hydrochloride, fruquintinib, tivozanib, regorafenib, axitinib, vandetanib, chiauranib, pazopanib hydrochloride, sunitinib malate, and pegaptanib octasodium.

[0008] In another aspect, a method of treating, alleviating, reducing, preventing, or delaying recurrence or metastasis of colorectal cancer (CRC) in a subject is provided, comprising co-administering to the subject an effective amount of magrolimab and bevancizumab. In some embodiments, the cancer is (i) unresectable, locally advanced, or (ii) metastatic. In some embodiments, the cancer is unresectable, locally advanced, and the subject is treatment naive. In another aspect, a method of treating previously treated progressive inoperable metastatic colorectal cancer in a subject is provided, comprising co-administering to the subject an effective amount of (a) magrolimab and (b) bevancizumab. In some embodiments, magrolimab is initially administered at a priming dose of less than 10 mg / kg, followed by one or more therapeutic doses of at least 15 mg / kg, e.g., at least 30 mg / kg, 45 mg / kg, 60 mg / kg. In some embodiments, magrolimab is administered initially at a priming dose of less than 5 mg / kg, then at one or more therapeutic doses of at least 30 mg / kg, e.g., 45 mg / kg, 60 mg / kg. In some embodiments, magrolimab is administered initially at a priming dose of 1 mg / kg, then at one or more therapeutic doses of 30 mg / kg, followed by one or more therapeutic doses of 60 mg / kg. In some embodiments, magrolimab is administered initially at a priming dose of 1 mg / kg, then at one or more therapeutic doses of 20 mg / kg, followed by one or more therapeutic doses of 45 mg / kg. In some embodiments, magrolimab is administered initially at a priming dose of 1 mg / kg, then at one or more therapeutic doses of 15 mg / kg, followed by one or more therapeutic doses of 30 mg / kg. In some embodiments, magrolimab is administered intravenously, subcutaneously, or intratumorally. In some embodiments, bevacizumab is administered in one or more doses ranging from 5 mg / kg to 15 mg / kg, e.g., from 5 mg / kg to 7.5 mg / kg, or from 7.5 mg / kg to 15 mg / kg.In some embodiments, bevacizumab is administered at one or more doses of 5 mg / kg. In some embodiments, bevacizumab is administered intravenously, subcutaneously, or intratumorally. In some embodiments, magrolimab and bevacizumab are administered over a first, second, and third 28 day cycle, (a) in the first 28 day cycle, magrolimab is administered at a dose of 1 mg / kg on day 1 and at a dose of 30 mg / kg weekly (QW) starting on day 8, and bevacizumab is administered at a dose of 5 mg / kg on days 1 and 15; (b) in the second 28 day cycle, magrolimab is administered at a dose of 30 mg / kg weekly (QW) and bevacizumab is administered at a dose of 5 mg / kg on days 1 and 15; and (c) in the third 28 day cycle, magrolimab is administered at a dose of 30 mg / kg Q2W and bevacizumab is administered at a dose of 5 mg / kg on days 1 and 15. In some embodiments, magrolimab and bevacizumab are administered over a first, second, and third 28 day cycle, (a) in the first 28 day cycle, magrolimab is administered at a dose of 1 mg / kg on day 1 and at a dose of 20 mg / kg weekly (QW) starting on day 8, and bevacizumab is administered at a dose of 5 mg / kg on days 1 and 15; (b) in the second 28 day cycle, magrolimab is administered at a dose of 20 mg / kg weekly (QW) and bevacizumab is administered at a dose of 5 mg / kg on days 1 and 15; and (c) in the third 28 day cycle, magrolimab is administered at a dose of 20 mg / kg Q2W and bevacizumab is administered at a dose of 5 mg / kg on days 1 and 15.In some embodiments, magrolimab and bevacizumab are administered over a first, second, and third 28 day cycle, (a) in the first 28 day cycle, magrolimab is administered at a dose of 1 mg / kg on day 1 and at a dose of 15 mg / kg weekly (QW) starting on day 8, and bevacizumab is administered at a dose of 5 mg / kg on days 1 and 15; (b) in the second 28 day cycle, magrolimab is administered at a dose of 15 mg / kg weekly (QW) and bevacizumab is administered at a dose of 5 mg / kg on days 1 and 15; and (c) in the third 28 day cycle, magrolimab is administered at a dose of 15 mg / kg Q2W and bevacizumab is administered at a dose of 5 mg / kg on days 1 and 15.

[0009] With respect to further embodiments of the methods described above and herein, in some embodiments, the method further comprises concurrently administering a chemotherapy regimen. In some embodiments, the method comprises concurrently administering a FOLFOX regimen, a FOLFIRI regimen, a XELIRI (also known as CAPIRI) regimen, a FOLFOXIRI regimen, a XELOXIRI regimen, or a FOLFIRINOX regimen. In some embodiments, the method comprises concurrently administering a FOLFIRI regimen or a XELIRI regimen. In some embodiments, the method comprises concurrently administering a FOLFIRI regimen. In some embodiments, the cancer has cell surface expression of CD47. In some embodiments, the cancer does not comprise a BRAF V600E mutation. In some embodiments, the cancer does not comprise high or observable or detectable microsatellite instability. In some embodiments, the cancer has one or more KRAS mutations, and the subject has not responded to anti-EGFR antibody therapy (e.g., the cancer has progressed or has not regressed). In some embodiments, the cancer is an adenocarcinoma originating from the colon or rectum. In some embodiments, the cancer has progressed after one or more prior systemic therapies. In some embodiments, the one or more prior therapies include administration of one or more agents selected from the group consisting of 5-fluorouracil (5-FU), oxaliplatin, bevacizumab, cetuximab, and panitumumab. In some embodiments, the treatment results in a reduction in total tumor burden of at least 15%, at least 20%, at least 30%, or at least 40%, as determined using a linear dimensional method (e.g., RECIST v1.1). In some embodiments, the method includes reducing the size or eliminating metastases. In some embodiments, the method further includes administering one or more therapeutic antibodies. In some embodiments, the method includes co-administering an antibody that binds to epidermal growth factor receptor (EGFR). In some embodiments, the antibody that binds to EGFR is selected from cetuximab and panitumumab.In some embodiments, the method further comprises co-administering one or more blockers or inhibitors of one or more T cell stimulatory immune checkpoint proteins or receptors. In some embodiments, the one or more immune checkpoint inhibitors comprise a proteinaceous (e.g., antibody) inhibitor of PD-L1 (CD274), PD-1 (PDCD1), or CTLA4. In some embodiments, the one or more immune checkpoint proteins or receptors are selected from CD274 (CD274, PDL1, PD-L1) and programmed cell death 1 (PDCD1, PD1, PD-1). In some embodiments, proteinaceous (e.g., antibody) inhibitors of CTLA4 include ipilimumab, tremelimumab, BMS-986218, AGEN1181, AGEN1884 (zalifrelimab), BMS-986249, MK-1308, REGN-4659, ADU-1604, CS-1002, BCD-145, APL-509, JS-007, BA-3071, ONC-392, AGEN-2041, JHL-1155, K N-044, CG-0161, ATOR-1144, PBI-5D3H5, FPT-155 (CTLA4 / PD-L1 / CD28), PF-06936308 (PD-1 / CTLA4), MGD-019 (PD-1 / C TLA4), KN-046 (PD-1 / CTLA4), MEDI-5752 (CTLA4 / PD-1), XmAb-20717 (PD-1 / CTLA4), and AK-104 (CTLA4 / PD-1).In some embodiments, proteinaceous (e.g., antibody) inhibitors of programmed cell death 1 (PDCD1; NCBI Gene ID: 5133; CD279, PD-1, PD1) include zimberelimab (AB122, GLS-010, WBP-3055), pembrolizumab (KEYTRUDA®, MK-3475, SCH900475), nivolumab (OPDIVO®, BMS-936558, MDX-1106), cemiplimab (LIBTAYO®; cemiplimab-rwlc, REGN-2810 ), pidilizumab (CT-011), AMG-404, MEDI0680 (AMP-514), spartalizumab (PDR001), tislelizumab (BGB-A317), toripalimab (JS-001), genolimzumab (CBT-501, APL-501, GB226), SHR-1201, camrelizumab (SHR-1210), sintilimab (TYVYT®, IBI-308), dostarlimab (TSR-042 , WBP-285), lambrolizumab (MK-3475); sasanlimab (PF-06801591), cetrelimab (JNJ-63723283), serplulimab (HLX-10), retifanlimab (MGA-012), balstilimab (AGEN2034), prorugolimab (BCD100), budigalimab (ABBV-181), bopratelimab (JTX-4014), AK-103 (HX-008), AK-105, CS1003, BI-754091, LZM-009, Sym-021, BAT-1306, P D1-PIK, tevotelimab (MGD013; PD-1 / LAG-3), RO-7247669 (PD-1 / LAG-3), FS-118 (LAG-3 / PD-L1), RO-7121661 (PD1 / TIM-3), RG7769 (PD-1 / TIM-3), PF-06936 308 (PD1 / CTLA4), MGD-019 (PD-1 / CTLA4), KN-046 (PD1 / CTLA4), XmAb-20717 (PD1 / CTLA4), AK-104 (CTLA4 / PD-1), and MEDI-5752 (CTLA4 / PD-1).In some embodiments, proteinaceous (e.g., antibody) inhibitors of the CD274 molecule (NCBI Gene ID: Gene ID:29126; B7-H, B7H1, PD-L1) are selected from the group consisting of atezolizumab (TECENTRIQ®), avelumab (BAVENCIO®; MSB0010718C), embafolimab (ASC22), durvalumab (IMFINZI®; MEDI-4736), BMS-936559 (MDX1105), cosibelimab (CK-301), lodapolimab (LY3300054), garivulimab (BGB A333), envafolimab (KN035), opucolimab (HLX20), manelimab (BCD135), CX-072, CBT-502 (TQB2450), MSB-2311, SHR-1316, sugemalimab (CS-1001; WBP3155), A167 (KL-A167, HBM9167), STI-A1015 (IMC-001), FAZ-053, BM The agonist is selected from S-936559 (MDX1105), INCB086550, GEN-1046 (PD-L1 / 4-1BB), FPT-155 (CTLA4 / PD-L1 / CD28), M7824 (PD-L1 / TGFβ-EC domain), CA-170 (PD-L1 / VISTA), CDX-527 (CD27 / PD-L1), LY-3415244 (TIM-3 / PDL1), INBRX-105 (4-1BB / PDL1), and GNS-1480 (PD-L1 / EGFR). In some embodiments, the method comprises co-administering an agonist of fms-related receptor tyrosine kinase 3 (FLT3). In some embodiments, the agonist of FLT3 is selected from GS-3583 and CDX-301. In some embodiments, the agent that inhibits binding between CD47 and SIRPα and the agent that inhibits binding between VEGFA and one or more VEGFA cognate receptors are administered in a combined synergistic amount.In some embodiments, administration of an agent that inhibits binding between CD47 and SIRPα and an agent that inhibits binding between VEGFA and one or more VEGFA cognate receptors provides a synergistic effect. In some embodiments, the synergistic effect is increased cancer cell death and / or decreased cancer cell growth when comparing the effect of the combination to either an agent that inhibits binding between CD47 and SIRPα or an agent that inhibits binding between VEGFA and one or more VEGFA cognate receptors alone. In some embodiments, the synergistic effect is increased phagocytosis of cancer cells by macrophages when comparing the effect of the combination to either an agent that inhibits binding between CD47 and SIRPα or an agent that inhibits binding between VEGFA and one or more VEGFA cognate receptors alone. In some embodiments, the synergistic effect is increased or enhanced tumor burden reduction when comparing the effect of the combination to either an agent that inhibits binding between CD47 and SIRPα or an agent that inhibits binding between VEGFA and one or more VEGFA cognate receptors alone. In some embodiments, the subject is a human.

[0010] In a further aspect, a kit is provided that includes one or more unit doses of (a) an agent that inhibits binding between CD47 and SIRPα, and (b) an agent that inhibits binding between vascular endothelial growth factor A (VEGFA) and one or more VEGFA cognate receptors. In some embodiments, the one or more VEGFA cognate receptors are selected from fms-related receptor tyrosine kinase 1 (FLT1, also known as VEGFR1) and kinase insert domain receptor (KDR, also known as VEGFR2). In some embodiments, the kit further includes one or more unit doses of a chemotherapy regimen. In some embodiments, the kit further includes components (e.g., active agents) for a FOLFOX regimen, a FOLFIRI regimen, a XELIRI (also known as CAPIRI) regimen, a FOLFOXIRI regimen, a XELOXIRI regimen, or a FOLFIRINOX regimen. In some embodiments, the kit includes components for a FOLFIRI regimen or a XELIRI regimen. In some embodiments, the kit includes components for a FOLFOX regimen, a FOLFIRI regimen, a XELIRI (also known as CAPIRI) regimen, a FOLFOXIRI regimen, a XELOXIRI regimen, or a FOLFIRINOX regimen. In some embodiments, the kit includes components for a FOLFIRI regimen or a XELIRI regimen. In some embodiments, the agent that inhibits binding between CD47 and SIRPα (e.g., magrolimab) and the agent that inhibits binding between vascular endothelial growth factor A (VEGFA) and one or more VEGFA cognate receptors (e.g., bevacizumab) are in separate containers. In some embodiments, the separate containers are selected from vials, ampoules, and pre-filled syringes. In some embodiments, the agent that inhibits binding between CD47 and SIRPα includes an antibody that binds to CD47. In some embodiments, the antibody that binds CD47 is selected from magrolimab, lemzoparlimab, retaplimab, ligfalimab, AO-176, simlidarlimab (IBI-322), gentulizumab, 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 agent that inhibits binding between CD47 and SIRPα comprises an antibody that binds to SIRPα. In some embodiments, the antibody that binds to SIRPα is selected from GS-0189 (also known as FSI-189), CC-95251, BI-765063, and APX-700. In some embodiments, the agent that inhibits binding between CD47 and SIRPα comprises a SIRPα-Fc fusion protein. In some embodiments, the SIRPα-Fc fusion protein is selected from ALX-148, TTI-621, TTI-622, JMT601 (CPO107), and SL-172154. In some embodiments, the kit further comprises one or more unit doses of one or more therapeutic antibodies. In some embodiments, the kit further comprises one or more blockers or inhibitors of one or more T cell inhibitory immune checkpoint proteins or receptors. In some embodiments, the kit comprises a proteinaceous (e.g., antibody) inhibitor of PD-L1 (CD274), PD-1 (PDCD1), or CTLA4. In some embodiments, the kit comprises a proteinaceous (e.g., antibody) inhibitor of PD-L1 (CD274) or PD-1 (PDCD1). In some embodiments, the proteinaceous (e.g., antibody) inhibitor of CTLA4 is selected from the group consisting of ipilimumab, tremelimumab, BMS-986218, AGEN1181, AGEN1884 (zalifrelimab), BMS-986249, MK-1308, REGN-4659, ADU-1604, CS-1002, BCD-145, APL-509, JS-007, BA-3071, ONC-392, AGEN2041, JHL-1155, KN -044, CG-0161, ATOR-1144, PBI-5D3H5, FPT-155 (CTLA4 / PD-L1 / CD28), PF-06936308 (PD-1 / CTLA4), MGD-019 (PD-1 / C TLA4), KN-046 (PD-1 / CTLA4), MEDI-5752 (CTLA4 / PD-1), XmAb-20717 (PD-1 / CTLA4), and AK-104 (CTLA4 / PD-1).In some embodiments, proteinaceous (e.g., antibody) inhibitors of programmed cell death 1 (PDCD1; NCBI Gene ID: 5133; CD279, PD-1, PD1) include, but are not limited to, zimberelimab (AB122, GLS-010, WBP-3055), pembrolizumab (KEYTRUDA®, MK-3475, SCH900475), nivolumab (OPDIVO®, BMS-936558, MDX-1106), cemiplimab (LIBTAYO®; cemiplimab-rwlc, REG N-2810), pidilizumab (CT-011), AMG-404, MEDI0680 (AMP-514), spartalizumab (PDR001), tislelizumab (BGB-A317), toripalimab (JS-001), genolimuzumab (CBT-501, APL-501, GB226), SHR-1201, camrelizumab (SHR-1210), sintilimab (TYVYT®, IBI-308), dostallimab (TSR-042, WBP-285), lambrolizumab (MK-3475); Sasanlimab (PF-06801591), cetrelimab (JNJ-63723283), serplulimab (HLX-10), retifanlimab (MGA-012), balstilimab (AGEN2034), prorugolimab (BCD100), budigalimab (ABBV-181), bopratelimab (JTX-4014), AK-103 (HX-008), AK-105, CS1003, BI-754091, LZM-009, Sym-021, BAT-1306, PD1-PIK, tebotelimab (MGD013 ;PD-1 / LAG-3), RO-7247669(PD-1 / LAG-3), FS-118(LAG-3 / PD-L1), RO-7121661(PD1 / TIM-3), RG7769(PD-1 / TIM-3), PF-06936308(PD1 / CT LA4), MGD-019 (PD-1 / CTLA4), KN-046 (PD1 / CTLA4), XmAb-20717 (PD1 / CTLA4), AK-104 (CTLA4 / PD-1), and MEDI-5752 (CTLA4 / PD-1).In some embodiments, proteinaceous (e.g., antibody) inhibitors of the CD274 molecule (NCBI Gene ID: Gene ID:29126; B7-H, B7H1, PD-L1) are selected from the group consisting of atezolizumab (TECENTRIQ®), avelumab (BAVENCIO®; MSB0010718C), embafolimab (ASC22), durvalumab (IMFINZI®; MEDI-4736), BMS-936559 (MDX1105), cosibelimab (CK-301), lodapolimab (LY3300054), galibrimab (BGB A333), embafolimab (KN035), opcolimab (HLX20), manelimab (BCD135), CX-072, CBT-502 (TQB2450), MSB-2311, SHR-1316, sugemalimab (CS-1001; WBP3155), A167 (KL-A167, HBM9167), STI-A1015 (IMC-001), FAZ-053, BMS-936559 (MDX1105), INCB086 550, GEN-1046 (PD-L1 / 4-1BB), FPT-155 (CTLA4 / PD-L1 / CD28), M7824 (PD-L1 / TGFβ-EC domain), CA-170 (PD-L1 / VISTA), CDX-527 (CD27 / PD-L1), LY-3415244 (TIM-3 / PDL1), INBRX-105 (4-1BB / PDL1), and GNS-1480 (PD-L1 / EGFR). In some embodiments, the kit further comprises co-administering an agonist of fms-related receptor tyrosine kinase 3 (FLT3). In some embodiments, the agonist of FLT3 is selected from GS3583 and CDX-301. [Brief description of the drawings]

[0011] [Figure 1]1 shows a schematic diagram of the clinical studies described herein. 5-FU=5-fluorouracil; CRC=colorectal cancer; EU=European Union; FOLFIRI=5-fluorouracil, irinotecan, and leucovorin; KRAS=Kirsten rat sarcoma; KRASmt=KRAS mutant; KRASwt=KRAS wild type; ROW=rest of world; US=United States; FOLFIRI: irinotecan 180 mg / m2, leucovorin 400 mg / m2, fluorouracil 400 mg / m2.

[0012] [Figure 2A] Figure 1 shows that irinotecan upregulates the expression of pro-phagocytic receptors and promotes in vitro phagocytosis of colorectal cancer cells. A. LS 174T cells were incubated with titrations of irinotecan for 24 h, washed, and stained for CALR and PS. The frequency of stained cells was analyzed and quantified using flow cytometry. Shaded areas indicate the reported IC50 for each drug. B. LS-174T or HCT-116 cells were pretreated with the indicated concentrations of irinotecan or oxaliplatin for 24 h. Tumor cells were washed, CFSE-labeled, and co-cultured with monocyte-derived macrophages at a target-to-effector ratio of 2:1 for 2 h. The phagocytic index, defined as the percentage of macrophages that phagocytosed tumor cells among all macrophages, was quantified using flow cytometry. 5F9, Magro = Magrolimab; CALR = calreticulin; CFSE = carboxyfluorescein succinimidyl ester; hr = time; IC50 = half maximal inhibitory concentration; MFI = median fluorescence intensity; PBS = phosphate buffered saline; PS = phosphatidylserine; SN 38 = irinotecan. [Figure 2B]Figure 1 shows that irinotecan upregulates the expression of pro-phagocytic receptors and promotes in vitro phagocytosis of colorectal cancer cells. A. LS 174T cells were incubated with titrations of irinotecan for 24 h, washed, and stained for CALR and PS. The frequency of stained cells was analyzed and quantified using flow cytometry. Shaded areas indicate the reported IC50 for each drug. B. LS-174T or HCT-116 cells were pretreated with the indicated concentrations of irinotecan or oxaliplatin for 24 h. Tumor cells were washed, CFSE-labeled, and co-cultured with monocyte-derived macrophages at a target-to-effector ratio of 2:1 for 2 h. The phagocytic index, defined as the percentage of macrophages that phagocytosed tumor cells among all macrophages, was quantified using flow cytometry. 5F9, Magro = Magrolimab; CALR = calreticulin; CFSE = carboxyfluorescein succinimidyl ester; hr = time; IC50 = half maximal inhibitory concentration; MFI = median fluorescence intensity; PBS = phosphate buffered saline; PS = phosphatidylserine; SN 38 = irinotecan.

[0013] [Diagram 3] Figure 1 shows that colorectal cancer cells undergo growth inhibition by irinotecan and oxaliplatin. Tumor cells were treated with titrations of irinotecan, oxaliplatin, or vehicle control and monitored for growth 24, 48, and 72 hours after drug treatment. Cell growth was determined indirectly using a commercially available reagent (Promega, Cell-titer Glo®) that measures intracellular adenosine triphosphate (ATP) levels and directly correlates to the number of viable cells. Treated cells were normalized to dimethylsulfoxide-treated control samples to determine the percentage of growth inhibition. DMSO = dimethylsulfoxide; Oxa = oxaliplatin; SN-38 = irinotecan.

[0014] [Figure 4]We show that the combination of irinotecan and magrolimab results in additive therapeutic effects in a chlordiazepoxide (CDX) model of colorectal cancer (CRC). IP = intraperitoneal; Magro = magrolimab. NOD scid gamma mice were implanted subcutaneously with 3 million HT-29 cells. When the mean tumor volume reached 60-120 mm3, mice were randomized into groups of 8 and treated with isotype or magrolimab by IP injection (250 μg, 3 times per week). Irinotecan (20 mg / kg, 3 times per week) and oxaliplatin (5 mg / kg, 2 times per week) were also administered by IP injection. Tumor volumes were generated using caliper measurements and reported for the duration of the study. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0015] 1. Introduction Provided is a method of treating previously treated progressive inoperable metastatic colorectal cancer in a subject, comprising co-administering to the subject an effective amount of (a) an agent that inhibits binding between CD47 and SIRPα (e.g., magrolimab), and (b) an agent that inhibits binding between vascular endothelial growth factor A (VEGFA) and one or more VEGFA cognate receptors (e.g., bevacizumab). Surprisingly, the combined administration of an agent that inhibits binding between CD47 and SIRPα (e.g., magrolimab) and an agent that inhibits binding between vascular endothelial growth factor A (VEGFA) and one or more VEGFA cognate receptors (e.g., bevacizumab) results in synergistic (i.e., more than additive) reduction in phagocytosis and tumor growth of colorectal cancer cells.

[0016] The role of chemotherapy in metastatic colorectal cancer Despite well-known genetic differences in the disease, chemotherapy treatment of CRC remains largely uniform. Patients with newly diagnosed mCRC are generally treated with 5-fluorouracil (5FU)-based regimens such as FOLFOX (5-FU, oxaliplatin, and leucovorin [LV]) or FOLFIRI (5FU, irinotecan, and leucovorin), alone or in combination with therapies that block EGFR or VEGF signaling.

[0017] A meta-analysis of seven phase 3 studies evaluating treatment regimens associating 5-FU / LV, oxaliplatin, and irinotecan demonstrated that patients receiving the three drugs showed prolonged survival compared to patients receiving a single two-drug, regardless of the first two-drug regimen used (Grothey, et al., J Clin Oncol (2004) 22(7):1209-14). However, capecitabine shows equivalence to 5-FU and is a well-tolerated alternative association to irinotecan or oxaliplatin. After disease progression, crossover second-line regimens associating fluoropyrimidine / oxaliplatin or fluoropyrimidine / irinotecan with another agent showed satisfactory response rates with stable disease over a period of several months (Tournigand, et al., J Clin Oncol (2004) 22(2):229-37). The association of FOLFIRI and FOLFOX6 was evaluated for first- or second-line crossover after progression. Both arms showed similar response rates (first-line: FOLFIRI 56% vs. FOLFOX 54% and second-line: FOLFIRI 4% vs. FOLFOX 15%). There were no notable differences in progression-free survival (PFS) (first-line: FOLFIRI 8.5 months vs. FOLFOX 8.0 months and second-line: FOLFIRI 2.5 months vs. FOLFOX 4.2 months) or overall survival (OS) (FOLFIRI-FOLFOX: 21.5 months vs. FOLFOX FOLFIRI 20.6 months).

[0018] Rationale for combination therapy co-targeting CD47 and VEGFA Cluster of differentiation 47 (CD47; NCBI Gene ID: 961) is a molecule that mediates cancer cell evasion of innate immune surveillance. CD47 expression is a well-characterized mechanism by which cancer cells, including cancer stem cells, overcome phagocytosis due to endogenous expression of pro-phagocytic "eat me" signals (Jaiswal, et al., Cell (2009) 138(2): 271-85; Majeti, et al., Cell (2009) 138(2): 286-99). Progression of normal cells to cancer cells involves changes in genes and / or gene expression that lead to programmed cell death and programmed cell elimination (Chao, et al., Nat Rev Cancer. (2012) 12(1): 58-67). Many of the steps in cancer progression subvert multiple mechanisms of programmed cell death, and expression of the dominant anti-phagocytic signal, CD47, may represent a critical checkpoint (Chao, et al., 2012, supra). Increased CD47 expression was first identified on leukemic stem cells in human acute myeloid leukemia (AML) (Majeti, et al., 2009, supra), and since then, CD47 expression has been found to be increased on the surface of cancer cells in a diverse set of human tumor types.

[0019] In mouse xenograft models, CD47-blocking monoclonal antibodies (mAbs) inhibit human xenograft tumor growth and metastasis by enabling phagocytosis and clearance of cancer cells from various hematological malignancies and solid tumors (Chao, et al., Cancer Res (2011) 71(4):1374-84; Chao, et al., Cell (2010) 142:699-713; Chao, et al., Blood (2011) 118(18):4890-901; Edris, et al., Proc Natl Acad Sci USA (2012) 109(17):6656-61; Kim, et al., Proc Natl Acad Sci USA (2012) 109(17):6656-61; Majeti, et al., supra; Willingham, et al., Proc Natl Acad Sci USA (2012) 109(17):6656-61). USA (2012) 109(17):6662-7). Binding of CD47 expressed by cancer cells to its ligand signal regulatory protein alpha (SIRPα) expressed on phagocytes results in inhibition of tumor cell phagocytosis. Thus, blocking the CD47 SIRPα signaling pathway with anti-CD47 antibodies results in phagocytosis and elimination of tumor cells. The selective targeting of tumor cells by anti-CD47 antibodies is due to the presence of pro-phagocytic signals that are primarily expressed on tumor cells and not on their normal cell counterparts (Chao, et al., Sci Transl Med (2010) 2(63):63ra94). In addition, anti-CD47 antibodies can induce anti-cancer T cell responses through cross-presentation of tumor antigens by macrophages and antigen-presenting cells following tumor cell phagocytosis (Liu, et al., Nat Med (2015) 21(10):1209-15; Tseng, et al., Proc Natl Acad Sci USA (2013) 110(27):11103-8).

[0020] Magrolimab is a humanized anti-CD47 mAb that blocks the interaction of CD47 with its receptors and allows phagocytosis of human cancer cells (Liu, et al., PLoS One. (2015) 10(9): e0137345). The activity of magrolimab depends primarily on blocking CD47 binding to SIRPα and not on recruiting crystallizable fragment (Fc)-dependent effector functions, although the presence of an immunoglobulin G4 (IgG4) Fc domain is required for its full activity. For this reason, magrolimab was engineered with a human IgG4 isotype that is relatively inefficient at recruiting Fc-dependent effector functions that may enhance toxic effects on normal CD47-expressing cells (Liu, et al., PLoS One. (2015), supra). Nonclinical studies using xenograft cancer models provide compelling evidence that magrolimab induces phagocytosis and clearance of cancer cells from human solid tumors and hematological malignancies. Based on this mechanism of action (MOA) and its potent preclinical activity, magrolimab is being developed as a potential treatment for solid tumors and hematological malignancies.

[0021] Vascular endothelial growth factor A (VEGFA, NCBI Gene ID: 7422; also referred to herein as VEGF) is a factor involved in tumor angiogenesis, permeability, and tumor vascularized survival (Gerber, et al., Cancer Res (2005) 65(3):671-80). VEGF inhibition induces disruption of recent neo-microvascularization and endothelial apoptosis (Erber, et al., FASEB J (2004) 18(2):338-40; Ferrara, et al., Endocrine Rev (2004) 25(4):581-611).

[0022] One VEGF pathway inhibitor is bevacizumab, a humanized monoclonal antibody that targets circulating VEGF and prevents tumor angiogenesis. The binding of bevacizumab to VEGF prevents the latter from binding to its endothelial cell membrane receptors (Flt-1 and kinase insert domain receptor (KDR)). The interaction of VEGF with its receptor in angiogenesis models induces tumor growth and neovascularization. In addition to antiangiogenic properties, targeting the VEGF pathway with bevacizumab has been reported to reduce the infiltration of immunosuppressive monocyte-derived suppressor cells and regulatory T cells, as well as upregulate cytotoxic T cells into the tumor microenvironment.

[0023] Randomized clinical studies have shown that bevacizumab in combination with fluoropyrimidine-based chemotherapy is an effective treatment for patients with mCRC, and such combinations are now considered standard of care in the first- and second-line settings (Hurwitz, et al., N Engl J Med (2004) 350(23):2335-42; Saltz, et al., J Clin Oncol (2008) 26(12):2013-9; Tebbutt, et al., J Clin Oncol (2010) 28(19):3191-8). Various studies have examined the efficacy of bevacizumab in patients who have not been previously exposed or treated with bevacizumab. In the bevacizumab-naive second-line setting, longer PFS (7.3 vs. 4.7 months, hazard ratio [HR] = 0.61, P value < 0.001) and OS (12.9 vs. 10.8 months, HR = 0.75, P value = 0.0011), as well as better response rates (22.7% vs. 8.6%, P value = 0.0001) were observed in the E3200 study comparing the combination of FOLFOX and bevacizumab with FOLFOX alone for patients with CRC that had progressed after FOLFOX therapy (Giantonio, et al., J Clin Oncol (2007) 25 (12): 1539-44).

[0024] The ML18147 study (Bennouna, et al., Lancet Oncol 2013) 14(1):29-37) and the BEBYP study (Masi, et al., Abstract LBA17, Ann Oncol. (2012) doi.org / 10.1016 / S0923-7534(20)34318-0) show that continued VEGF inhibition with bevacizumab plus standard second-line chemotherapy (switched from first-line regimen) beyond the first disease progression significantly extends OS and PFS in patients with mCRC. Continuation of bevacizumab for patients who progressed after first-line chemotherapy was still useful for improving PFS (5.7 vs. 4.1 months, HR=0.68, P-value<0.001) and OS (11.2 vs. 9.9 months, HR=0.81, P-value=0.0062) compared with standard chemotherapy alone.

[0025] Rationale for dose selection of magrolimab The rationale for the magrolimab dose proposed in this study is derived from safety, efficacy, and PK / pharmacodynamics (PD) data and modeling and simulation analyses based on data from all ongoing and completed clinical studies with magrolimab in patients with solid tumors, non-Hodgkin's lymphoma (NHL), and acute myeloid leukemia (AML) / myelodysplastic syndrome (MDS). In addition, non-clinical studies have demonstrated activity against both human solid tumors (e.g., breast, ovarian, pancreatic, colon, leiomyosarcoma, bladder, prostate, etc.) and hematological malignancies (acute myeloid leukemia (AML), acute lymphoblastic leukemia, non-Hodgkin's lymphoma (NHL), myeloma, myelodysplastic syndrome (MDS), among others).

[0026] In a first-in-human study of magrolimab in patients with solid tumors and lymphomas, after an initial priming dose of 1 mg / kg on day 1, magrolimab was tested as monotherapy at doses up to 45 mg / kg weekly. The use of an initial 1 mg / kg priming dose was integrated into the dosing regimen to mitigate on-target anemia induced by CD47 blockade. The initial priming dose results in the clearance of senescent RBCs that are sensitive to CD47 blockade and causes reticulocytosis of young RBCs that are unaffected by CD47 blockade (Chen, et al., Blood (ASH Annual Meeting Abstracts) (2018) 132 (Suppl 1): 2327). Utilizing a priming dose results in an initial, transient, mild anemia that generally normalizes to baseline over several weeks, even in the presence of repeated therapeutic doses of magrolimab (Advani, et al., N Engl J Med (2018) 379(18):1711-21; Liu, et al., PLoS One. (2015) 10(9):e0137345; Sikic, et al., J Clin Oncol (2019) 37(12):946-53). Based on PK-PD modeling, a maintenance dose of 30 mg / kg every 2 weeks is expected to provide >90% occupancy of CD47 receptors in peripheral blood and tumor tissue, and is therefore expected to provide maximum efficacy while maintaining adequate safety. In solid tumors where combination therapy is given according to 3-week cycles, dosing of magrolimab every 3 weeks optimizes patient and caregiver convenience. Magrolimab 60 mg / kg every 3 weeks is predicted to provide similar trough concentrations and receptor occupancy (RO) as the 30 mg / kg dose every 2 weeks, which has been used in Phase 3 studies in AML and MDS. Updated pharmacokinetic (PK) modeling from study 5F9005 (NCT03248479) showed that the 45 mg / kg every 3 weeks dose of magrolimab was suboptimal in maintaining trough concentrations compared with dosing of 30 mg / kg every 2 weeks and 60 mg / kg every 3 weeks.Maintaining adequate trough concentrations may be necessary for optimal efficacy, given that some patients may experience dose delays due to toxicity. Furthermore, PK / pharmacodynamic (PD) modeling also indicates that in these extended interval dosing regimens, RO will be maintained at maximal levels (>90%) in peripheral blood and tumor tissue. The proposed dosing regimen of magrolimab in this study is expected to have an acceptable safety profile based on the totality of safety data in multiple tumor populations, both as monotherapy and in combination with other tumor-targeting antibodies and chemotherapeutic agents.

[0027] 2. Drugs that inhibit the binding between CD47 and SIRPα a. An antibody or antigen-binding fragment thereof that binds to CD47 In various embodiments, the agent that inhibits binding between CD47 and SIRPα is an antibody or antigen-binding fragment thereof that binds to CD47 (also known as IAP, MER6, OA3; NCBI Gene ID: 961; UniProt Q08722). In various embodiments, the antibody that binds to CD47 has an Fc with effector function. In various embodiments, the antibody that binds to CD47 is an IgG4 or IgG1. Examples of useful anti-CD47 antibodies include, but are not limited to, magrolimab, lemzoparlimab, retaplimab, ligufalimab (AK117), AO-176, simlidarlimab (IBI-322), gentulizumab, ZL-1201, IMC-002, SRF-231, CC-90002 (also known as INBRX-103), NI-1701 (also known as TG-1801), STI-6643 (Vx-1004), CNTO-7108, RCT-1938, RRx-001, DSP-107, VT-1021, and SGN-CD47M.

[0028] In various embodiments, the antibody targeting CD47 is a bispecific antibody. Examples of bispecific antibodies targeting CD47 include IBI-322 (CD47 / PD-L1), IMM-0306 (CD47 / CD20), TJ-L1C4 (CD47 / PD-L1), HX-009 (CD47 / PD-1), PMC-122 (CD47 / PD-L1), PT-217, (CD47 / DLL3), IMM-26011 (CD47 / FLT3 ), IMM-0207 (CD47 / VEGF), IMM-2902 (CD47 / HER2), BH29xx (CD47 / PD-L1), IMM-03 (CD47 / CD20), IMM-2502 (CD47 / PD-L1), HMBD-004B (CD47 / BCMA), HMBD-004A (CD47 / CD33). Examples of anti-CD47 antibodies include, but are not limited to, IBI-188, TJC-4, SHR-1603, HLX-24, LQ-001, IMC-002, ZL-1201, IMM-01, B6H12, GenSci-059, TAY-018, PT-240, 1F8-GMCSF, SY-102, and KD-015.

[0029] In various embodiments, antibodies targeting CD47 comprise VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2 and VL-CDR3, each of which comprises the following amino acid sequences (according to Kabat): SEQ ID NOs: 1, 2, 3, 4, 5, and 6; SEQ ID NOs: 7, 8, 9, 10, 11, and 12; SEQ ID NOs: 13, 14, 15, 16, 17, and 18, SEQ ID NOs: 19, 20, 21, 22, 23, and 24, SEQ ID NOs: 210, 211, 212, 213, 214, and 215, SEQ ID NOs: 216, 217, 218, 219, 220, and 221, or SEQ ID NOs: 345, 346, 347, 348, 23, and 349.

[0030] In various embodiments, antibodies targeting CD47 comprise VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2 and VL-CDR3, each of which comprises the following amino acid sequences (according to IMGT): SEQ ID NOs: 25, 26, 27, 28, 29, and 6; SEQ ID NOs: 30, 31, 32, 33, 34, and 12; SEQ ID NOs: 35, 36, 37, 38, 39, and 18; SEQ ID NOs: 40, 41, 42, 43, 44, and 24, SEQ ID NOs: 222, 223, 224, 225, 226, and 215, SEQ ID NOs: 227, 228, 229, 230, 231, and 221, or SEQ ID NOs: 350, 351, 352, 353, 44, and 354.

[0031] In various embodiments, antibodies targeting CD47 comprise VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2 and VL-CDR3, each of which comprises the following amino acid sequences (according to Chothia): SEQ ID NOs: 45, 46, 47, 48, 29, and 49, SEQ ID NOs: 50, 51, 52, 53, 34, and 54, SEQ ID NOs: 55, 56, 57, 58, 39, and 59; SEQ ID NOs: 60, 61, 62, 62, 44 and 64, SEQ ID NOs: 232, 233, 234, 235, 226, and 236, SEQ ID NOs: 232, 237, 238, 239, 231, and 240, or SEQ ID NOs: 355, 356, 357, 358, 44, and 359.

[0032] In various embodiments, antibodies targeting CD47 comprise VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2 and VL-CDR3, each of which comprises the following amino acid sequences (according to Honegger): SEQ ID NOs: 65, 66, 67, 68, 69, and 49; SEQ ID NOs: 70, 71, 72, 73, 74, and 54, SEQ ID NOs: 75, 76, 77, 78, 79, and 59; SEQ ID NOs: 80, 81, 82, 83, 84, and 64, SEQ ID NOs: 241, 242, 243, 244, 245, and 246, SEQ ID NOs: 247, 248, 249, 239, 250, and 251, SEQ ID NOs: 342, 81, 82, 83, 84, and 64, or SEQ ID NOs: 360, 361, 362, 363, 84, and 359.

[0033] In various embodiments, antibodies targeting CD47 comprise VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2 and VL-CDR3, each of which comprises the following amino acid sequences: SEQ ID NOs: 1, 2, 3, 4, 5, and 6 (according to Kabat); SEQ ID NOs: 25, 26, 27, 28, 29, and 6 (according to IMGT); SEQ ID NOs: 45, 46, 47, 48, 29, and 49 (according to Chothia), or SEQ ID NOs: 65, 66, 67, 68, 69, and 49 (by Honegger).

[0034] In various embodiments, antibodies targeting CD47 comprise VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2 and VL-CDR3, each of which comprises the following amino acid sequences: SEQ ID NOs: 7, 8, 9, 10, 11, and 12 (according to Kabat); SEQ ID NOs: 30, 31, 32, 33, 34, and 12 (according to IMGT); SEQ ID NOs: 50, 51, 52, 53, 34, and 54 (from Chothia), or SEQ ID NOs: 70, 71, 72, 73, 74, and 54 (by Honegger).

[0035] In various embodiments, antibodies targeting CD47 comprise VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2 and VL-CDR3, each of which comprises the following amino acid sequences: SEQ ID NOs: 13, 14, 15, 16, 17, and 18 (according to Kabat); SEQ ID NOs: 35, 36, 37, 38, 39, and 18 (according to IMGT); SEQ ID NOs: 55, 56, 57, 58, 39, and 59 (from Chothia), or SEQ ID NOs: 80, 81, 82, 83, 84, and 64 (according to Honegger).

[0036] In various embodiments, antibodies targeting CD47 comprise VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2 and VL-CDR3, each of which comprises the following amino acid sequences: SEQ ID NOs: 19, 20, 21, 22, 23, and 24 (according to Kabat); SEQ ID NOs: 40, 41, 42, 43, 44, and 24 (according to IMGT); SEQ ID NOs: 60, 61, 62, 62, 44 and 64 (according to Chothia), or SEQ ID NOs: 80, 81, 82, 83, 84, and 64 (according to Honegger).

[0037] In various embodiments, antibodies targeting CD47 comprise VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2 and VL-CDR3, each of which comprises the following amino acid sequences: SEQ ID NOs: 210, 211, 212, 213, 214, and 215 (according to Kabat); SEQ ID NOs: 222, 223, 224, 225, 226, and 215 (according to IMGT); SEQ ID NOs: 232, 233, 234, 235, 226, and 236 (from Chothia), or SEQ ID NOs: 241, 242, 243, 244, 245, and 246 (by Honegger).

[0038] In various embodiments, antibodies targeting CD47 comprise VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2 and VL-CDR3, each of which comprises the following amino acid sequences: SEQ ID NOs: 216, 217, 218, 219, 220, and 221 (according to Kabat); SEQ ID NOs: 227, 228, 229, 230, 231, and 221 (according to IMGT); SEQ ID NOs: 232, 237, 238, 239, 231, and 240 (from Chothia), or SEQ ID NOs: 247, 248, 249, 239, 250, and 251 (by Honegger).

[0039] In various embodiments, antibodies targeting CD47 comprise VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2 and VL-CDR3, each of which comprises the following amino acid sequences: SEQ ID NOs: 339, 20, 21, 22, 23, and 24 (according to Kabat); SEQ ID NOs: 340, 41, 42, 43, 44, and 24 (according to IMGT); SEQ ID NOs: 341, 61, 62, 63, 44, and 64 (from Chothia), or SEQ ID NOs: 342, 81, 82, 83, 84, and 64 (according to Honegger).

[0040] In various embodiments, antibodies targeting CD47 comprise VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2 and VL-CDR3, each of which comprises the following amino acid sequences: SEQ ID NOs: 345, 346, 347, 348, 23, and 349 (according to Kabat); SEQ ID NOs: 350, 351, 352, 353, 44, and 354 (according to IMGT); SEQ ID NOs: 355, 356, 357, 358, 44, and 359 (from Chothia), or SEQ ID NOs: 360, 361, 362, 363, 84, and 359 (by Honegger).

[0041] In various embodiments, antibodies targeting CD47 comprise a VH and a VL that comprise the amino acid sequences set forth below, or that are at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequences set forth below, respectively. SEQ ID NOs: 85 and 86, SEQ ID NOs: 87 and 88, SEQ ID NOs: 89 and 90, SEQ ID NOs: 91 and 92, SEQ ID NOs: 252 and 253, SEQ ID NOs: 254 and 255, SEQ ID NOs: 343 and 344, or SEQ ID NOs: 364 and 365. Sequence identity can be determined according to the BLAST algorithm (blast.ncbi.nlm.nih.gov / Blast.cgi) using default settings.

[0042] The amino acid sequences of the CDRs and variable regions (VH / VL) of exemplary anti-CD47 antibodies that can be used in the methods of the invention are set forth in Tables A1, A2, A3, A4 and B. [Table A1] [Table A2] [Table A3] [Table A4] [Table B]

[0043] Additional anti-CD47 antibodies useful in the method include those disclosed in WO 199727873, WO 199940940, WO 2002092784, WO 2005044857, WO 2009046541, WO 2010070047, WO 2011143624, WO 2012170250, WO 2013109752, WO 2013119714, WO 2014087248, WO 2015191861, WO 201611262, WO 2015 ... No. 2016022971, No. 2016023040, No. 2016024021, No. 2016081423, No. 2016109415, No. 2016141328, No. 20161884 No. 49, No. 2017027422, No. 2017049251, No. 2017053423, No. 2017121771, No. 2017194634, No. 2017196793, No. 201721 No. 5585, No. 2018075857, No. 2018075960, No. 2018089508, No. 2018095428, No. 2018137705, No. 2018233575, No. 2019 No. 027903, No. 2019034895, No. 2019042119, No. 2019042285, No. 2019042470, No. 2019086573, No. 2019108733, No. 20 Examples of such compounds include those described in No. 19138367, No. 2019144895, No. 2019157843, No. 2019179366, No. 2019184912, No. 2019185717, No. 2019201236, No. 2019238012, No. 2019241732, No. 2020019135, No. 2020036977, No. 2020043188, and No. 2020009725.

[0044] b. An antibody or antigen-binding fragment thereof that binds to SIRPα In various embodiments, the agent that inhibits binding between CD47 and SIRPαCD47 is administered with signal regulatory protein alpha (SIRPα) (NCBI Gene ID: 140885; UniProt P78324). Exemplary antibodies that bind to SIRPα include, but are not limited to, GS-0189 (FSI-189), ES-004, BI765063, ADU1805, and CC-95251.

[0045] In certain embodiments, the antibody may comprise one or more CDRs of 1H9. In some embodiments, the antibody may comprise all of the CDRs of 1H9. In some embodiments, the antibody may comprise one or more variable sequences of 1H9. In some embodiments, the antibody may comprise each variable sequence of 1H9. In some embodiments, the antibody may comprise the heavy chain of 1H9. In some embodiments, the antibody may comprise the light chain of 1H9. In some embodiments, the antibody may comprise the heavy and light chains of 1H9. In some embodiments, the antibody is 1H9.

[0046] In certain embodiments, the antibody may comprise one or more CDRs of 3C2. In some embodiments, the antibody may comprise all CDRs of 3C2. In some embodiments, the antibody may comprise one or more variable sequences of 3C2. In some embodiments, the antibody may comprise each variable sequence of 3C2. In some embodiments, the antibody may comprise a heavy chain of 3C2. In some embodiments, the antibody may comprise a light chain of 3C2. In some embodiments, the antibody may comprise a heavy chain and a light chain of 3C2. In some embodiments, the antibody is 3C2.

[0047] In some embodiments, the antibody may comprise one or more CDRs of 9B11. In some embodiments, the antibody may comprise all of the CDRs of 9B11. In some embodiments, the antibody may comprise one or more variable sequences of 9B11. In some embodiments, the antibody may comprise each variable sequence of 9B11. In some embodiments, the antibody may comprise a heavy chain of 9B11. In some embodiments, the antibody may comprise a light chain of 9B11. In some embodiments, the antibody may comprise a heavy chain and a light chain of 9B11. In some embodiments, the antibody is 9B11.

[0048] In some embodiments, the antibody may comprise one or more CDRs of 7E11. In some embodiments, the antibody may comprise all of the CDRs of 7E11. In some embodiments, the antibody may comprise one or more variable sequences of 7E11. In some embodiments, the antibody may comprise each variable sequence of 7E11. In some embodiments, the antibody may comprise a heavy chain of 7E11. In some embodiments, the antibody may comprise a light chain of 7E11. In some embodiments, the antibody may comprise a heavy chain and a light chain of 7E11. In some embodiments, the antibody is 7E11.

[0049] Additional anti-SIRPα antibodies for use in the present invention include those disclosed in International Publication Nos. 200140307, ​​2002092784, 2007133811, 2009046541, 2010083253, 2011076781, 2013056352, 2015138600, 2016179399, 2016205042, 2017178653, and 2017178653. Examples include those described in No. 2018026600, No. 2018057669, No. 2018107058, No. 2018190719, No. 2018210793, No. 2019023347, No. 2019042470, No. 2019175218, No. 2019183266, No. 2020013170, No. 2020068752, and No. 2020088580.

[0050] In various embodiments, the antibody targeting SIRPα comprises VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2, and VL-CDR3, each of which comprises the following amino acid sequences (according to Kabat): SEQ ID NOs: 93, 94, 95, 96, 97, and 98, SEQ ID NOs: 99, 100, 101, 102, 103, and 104, SEQ ID NOs: 99, 100, 105, 102, 103, and 106, SEQ ID NOs: 107, 108, 109, 110, 111, and 112, SEQ ID NOs: 113, 114, 115, 116, 117, and 118, or SEQ ID NOs: 119, 120, 121, 122, 123, and 124.

[0051] In various embodiments, the antibody targeting SIRPα comprises VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2, and VL-CDR3, each of which comprises the following amino acid sequences (according to IMGT): SEQ ID NOs: 125, 126, 127, 128, 129, and 98; SEQ ID NOs: 125, 130, 131, 132, 29, and 104, SEQ ID NOs: 125, 130, 133, 132, 29, and 106; SEQ ID NOs: 134, 135, 136, 137, 138, and 112; SEQ ID NOs: 139, 130, 140, 141, 142, and 118, or SEQ ID NOs: 143, 144, 145, 146, 44, and 124.

[0052] In various embodiments, an antibody targeting SIRPα comprises VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2, and VL-CDR3, each of which comprises the following amino acid sequences (according to Chothia): SEQ ID NOs: 147, 148, 149, 150, 129, and 151, SEQ ID NOs: 147, 152, 153, 154, 29, and 155, SEQ ID NOs: 147, 152, 156, 154, 29, and 157, SEQ ID NOs: 158, 159, 160, 161, 138, and 162, SEQ ID NOs: 163, 152, 164, 165, 142, and 166, or SEQ ID NOs: 167, 168, 169, 170, 44, and 171.

[0053] In various embodiments, the antibody targeting SIRPα comprises VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2 and VL-CDR3, each of which comprises the following amino acid sequences (according to Honegger): SEQ ID NOs: 172, 173, 174, 175, 176, and 151; SEQ ID NOs: 172, 177, 178, 179, 180, and 155; SEQ ID NOs: 172, 181, 182, 179, 180, and 157, SEQ ID NOs: 183, 184, 185, 186, 187, and 162; SEQ ID NOs: 188, 189, 190, 191, 192 and 166, or SEQ ID NOs: 193, 194, 195, 196, 197 and 171.

[0054] In various embodiments, the antibody targeting SIRPα comprises VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2, and VL-CDR3, each of which comprises the following amino acid sequences: SEQ ID NOs: 93, 94, 95, 96, 97, and 98 (according to Kabat); SEQ ID NOs: 125, 126, 127, 128, 129, and 98 (according to IMGT); SEQ ID NOs: 147, 148, 149, 150, 129, and 151 (from Chothia), or SEQ ID NOs: 172, 173, 174, 175, 176, and 151 (by Honegger).

[0055] In various embodiments, the antibody targeting SIRPα comprises VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2, and VL-CDR3, each of which comprises the following amino acid sequences: SEQ ID NOs: 99, 100, 101, 102, 103, and 104 (according to Kabat); SEQ ID NOs: 125, 130, 131, 132, 29, and 104 (according to IMGT); SEQ ID NOs: 147, 152, 153, 154, 29, and 155 (from Chothia), or SEQ ID NOs: 172, 177, 178, 179, 180, and 155 (by Honegger).

[0056] In various embodiments, the antibody targeting SIRPα comprises VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2, and VL-CDR3, each of which comprises the following amino acid sequences: SEQ ID NOs: 99, 100, 105, 102, 103, and 106 (according to Kabat); SEQ ID NOs: 125, 130, 133, 132, 29, and 106 (according to IMGT); SEQ ID NOs: 147, 152, 156, 154, 29, and 157 (from Chothia), or SEQ ID NOs: 172, 181, 182, 179, 180, and 157 (by Honegger).

[0057] In various embodiments, the antibody targeting SIRPα comprises VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2, and VL-CDR3, each of which comprises the following amino acid sequences: SEQ ID NOs: 107, 108, 109, 110, 111, and 112 (according to Kabat); SEQ ID NOs: 134, 135, 136, 137, 138, and 112 (according to IMGT); SEQ ID NOs: 158, 159, 160, 161, 138, and 162 (from Chothia), or SEQ ID NOs: 183, 184, 185, 186, 187, and 162 (by Honegger).

[0058] In various embodiments, the antibody targeting SIRPα comprises VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2, and VL-CDR3, each of which comprises the following amino acid sequences: SEQ ID NOs: 113, 114, 115, 116, 117, and 118 (according to Kabat); SEQ ID NOs: 139, 130, 140, 141, 142, and 118 (according to IMGT); SEQ ID NOs: 163, 152, 164, 165, 142, and 166 (from Chothia), or SEQ ID NOs: 188, 189, 190, 191, 192, and 166 (by Honegger).

[0059] In various embodiments, the antibody targeting SIRPα comprises VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2, and VL-CDR3, each of which comprises the following amino acid sequences: SEQ ID NOs: 119, 120, 121, 122, 123 and 124 (according to Kabat), SEQ ID NOs: 143, 144, 145, 146, 44 and 124 (according to IMGT), SEQ ID NOs: 167, 168, 169, 170, 44 and 171 (from Chothia), or SEQ ID NOs: 193, 194, 195, 196, 197 and 171 (according to Honegger).

[0060] In various embodiments, the antibody targeting SIRPα comprises a VH and a VL that comprise the amino acid sequences set forth below, or that are at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequences set forth below, respectively. SEQ ID NOs: 198 and 199, SEQ ID NOs: 200 and 201, SEQ ID NOs: 202 and 203, SEQ ID NOs: 204 and 205, SEQ ID NOs: 206 and 207, or SEQ ID NOs: 208 and 209. Sequence identity can be determined according to the BLAST algorithm (blast.ncbi.nlm.nih.gov / Blast.cgi) using default settings.

[0061] The amino acid sequences of the CDRs and variable regions (VH / VL) of exemplary anti-SIRPα antibodies that can be used in the methods of the invention are set forth in Tables C1, C2, C3, C4 and D. [Table C1] [Table C2] [Table C3] [Table C4] [Table D]

[0062] c.SIRPα-Fc fusion protein In various embodiments, the agent that inhibits binding between CD47 and SIRPαCD47 is a SIRPα-Fc fusion protein or a "high affinity SIRPα reagent," which includes SIRPα-derived polypeptides and analogs thereof. High affinity SIRPα reagents are described in WO2013109752(A1), specifically incorporated herein by reference. High affinity SIRPα reagents are variants of native SIRPα proteins. In some embodiments, the high affinity SIRPα reagents are soluble, the polypeptides lack the SIRPα transmembrane domain, and contain at least one amino acid change relative to the wild-type SIRPα sequence, where the amino acid change increases the affinity of the SIRPα polypeptide to bind to CD47, e.g., by decreasing the off-rate by at least 10-fold, at least 20-fold, at least 50-fold, at least 100-fold, at least 500-fold, or more.

[0063] A high affinity SIRPα reagent comprises a sufficient portion of SIRPα (usually between the signal sequence and the transmembrane domain) to bind CD47 with appreciable affinity, e.g., high affinity, or a fragment thereof that retains binding activity. A high affinity SIRPα reagent typically comprises at least the d1 domain of SIRPα with modified amino acid residues to enhance affinity. In some embodiments, the SIRPα variant is a fusion protein, e.g., fused in frame with a second polypeptide. In some embodiments, the second polypeptide can increase the size of the fusion protein, e.g., so that the fusion protein is not rapidly cleared from the circulation. In some embodiments, the second polypeptide is a portion or the entirety of an immunoglobulin Fc region. The Fc region aids in phagocytosis by providing an "eat me" signal that enhances the blockade of the "don't eat me" signal provided by the high affinity SIRPα reagent. In other embodiments, the second polypeptide is any suitable polypeptide that is substantially similar to Fc, e.g., providing increased size, a multimerization domain, and / or additional binding or interaction with lg molecules. The amino acid changes that result in increased affinity are localized to the d1 domain, and thus high affinity SIRPα reagents comprise the d1 domain of human SIRPα with at least one amino acid change relative to the wild-type sequence in the d1 domain. Such high affinity SIRPα reagents optionally include additional amino acid sequences, such as antibody Fc sequences, portions of the wild-type human SIRPα protein other than the d1 domain, including but not limited to residues 150-374 of the native protein or fragments thereof, typically adjacent to the d1 domain. High affinity SIRPα reagents may be monomeric or multimeric, i.e., dimers, trimers, tetramers, and the like.

[0064] Useful exemplary SIRPα-Fc fusion proteins include ALX-148 (also known as evolupercept, described in WO 2013109752), timdalpacept, TTI-621 or TTI-622 (described in WO 2014094122), SIRPα-F8, JY002-M2G1(N297A), JMT601(CPO107), SS002M91, SIRP alpha-IgG4-Fc-Fc, and hCD172a(SIRPa)-Fc-LIGHT.

[0065] 3. Agents that inhibit the binding between vascular endothelial growth factor A (VEGFA) and one or more of the VEGFA cognate receptors The methods described herein involve the co-administration of an agent that inhibits binding between CD47 and SIRPα and an agent that inhibits binding between vascular endothelial growth factor A (VEGFA) and one or more VEGFA cognate receptors (VEGFA / VEFGR inhibitors). VEGFA has alternative acronyms VEGF, MVCD1, VPF and has been assigned NCBI Gene ID: 7422; Uniprot P15692). VEGFA cognate receptors include VEGFR1 (fms-related receptor tyrosine kinase 1 (FLT1; NCBI Gene ID: 2321) and VEGFR2 (kinase insert domain receptor (KDR, also known as CD309, FLK1; NCBI Gene ID: 3791).

[0066] Illustrative examples of agents that inhibit binding between VEGFA and one or more VEGFA cognate receptors include, but are not limited to, antibodies that bind to VEGFA, antibodies that bind to VEGFR2, VEGFA-Fc fusion proteins, and small molecule inhibitors.

[0067] Exemplary antibodies that bind VEGFA useful in the present methods include, but are not limited to, bevacizumab, ranibizumab, brolucizumab, ibonesimab, sevacizumab, and faricimab. In some embodiments, the antibody that binds VEGFA is bevacizumab.

[0068] Exemplary antibodies that bind VEGFR2 useful in the present methods include, but are not limited to, ramucirumab.

[0069] Exemplary VEGFA-Fc fusion proteins useful in the present methods include, but are not limited to, conbercept and aflibercept.

[0070] Exemplary small molecule inhibitors of VEGFA and one or more VEGFA cognate receptors useful in the present methods include, but are not limited to, surufatinib, catequintinib hydrochloride, fruquintinib, tivozanib, regorafenib, axitinib, vandetanib, chiauranib, pazopanib hydrochloride, sunitinib malate, and pegaptanib octasodium.

[0071] In various embodiments, the antibody that binds to VEGFA comprises VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2, and VL-CDR3, each of which comprises the following amino acid sequences (according to Kabat): SEQ ID NOs: 258, 259, 260, 261, 262, and 263, SEQ ID NOs: 264, 259, 265, 261, 262, and 263, SEQ ID NOs: 266, 267, 268, 269, 270, and 271, or SEQ ID NOs: 272, 273, 274, 275, 276, and 277.

[0072] In various embodiments, the antibody that binds to VEGFA comprises VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2, and VL-CDR3, each of which comprises the following amino acid sequences (according to IMGT): SEQ ID NOs: 278, 279, 280, 281, 282, and 263, SEQ ID NOs: 283, 279, 284, 281, 282, and 263; SEQ ID NOs: 285, 286, 287, 288, 289, and 271, or SEQ ID NOs: 290, 291, 292, 293, 294, and 277.

[0073] In various embodiments, the antibody that binds VEGFA comprises VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2, and VL-CDR3, each of which comprises the following amino acid sequences according to Chothia: SEQ ID NOs: 295, 296, 297, 298, 282, and 299, SEQ ID NOs: 300, 296, 301, 298, 282, and 299, SEQ ID NOs: 302, 303, 304, 305, 289, and 306, or SEQ ID NOs: 307, 308, 309, 310, 294, and 311.

[0074] In various embodiments, the antibody that binds VEGFA comprises VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2, and VL-CDR3, each of which comprises the following amino acid sequences according to Honegger: SEQ ID NOs: 312, 313, 314, 315, 316, and 299, SEQ ID NOs: 317, 313, 318, 315, 316, and 299, SEQ ID NOs: 319, 320, 321, 322, 323, and 306, or SEQ ID NOs: 324, 325, 326, 327, 328, and 311.

[0075] In various embodiments, the antibody that binds to VEGFA comprises VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2, and VL-CDR3, each of which comprises the following amino acid sequences: SEQ ID NOs: 258, 259, 260, 261, 262, and 263 (according to Kabat); SEQ ID NOs: 278, 279, 280, 281, 282, and 263 (according to IMGT); SEQ ID NOs: 295, 296, 297, 298, 282, and 299 (from Chothia), or SEQ ID NOs: 312, 313, 314, 315, 316, and 299 (by Honegger).

[0076] In various embodiments, the antibody that binds to VEGFA comprises VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2, and VL-CDR3, each of which comprises the following amino acid sequences: SEQ ID NOs: 264, 259, 265, 261, 262, and 263 (according to Kabat); SEQ ID NOs: 283, 279, 284, 281, 282, and 263 (according to IMGT); SEQ ID NOs: 300, 296, 301, 298, 282, and 299 (according to Chothia), or SEQ ID NOs: 317, 313, 318, 315, 316, and 299 (by Honegger).

[0077] In various embodiments, the antibody that binds to VEGFA comprises VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2, and VL-CDR3, each of which comprises the following amino acid sequences: SEQ ID NOs: 266, 267, 268, 269, 270, and 271 (according to Kabat); SEQ ID NOs: 285, 286, 287, 288, 289, and 271 (according to IMGT); SEQ ID NOs: 302, 303, 304, 305, 289, and 306 (according to Chothia), or SEQ ID NOs: 319, 320, 321, 322, 323, and 306 (by Honegger).

[0078] In various embodiments, the antibody that binds to VEGFA comprises VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2, and VL-CDR3, each of which comprises the following amino acid sequences: SEQ ID NOs: 272, 273, 274, 275, 276, and 277 (according to Kabat); SEQ ID NOs: 290, 291, 292, 293, 294, and 277 (according to IMGT); SEQ ID NOs: 307, 308, 309, 310, 294, and 311 (from Chothia), or SEQ ID NOs: 324, 325, 326, 327, 328, and 311 (by Honegger).

[0079] In various embodiments, the antibody that binds VEGFA comprises a VH and a VL that comprise the amino acid sequences shown below, or that are at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequences shown below, respectively. SEQ ID NO: 329, 330, 331, 332, 333, 334, 335, 336, 337, or 338. Sequence identity can be determined according to the BLAST algorithm (blast.ncbi.nlm.nih.gov / Blast.cgi) using default settings.

[0080] The amino acid sequences of the CDRs and variable regions (VH / VL) of exemplary anti-VEGFA antibodies that can be used in the methods of the invention are set forth in Tables E1, E2, E3, E4, and F. [Table E1] [Table E2] [Table E3] Table E4 [Table F]

[0081] 4. Additional concomitant medications Additional agents suitable for treating hematological malignancies, such as small molecules, antibodies, adoptive cell therapy, and chimeric antigen receptor T cells (CAR-T), checkpoint inhibitors, and vaccines, can be administered in combination with the agents that inhibit the binding between CD47 and SIRPα (e.g., magrolimab) and VEGFA / VEGFR inhibitors (e.g., bevacizumab) described herein. Additional immunotherapeutic agents for hematological malignancies are described in Dong, et al, J Life Sci (Westlake Village). 2019 June; 1(1): 46-52, and Cuesta-Mateos, et al, Front. Immunol. 8: 1936. doi: 10.3389 / fimmu.2017.01936, each of which is incorporated herein by reference in its entirety for all purposes.

[0082] In various embodiments, the agents that inhibit the binding between CD47 and SIRPα (e.g., magrolimab) and VEGFA / VEGFR inhibitors (e.g., bevacizumab) described herein may be administered in combination with one or more additional therapeutic agents, such as inhibitory immune checkpoint blockers or inhibitors, stimulatory immune checkpoint stimulators, agonists, or activators, chemotherapeutic agents, anti-cancer agents, radiotherapeutic agents, anti-tumor agents, anti-proliferative agents, anti-angiogenic agents, anti-inflammatory agents, immunotherapeutic agents, therapeutic antigen binding molecules (mono- and multispecific antibodies in any format and fragments thereof), and the like. fragments (e.g., but not limited to, DARTs®, Duobodies®, BiTEs®, BiKEs, TriKEs, XmAbs®, TandAbs®, scFv, Fab, Fab derivatives), bispecific antibodies, non-immunoglobulin antibody mimetics (e.g., but not limited to, adnectins, affibody molecules, affilins, affimers, affitins, alphabodies, anticalins, peptide aptamers, armadillo repeat proteins, and / or nanoCLAMPs), antibody-drug conjugates (ADCs), antibody-peptide conjugates), oncolytic viruses, gene modifiers or editors, cells comprising a chimeric antigen receptor (CAR), including, for example, T cell immunotherapeutics, NK cell immunotherapeutics, or macrophage immunotherapeutics, cells comprising a genetically engineered T cell receptor (TCR-T), or any combination thereof.

[0083] In various embodiments, the agents that inhibit binding between CD47 and SIRPα (e.g., magrolimab) and VEGFA / VEGFR inhibitors (e.g., bevacizumab) described herein are further combined with one or more additional therapeutic agents, including, but not limited to, inhibitors, agonists, antagonists, ligands, modulators, stimulators, blockers, activators or suppressors of a target (e.g., polypeptides or polynucleotides), including, but not limited to, Abelson murine leukemia viral oncogene homolog 1 gene (ABV) inhibitors. L, e.g., ABL1), acetyl-CoA carboxylase (e.g., ACC1 / 2), activated CDC kinase (ACK, e.g., ACK1), adenosine deaminase, adenosine receptors (e.g., A2BR, A2aR, A3aR), adenylyl cyclase, ADP-ribosyl cyclase-1, adrenal cortex hormone receptor (ACTH), aerolysin, AKT1 gene, Alk-5 protein kinase, alkaline phosphatase, alpha 1 adrenergic receptor, alpha 2 adrenergic receptor, alpha-ketoglutarate dehydrogenase (ketoglutarate dehydrogenase (KGDH), aminopeptidase N, AMP-activated protein kinase, anaplastic lymphoma kinase (ALK, e.g., ALK1), androgen receptor, angiopoietin (e.g., ligand-1, ligand-2), angiotensinogen (AGT) gene, mouse thymoma viral oncogene homolog 1 (AKT) protein kinase (e.g., AKT1, AKT2, AKT3), apolipoprotein AI (APOA1) gene, apoptosis-inducing factor, apoptosis protein (e.g., 1, 2), apoptosis signal-regulating kinase (AKI),kinase, ASK (e.g., ASK1), arginase (I), arginine deiminase, aromatase, asteroid homolog 1 (ASTE1) gene, ataxia telangiectasia and Rad3-related (ATR) serine / threonine protein kinase, Aurora protein kinase (e.g., 1, 2), Axl tyrosine kinase receptor, 4-1BB ligand (CD137L), Baculoviral IAP repeat containing 5 (BIRC5) gene, basigin, B-cell lymphoma 2 (B-cell lymphoma 2, BCL2 gene, Bcl2 binding component 3, Bcl2 protein, BCL2L11 gene, BCR (breakpoint cluster region) protein and gene, beta-adrenergic receptor, beta-catenin, B-lymphocyte antigen CD19, B-lymphocyte antigen CD20, B-lymphocyte cell adhesion molecule, B-lymphocyte stimulatory factor ligand, bone morphogenetic protein-10 ligand, bone morphogenetic protein-9 ligand modulator, brachyury protein, bradykinin receptor, B-Raf proto-oncogene (BRAF), Brc-Abl tyrosine kinase, bromodomain and ectodomain (BET) bromodomain-containing proteins (e.g., BRD2, BRD3, BRD4), Bruton's tyrosine kinase (BTK), calmodulin, calmodulin-dependent protein kinase (CPK), kinase, CaMK, e.g., CAMKII), cancer testis antigen 2, cancer testis antigen NY-ESO-1, cancer / testis antigen 1B (CTAG1) gene, cannabinoid receptors (e.g., CB1, CB2), carbonic anhydrase, casein kinase (CK, e.g., CKI, CKII), caspases (e.g., caspase-3, caspase-7, caspase-9), caspase-8 apoptosis-associated cysteine ​​peptidase CASP8-FADD-like regulator, caspase recruitment domain protein-15, cathepsin G, CCR5 gene, CDK-activating kinase (CDK-activatingkinase, CAK), checkpoint kinases (e.g., CHK1, CHK2), chemokine (CC motif) receptors (e.g., CCR2, CCR4, CCR5, CCR8), chemokine (CXC motif) receptors (e.g., CXCR1, CXCR2, CXCR3, and CXCR4), chemokine CC21 ligand, cholecystokinin CCK2 receptor, chorionic gonadotropin, c-Kit (tyrosine-protein kinase Kit or CD117), CISH (cytokine-inducible SH2-containing protein), claudins (e.g., 6, 18), cluster of differentiation antigens (cluster of differentiation antigens), differentiation (CD), e.g., CD4, CD27, CD29, CD30, CD33, CD37, CD40, CD40 ligand receptor, CD40 ligand, CD40LG gene, CD44, CD45, CD47, CD49b, CD51, CD52, CD55, CD58, CD66e (CEACAM6), CD70 gene, CD74, CD79, CD79b, CD79B gene, CD80, CD95, CD99, CD117, CD122, CDw123, CD134, CDw137, CD158a, CD158b1, CD158b2, CD223, CD276 antigen; clusterin (CLU) gene, clusterin, c-Met (hepatocyte growth factor receptor receptor, HGFR), complement C3, connective tissue growth factor, COP9 signalosome subunit 5, CSF-1 (colony stimulating factor 1 receptor), CSF2 gene, CTLA-4 (cytotoxic T-lymphocyte protein 4) receptor, C-type lectin domain protein 9A (CLEC9A), cyclin D1, cyclin G1, cyclin-dependent kinase (CDK, e.g., CDK1, CDK12, CDK1B, CDK2-9), cyclooxygenase (e.g., COX1, COX2), CYP2B1 gene, cysteine ​​palmitoyltransferase porcupine, cytochrome P450 11B2, cytochrome P450 17, cytochrome P450 17A1, cytochrome P450 2D6, cytochrome P4503A4, cytochrome P450 reductase, cytokine signaling-1, cytokine signaling-3, cytoplasmic isocitrate dehydrogenase, cytosine deaminase, cytosine DNA methyltransferase, cytotoxic T lymphocyte protein-4, DDR2 gene, DEAD-box helicase 6 (DDX6), death receptor 5 (DR5, TRAILR2), death receptor 4 (DR4, TRAILR1), delta-like protein ligands (e.g., 3, 4), deoxyribonucleases, deubiquitinating enzymes (DUBs), Dickkopf-1 ligand, dihydrofolate reductase (DHFR), dihydropyrimidine dehydrogenase, dipeptidyl peptidase IV, discoidin domain receptor receptor, DDR (e.g., DDR1), diacylglycerol kinase zeta (DGKZ), DNA binding protein (e.g., HU-beta), DNA-dependent protein kinase, DNA gyrase, DNA methyltransferase, DNA polymerase (e.g., alpha), DNA primase, dUTP pyrophosphatase, L-dopachrome tautomerase, E3 ubiquitin-protein ligase (e.g., RNF128, CBL-B), echinoderm microtubule-like protein 4, EGFR tyrosine kinase receptor, elastase, elongation factor 1 alpha 2, elongation factor 2, endoglin, endonuclease, endoplasmic reticulum aminopeptidase (ERAP, e.g., ERAP1, ERAP2), endoplasmin, endosialin, endostatin, endothelin (e.g., ET-A, ET-B), enhancer of zeste homolog 22, EZH2), ephrin (EPH) tyrosine kinase (e.g., Epha3, Ephb4), ephrin B2 ligand, epidermal growth factor, epidermal growth factor receptor (EGFR), epidermal growth factor receptor (EGFR) gene, epigen, epithelial cell adhesion molecule (EpCAM), Erb-b2 (v-erb-b2 avian erythroblastic leukemia viral oncogene homolog 2) tyrosine kinase receptor, Erb-b3 tyrosine kinase receptor, Erb-b4 tyrosine kinase receptor, E-selectin, estradiol 17 beta dehydrogenase, estrogen receptor (e.g., alpha, beta), estrogen-related receptor, eukaryotic translation initiation factor 5A (EIF5A) gene, exportin 1, extracellular signal-related kinase (e.g., 1, 2), extracellular signal-regulated kinase (EGFR) kinase (ERK), hypoxia-inducible factor prolyl hydroxylase (HIF-PH or EGLN), factor (e.g., Xa, VIIa), farnesoid x receptor (FXR), Fas ligand, fatty acid synthase (FASN), ferritin, FGF-2 ligand, FGF-5 ligand, fibroblast growth factor (FGF, e.g., FGF1, FGF2, FGF4), fibronectin, focal adhesion kinase (FAK, e.g., FAK2), folate hydrolase prostate-specific membrane antigen 1 (folate hydrolase prostate-specific membrane antigen 2),1, FOLH1, folate receptor (e.g., alpha), folate, folate transporter 1, FYN tyrosine kinase, paired basic amino acid cleaving enzyme (FURIN), beta-glucuronidase, galactosyltransferase, galectin-3, ganglioside GD2, glucocorticoid, glucocorticoid-inducible TNFR-related protein GITR receptor, glutamate carboxypeptidase II, glutaminase, glutathione S-transferase P, glycogen synthase kinase (GSK, e.g., 3-beta), glypican 3 (GPC3), gonadotropin-releasing hormone (GNRH), Granulocyte macrophage colony stimulating factor (GM-CSF) receptor, Granulocyte-colony stimulating factor (GPC3) receptor, GCSF ligand, growth factor receptor-bound protein 2 (GRB2), Grp78 (78 kDa glucose-regulated protein) calcium-binding protein, molecular chaperone groEL2 gene, heme oxygenase 1 (HO1), heme oxygenase 2 (HO2), heat shock proteins (e.g., 27, 70, 90 alpha, beta), heat shock protein genes, heat-stable enterotoxin receptor, hedgehog protein, heparanase, hepatocyte growth factor, HERV-H LTR-associated protein 2, hexose kinase, histamine H2 receptor, histone methyltransferase (DOT1L), histone deacetylase (histone deacetylase) deacetylase, HDAC, e.g., 1, 2, 3, 6, 10, 11), histone H1, histone H3, HLA class I antigen (A-2 alpha), HLA class II antigen, HLA class I antigen alpha G (HLA-G), non-classical HLA, homeobox protein NANOG, HSPB1 gene, human leukocyte antigen (HLA-G), ...antigen, HLA), human papillomavirus (e.g., E6, E7) proteins, hyaluronic acid, hyaluronidase, hypoxia inducible factor-1 alpha (HIF1α), Imprinted Maternal Ly Expressed Transcript (H19) gene, mitogen-activated protein kinase 1 (MAP4K1), tyrosine-protein kinase HCK, I-kappa-B kinase (IKK, e.g., IKKbe), IL-1 alpha, IL-1 beta, IL-12, IL-12 gene, IL-15, IL-17, IL-2 gene, IL-2 receptor alpha subunit, IL-2, IL-3 receptor, IL-4, IL-6, IL-7, IL-8, immunoglobulin (e.g., G, G1, G2, K, M), immunoglobulin Fc receptor, immunoglobulin gamma Fc receptor (e.g., I, III, IIIA), Indian Indoleamine 2,3-dioxygenase (IDO, e.g., IDO1 and IDO2), indoleamine pyrrole 2,3-dioxygenase 1 inhibitors, insulin receptor, insulin-like growth factors (e.g., 1, 2), integrin alpha-4 / beta-1, integrin alpha-4 / beta-7, integrin alpha-5 / beta-1, integrin alpha-V / beta-3, integrin alpha-V / beta-5, integrin alpha-V / beta-6, intercellular adhesion molecule 1 adhesion molecule 1 (ICAM-1), interferons (e.g., alpha, alpha 2, beta, gamma), interferon-inducible protein absent in melanoma 2 (AIM2), interferon type I receptor, interleukin 1 ligand, interleukin 13 receptor alpha 2, interleukin 2 ligand, interleukin-1 receptor-associated kinase 4 (IRAK4), interleukin-2, interleukin-29 ligand, interleukin 35 (IL-35), isocitrate dehydrogenase (e.g., IDH1, IDH2), Janus kinase (JAK, e.g., JAK1, JAK2), Jun N-terminal kinase, kallikrein-related peptidase 33, KLK3 gene, killer cell Ig-like receptor, kinase insert domain receptor (KDR), kinesin-like protein KIF11, Kirsten rat sarcoma viral oncogene homolog (KRAS) gene, kisspeptin (KiSS-1) receptor, KIT gene, v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog (KIT) tyrosine kinase, lactoferrin, lanosterol-14 demethylase, LDL receptor-related protein-1, leukocyte immunoglobulin-like receptor subfamily B member 1 (ILT2), leukocyte immunoglobulin-like receptor subfamily B member 2 (ILT4), leukotriene A4 hydrolase, listeriolysin, L-selectin, progesterone receptor, lyase, lymphocyte activation gene 3 protein 3, LAG-3), lymphocyte antigen 75, lymphocyte functional antigen-3 receptor, lymphocyte-specific protein tyrosine kinase (LCK), lymphotactin, Lyn (Lck / Yes novel) tyrosine kinase, lysine demethylases (e.g., KDM1, KDM2, KDM4, KDM5, KDM6, A / B / C / D), lysophosphatidic acid-1 receptor, lysosomal-associated membrane protein family (LAMP) genes, lysyl oxidase homolog 2, lysyl oxidase protein (LOX), 5-lipoxygenase (5-LOX), hematopoietic progenitor kinase 1 (HPK1), hepatocyte growth factor receptor (MET) gene, macrophage colony-stimulating factor (MCF) gene, macrophage migration inhibitory factor (MCSF) ligand, macrophage migration inhibitory factor, MAGEC1 gene, MAGEC2 gene, major vault protein, MAPK-activated protein kinase (e.g., MK2), Mas-related G-protein-coupled receptor, matrix metalloproteinase (matrixmetalloprotease, MMP (e.g., MMP2, MMP9), Mcl-1 differentiation protein, Mdm2 p53 binding protein, Mdm4 protein, Melan-A (MART-1) melanoma antigen, melanocyte protein Pmel 17, melanocyte stimulating hormone ligand, melanoma antigen family A3 A3, MAGEA3 genes, melanoma-associated antigens (e.g., 1, 2, 3, 6), membrane copper amine oxidase, mesothelin, MET tyrosine kinase, metabotropic glutamate receptor 1, metalloreductase STEAP1 (six transmembrane epithelial antigen of the prostate 1), metastin, methionine aminopeptidase-2, methyltransferase, mitochondrial 3 ketoacyl-CoA thiolase, mitogen-activated protein kinase (MAPK), mitogen-activated protein kinase (MEK, e.g., MEK1, MEK2), mTOR (mechanistic target of rapamycin (serine / threonine kinase), mTOR complex (e.g., 1, 2), mucins (e.g., 1, 5A, 16), mut T homolog (MTH, e.g., MTH1), Myc proto-oncogene protein, myeloid cell leukemia 1 1, MCL1 gene, myristoylated alanine-rich protein kinase C substrate (MARCKS) protein, NAD ADP ribosyltransferase, natriuretic peptide receptor C, neural cell adhesion molecule 1, neurokinin 1 (NK1) receptor, neurokinin receptor, neuropilin 2, NF-kappa B activating protein, NIMA-related kinase 9 (NEK9), nitric oxide synthase, NK cell receptor, NK3 receptor, NKG2 AB-activating NK receptor, NLRP3 (NACHT LRR PYD domain protein 3) modulator, noradrenaline transporter, Notch (e.g., Notch-2 receptor, Notch-3 receptor, Notch-4 receptor), nuclear erythroid 2-related factor 2, nuclear factorNF-kappa B, nucleolin, nucleophosmin, nucleophosmin-anaplastic lymphoma kinase (NPM-ALK), 2-oxoglutarate dehydrogenase, 2,5-oligoadenylate synthetase, O-methylguanine DNA methyltransferase, opioid receptors (e.g., delta), ornithine decarboxylase, orotate phosphoribosyltransferase, orphan nuclear hormone receptor NR4A1, osteocalcin, osteoclast differentiation factor, osteopontin, OX-40 (tumor necrosis factor receptor superfamily member 4 TNFRSF4, or CD134) receptor, P3 protein, p38 kinase, p38 MAP kinase, p53 tumor suppressor protein, parathyroid hormone ligand, peroxisome proliferator-activated receptor receptors, PPAR (e.g., alpha, delta, gamma), P-glycoprotein (e.g., 1), phosphatase and tensin homolog (PTEN), phosphatidylinositol 3-kinase (PI3K), phosphoinositide-3 kinase (PI3K, e.g., alpha, delta, gamma), phosphorylase kinase (PK), PKN3 gene, placental growth factor, platelet-derived growth factor (PDGF, e.g., alpha, beta), platelet-derived growth factor (PDGF, e.g., alpha, beta), multidrug resistance transporter, plexin B1, PLK1 gene, polo-like kinase kinase (PLK), polo-like kinase 1, poly(ADP-ribose) polymerase (PARP, e.g., PARP1, PARP2, and PARP3, PARP7, and mono-PARPs), preferentially expressed antigen in melanoma (PRAME) gene, prenyl-binding protein (PBP),protein (PrPB), Probable transcription factor PML, Progesterone receptor, Programmed cell death 1 (PD-1), Programmed cell death ligand 1 inhibitor (PD-L1), Prosaposin (PSAP) gene, Prostanoid receptor (EP4), Prostaglandin E2 synthase, Prostate specific antigen, Prostatic acid phosphatase, Proteasome, Protein E7, Protein farnesyltransferase, Protein kinase (PK, e.g., A, B, C), Protein tyrosine kinase, Protein tyrosine phosphatase beta, Proto-oncogene serine / threonine-protein kinase (PIM, e.g., PIM-1, PIM-2, PIM-3), P-selectin, Purine nucleoside phosphorylase, Purinergic receptor P2X ligand-gated ion channel 7 (P2X7), Pyruvate dehydrogenase dehydrogenase, PDH), pyruvate dehydrogenase kinase, pyruvate kinase (PYK), 5-alpha-reductase, Raf protein kinase (e.g., 1, B), RAF1 gene, Ras gene, Ras GTPase, RET gene, Ret tyrosine kinase receptor, retinoblastoma-associated protein, retinoic acid receptor (e.g., gamma), retinoid X receptor, Rheb (Ras homolog enriched in brain) GTPase, Rho (Ras homolog)-associated protein kinase 2, ribonuclease, ribonucleotide reductase (e.g., M2 subunit), ribosomal protein S6 kinase, RNA polymerase (e.g., I, II), Ron (Recepteur d'Origine Nantais tyrosine kinase, ROS1 (ROS proto-oncogene 1, receptor tyrosine kinase) gene, Ros1 tyrosine kinase, Runt-related transcription factor 3, gamma-secretase, S100 calcium-binding protein A9, sarcoplasmic reticulum calcium ATPase, second mitochondria-derived activator of caspasecaspases (SMAC) proteins, secreted frizzled-associated protein-2, secreted phospholipase A2, semaphorin-4D, serine proteases, serine / threonine kinases (STK), serine / threonine-protein kinases (TBK, e.g., TBK1), signal transduction and transcription (STAT, e.g., STAT-1, STAT-3, STAT-5), signaling lymphocytic activation molecule (SLAM) family member 7, six-transmembrane epithelial antigen of the prostate (STEAP) gene, SL cytokine ligand, smoothened (SMO) receptor, sodium iodide cotransporter, sodium phosphate cotransporter 2B, somatostatin receptors (e.g., 1, 2, 3, 4, 5), sonic hedgehog proteins, Son of Sevenless sevenless (SOS), specific protein 1 (Sp1) transcription factor, sphingomyelin synthase, sphingosine kinase (e.g., 1, 2), sphingosine-1-phosphate receptor-1, spleen tyrosine kinase (SYK), SRC gene, Src tyrosine kinase, Stabilin-1 (STAB1), STAT3 gene, steroid sulfatase, Stimulator of interferon genes (STING) receptor, stimulator of interferon genes protein, Stromal cell-derived factor 1 ligand, SUMO (small ubiquitin-like modifier), superoxide dismutase, suppressor of cytokine signaling modulators (SOCS), survivin protein, synapsin 3, syndecan-1, synuclein alpha, T cell surface glycoprotein CD28, tank-binding kinase (TBK), TATA box-binding protein-associated factor RNA polymerase I subunit B (TAF1B) gene, T cell CD3 glycoprotein zeta chain, T cell differentiation antigen CD6, T cell immunoglobulin and mucin domain-containing-3 (TIM-3), T cell surface glycoprotein CD8, Tec protein tyrosine kinase, Tek tyrosine kinase receptor, telomerase, telomerase reverse transcriptase (TERT) gene, tenascin, three prime repair exonuclease 1 repair exonuclease 1 (TREX1), Three prime repair exonuclease 2 (TREX2), thrombopoietin receptor, thymidine kinase, thymidine phosphorylase, thymidylate synthase, thymosin (e.g., alpha 1), thyroid hormone receptor, thyrotropin receptor, tissue factor, TNF-related apoptosis-inducing ligand, TNFR1-associated death domain protein, TNF-related apoptosis-inducing ligand (TRAIL) receptor, TNFSF11 gene, TNFSF9 gene, Toll-like receptor (TLR, e.g., 1-13), topoisomerase (e.g., I, II, III), transcription factor, transferase, transferrin (TF), transforming growth factor alpha (TGFα), transforming growth factor beta (transforming growth factorbeta (TGFB) and their isoforms, TGF beta 2 ligand, transforming growth factor TGF-beta receptor kinase, transglutaminase, translocation-associated protein, transmembrane glycoprotein NMB, Trop-2 calcium signal transducer, trophoblast glycoprotein (TPBG) gene, trophoblast glycoprotein, Tropomyosin receptor kinase (Trk) receptor (e.g., TrkA, TrkB, TrkC), tryptophan 2,3-dioxygenase (TDO), tryptophan 5-hydroxylase, tubulin, tumor necrosis factor (TNF, e.g., alpha, beta), tumor necrosis factor 13C receptor, tumor progression locus 2 (TPL2), tumor protein 53 (TP53) gene, tumor suppressor candidate 2 2, TUSC2 gene, tumor-specific neoantigen, tyrosinase, tyrosine hydroxylase, tyrosine kinase (TK), tyrosine kinase receptor, tyrosine kinase with immunoglobulin-like and EGF-like domain (TIE) receptor, tyrosine protein kinase ABL1 inhibitor, ubiquitin, ubiquitin carboxyl hydrolase isozyme L5, ubiquitin thioesterase-14, ubiquitin-conjugating enzyme E2I (UBE2I, UBC9), ubiquitin-specific-processing protease 7 (USP7), urease, urokinase plasminogen activator, uteroglobin, vanilloid VR1, vascular cell adhesion protein 1, vascular endothelial growth factor receptor (VEGFR), V-domain Ig suppressor of T cell activation (V-domain Ig suppressor of T cell activation) Ig suppressor of T-cellactivation, VISTA), VEGF-1 receptor, VEGF-2 receptor, VEGF-3 receptor, VEGF-A, VEGF-B, vimentin, vitamin D3 receptor, proto-oncogene tyrosine-protein kinase, Mer (Mer tyrosine kinase receptor modulator), YAP (Yes-associated protein modulator), Wee-1 protein kinase, Werner Syndrome RecQ Like Helicase (WRN), Wilms tumor antigen 1, Wilms tumor protein, WW domain-containing transcriptional regulator protein 1 (TAZ), X-linked inhibitor of apoptosis protein, zinc finger protein transcription factor, or a combination thereof.

[0084] In various embodiments, the agents that inhibit binding between CD47 and SIRPα (e.g., magrolimab) and VEGFA / VEGFR inhibitors (e.g., bevacizumab) described herein are combined with one or more additional therapeutic agents, which may be classified by mechanism of action, for example, the following groups of mechanisms: antimetabolites / anticancer drugs, such as pyrimidine analogs floxuridine, capecitabine, cytarabine, CPX-351 (liposomal cytarabine, daunorubicin), and TAS-118; alpha 1 adrenergic receptor / alpha 2 adrenergic receptor antagonists, such as phenoxybenzamine hydrochloride (injection, pheochromocytoma); androgen receptor antagonists, such as nilutamide; anti-cadherin antibodies, such as HKT-288; anti-leucine-rich repeat containing 15 ( ... 15, LRRC15) antibodies, such as ABBV-085.ARGX-110; angiotensin receptor blockers, nitric oxide donors; antisense oligonucleotides, such as AEG35156, IONIS-KRAS-2.5Rx, EZN-3042, RX-0201, IONIS-AR-2.5Rx, BP-100 (prexigebersen), IONIS-STAT3-2.5Rx; anti-angiopoietin (ANG)-2 antibodies, such as MEDI3617 and LY3127804; anti-ANG-1 / ANG-2 antibodies, such as AMG-7 80; anti-CSF1R antibodies, e.g., emacutuzumab, LY3022855, AMG-820, FPA-008 (caviralizumab); anti-endoglin antibodies, e.g., TRC105 (carotuximab); anti-ERBB antibodies, e.g., CDX-3379, HLX-02, seribantumab; anti-HER2 antibodies, e.g., HERCEPTIN® (trastuzumab), trastuzumab biosimilar, margetuximab, MEDI4276, BAT-8001, pertuzumab (Perjeta), RG6264, ZW25 (bispecific HER2-directed antibody targeting extracellular domains 2 and 4; Cancer Discov. 2019 Jan;9(1):8;PMID:30504239); anti-HLA-DR antibodies, e.g., IMMU-114;anti-IL-3 antibodies, e.g., JNJ-56022473; anti-TNF receptor superfamily member 18 (TNFRSF18, GITR; NCBI gene number: 8784) antibodies, e.g., MK-4166, MEDI1873, FPA-154, INCAGN-1876, TRX-518, BMS-986156, MK-1248, GWN-323; and those described in, for example, International Patent Publication Nos. 2017 / 096179, 2017 / 096276, 2017 / 096189, and 2018 / 089628; anti-EphA3 antibodies, e.g., KB-004; anti-CD 37 antibodies, such as otlertuzumab (TRU-016); anti-FGFR-3 antibodies, such as LY3076226, B-701; anti-FGFR-2 antibodies, such as GAL-F2; anti-C5 antibodies, such as ALXN-1210; anti-EpCAM antibodies, such as VB4-845; anti-CEA antibodies, such as RG-7813; anti-carcinoembryonic-antigen-related-cell-adhesion-molecule-6 (CEACAM6, CD66C) antibodies, such as BAY-1834942, NEO-201 (CEACAM 5 / 6; anti-GD2 antibodies, e.g., APN-301; anti-interleukin-17 (IL-17) antibodies, e.g., CJM-112; anti-interleukin-1 beta antibodies, e.g., canakinumab (ACZ885), VPM087; anti-carbonic anhydrase 9 (CA9, CAIX) antibodies, e.g., TX-250; anti-mucin 1 (Mucin 1, MUC1) antibodies, such as gatipotuzumab, Mab-AR-20.5; anti-KMA antibodies, such as MDX-1097; anti-CD55 antibodies, such as PAT-SC1; anti-c-Met antibodies, such as ABBV-399; anti-PSMA antibodies, such as ATL-101; anti-CD100 antibodies, such as VX-15; anti-EPHA3 antibodies, such as fibatuzumab; anti-APRIL antibodies, such as BION-1301; anti-fibroblast activation protein (FAP) / IL-2R antibodies, such as RG7461;Anti-fibroblast activation protein (FAP) / TRAIL-R2 antibodies, such as RG7386; anti-fucosyl-GM1 antibodies, such as BMS-986012; anti-IL-8 (interleukin-8) antibodies, such as HuMax-Inflam; anti-myostatin inhibitors, such as landogrozumab; anti-delta-like protein ligand 3 (DDL3) antibodies, such as rovalpituzumab tesirin; tesirine; anti-DLL4 (delta-like ligand 4) antibodies, e.g., demcizumab; anti-clusterin antibodies, e.g., AB-16B5; anti-ephrin-A4 (EFNA4) antibodies, e.g., PF-06647263; anti-mesothelin antibodies, e.g., BMS-986148, anti-MSLN-MMAE; anti-sodium phosphate cotransporter 2B (NaP2B) antibodies, such as rifastuzumab; anti-TGFβ antibodies, e.g., SAR439459; anti-transforming growth factor-beta (TGFβ) antibodies, e.g., SAR439459; transforming growth factor-beta (TGF-beta) antibodies, e.g., ABBV-151, LY3022859, NIS793, XOMA089; purine analogs, folate antagonists (e.g., pralatrexate), cladribine, pentostatin, fludarabine, and related inhibitors; natural products, e.g., vinca alkaloids (vinblastine, vincristine), and microtubule disruptors, e.g., taxanes (paclitaxel, docetaxel), vinblastine, nocodazole, epothilones, vinorelbine (NAVELBINE®), and epipodophyllotoxins. antiproliferative / antimitotic agents, including rifampin (etoposide, teniposide); DNA damaging agents, such as actinomycin, amsacrine, busulfan, carboplatin, chlorambucil, cisplatin, cyclophosphamide (CYTOXAN®), dactinomycin, daunorubicin, doxorubicin, DEBDOX, epirubicin, ifosfamide, melphalan, mechlorethamine, mitomycin C, mitoxantrone, nitrosoureas, procarbazine, taxol, taxotere, teniposide, etoposide, and triethylenethiophosphoramide;DNA hypomethylating agents such as guadecitabine (SGI-110), oral decitabine and cedazuridine (ASTX727); antibiotics such as dactinomycin, daunorubicin, doxorubicin, idarubicin, anthracyclines, mitoxantrone, bleomycin, primycin (mithramycin); enzymes such as L-asparaginase, which metabolizes L-asparagine throughout the body and eliminates cells that do not have the ability to synthesize asparagine themselves; DNAi oligonucleotides targeting Bcl-2, such as PNT2258; latent human immunodeficiency virus (LHIV)-associated leukemia ... virus, HIV), e.g., panobinostat and romidepsin; asparaginase stimulators, e.g., crisantaspase (Erwinase®) and GRASPA (ERY-001, ERY-ASP), calaspargase pegol, pegaspargase; pan-Trk, ROS1, and ALK inhibitors, e.g., entrectinib, TPX-0005; anaplastic lymphoma kinase (ALK) inhibitors, e.g., alectinib, ceritinib, Alecensa (RG7853), ALUNBRIG® (brigatinib); antiproliferative / antimitotic alkylating agents, e.g., nitrogen mustard cyclophosphamide and analogs (e.g., melphalan, chlorambucil, hexamethylmelamine, thiotepa), alkylnitrosoureas (e.g., carbapenem, carbamazepine ... antiproliferative / antimitotic antimetabolites such as folic acid analogs (methotrexate); platinum coordination complexes (e.g., cisplatin, oxicoplatin, and carboplatin), procarbazine, hydroxyurea, mitotane, and aminoglutethimide; hormones, hormone analogs (e.g., estrogens, tamoxifen, goserelin, bicalutamide, and nilutamide), and aromatase inhibitors (e.g., letrozole and anastrozole); antiplatelet agents; anticoagulants such as heparin, synthetic heparin salts, and other inhibitors of thrombin; fibrinolytic agents such as tissue plasminogen activator, streptokinase, urokinase, aspirin, dipyridamole, ticlopidine, and clopidogrel; antimigratory agents;Antisecretory agents (e.g., breveldin); immunosuppressants, e.g., tacrolimus, sirolimus, azathioprine, and mycophenolate; growth factor inhibitors and vascular endothelial growth factor inhibitors; fibroblast growth factor inhibitors, e.g., FPA14; AMP-activated protein kinase stimulators, e.g., metformin hydrochloride; ADP-ribosyl cyclase-1 inhibitors, e.g., daratumumab (DARZALEX®); caspase recruitment domain protein-15 stimulators, e.g., mifamurtide (liposomal); CCR5 chemokine antagonists, e.g., MK-7690 (vicriviroc); CDC7 tandem Protein kinase inhibitors, such as TAK-931; cholesterol side chain cleavage enzyme inhibitors, such as ODM-209; dihydropyrimidine dehydrogenase / orotate phosphoribosyltransferase inhibitors, such as cefezone (tegafur + gimeracil + oteracil potassium); DNA polymerase / ribonucleotide reductase inhibitors, such as clofarabine; DNA interference oligonucleotides, such as PNT2258, AZD-9150; estrogen receptor modulators, such as bazedoxifene; estrogen receptor agonists / progesterone receptor antagonists, such as TRI-CYCLEN LO (norethindrone + ethinyl estradiol); HLA class I antigen A-2 alpha modulators, such as FH-MCVA2TCR; HLA class I antigen A-2 alpha / MART-1 melanoma antigen modulators, such as MART-1 F5 TCR engineered PBMC; human granulocyte colony stimulating factor, e.g., PF-06881894; GNRH receptor agonists, e.g., leuprorelin acetate, leuprorelin acetate sustained release depot (ATRIGEL), triptorelin pamoate, goserelin acetate; GNRH receptor antagonists, e.g., elagolix, relugolix, degarelix; endoplasmin modulators, e.g., anlotinib; H+K+ATPase inhibitors, e.g., omeprazole, esomeprazole; ICAM-1 / CD55 modulators, e.g., cavatak (V-937); IL-15 / IL-12 modulators, e.g., SAR441000;Interleukin 23A inhibitors, such as guselkumab; lysine-specific histone demethylase 1 inhibitors, such as CC-90011; IL-12 MRNA, such as MEDI 1191; RIG-I modulators, such as RGT-100; NOD2 modulators such as SB-9200 and IR-103; progesterone receptor agonists, such as levonorgestrel; protein cereblon modulators, such as CC-92480, CC-90009; protein cereblon modulators / DNA binding protein Ikaros inhibitors / zinc finger binding protein Aiolos inhibitors, such as iverdomid; retinoid X receptor modulators, such as alitretinoin, bexarotene (oral formulation); RIP-1 kinase inhibitors, such as GSK-31; 45095; selective estrogen receptor degraders, e.g., AZD9833; SUMO inhibitors, e.g., TAK-981; thrombopoietin receptor agonists, e.g., eltrombopag; thyroid hormone receptor agonists, e.g., levothyroxine sodium; TNF agonists, e.g., tasonermin; tyrosine phosphatase substrate 1 inhibitors, e.g., CC-95251; HER2 inhibitors, e.g., neratinib, tucatinib (ONT-380); EGFR / ErbB2 / Ephb4 inhibitors, e.g., tecevatinib; EGFR / HER2 inhibitors, e.g., TAK-788; EGFR family tyrosine kinase receptor EGFR / ErbB-2 inhibitors, e.g., balitinib; mutant-selective EGFR inhibitors such as PF-06747775, EGF816 (nazartinib), ASP8273, ACEA-0010, BI-1482694; epha2 inhibitors, e.g., MM-310; polycomb protein (EED) inhibitors, e.g., MAK683; DHFR inhibitors / folate transporter 1 modulators / folate receptor antagonists, e.g., pralatrexate; DHFR / GAR transformylase / thymidylate synthase / transferase inhibitors, e.g., pemetrexed disodium; p38 MAP kinase inhibitors, e.g., ralimetinib; PRMT inhibitors, e.g., MS203, PF-06939999, GSK3368715, GSK3326595; Sphingosine kinase 2 2, SK2) inhibitors, such as opaganib; nuclear erythroid 2-related factor 2 stimulators, such as omaveloxolone (RTA-408); tropomyosin receptor kinase (TRK) inhibitors, such as LOXO-195, ONO-7579; mucin 1 inhibitors, such as GO-203-2C; MARCKS protein inhibitors, such as BIO-11006; folate antagonists, such as arfolithixolin; galectin-3 inhibitors, such as GR-MD-02; phosphorylated P68 inhibitors, such as RX-5902; CD95 / TNF modulators, such as ofranergene obadenovec; pan-PIM kinase inhibitors, such as INCB-053914;IL-12 gene stimulators, e.g., EGEN-001, tavokinogene telseplasmid; heat shock protein HSP90 inhibitors, e.g., TAS-116, PEN-866; VEGF / HGF antagonists, e.g., MP-0250; VEGF ligand inhibitors, e.g., bevacizumab biosimilars; VEGF receptor antagonists / VEGF ligand inhibitors, e.g., ramucirumab; VEGF-1 / VEGF-2 / VEGF-3 receptor antagonists; fruquintinib, etc.; VEGF-1 / VEGF-2 receptor modulators, e.g., HL A-A2402 / HLA-A0201 restricted epitope peptide vaccines; placental growth factor ligand inhibitors / VEGF-A ligand inhibitors, e.g., aflibercept; SYK tyrosine kinase / JAK tyrosine kinase inhibitors such as ASN-002; Trk tyrosine kinase receptor inhibitors, e.g., larotrectinib sulfate; JAK3 / JAK1 / TBK1 kinase inhibitors, e.g., CS-12912; IL-24 antagonists, e.g., AD-IL24; NLRP3 (NACHT LRR PYD domain protein 3) modulators, e.g., BMS-986299; RIG-I agonists, e.g., RGT-100; aerolysin stimulators, e.g., topsalisin; P-glycoprotein 1 inhibitors, e.g., HM-30181A; CSF-1 antagonists, e.g., ARRY-382, BLZ-945; CCR8 inhibitors such as JTX-1811, I-309, SB-649701, HG-1013, RAP-310; anti-mesothelin antibodies, e.g., SEL-403; thymidine kinase stimulators, e.g., agratimagenbesadenovec; Polo-like Kinase 1 inhibitors, e.g., PCM-075, onvansertib; NAE inhibitors, e.g., pevonedistat (MLN-4924); Trop-2 inhibitors, e.g., sacituzumab govitecan (TRODELVY®), TAS-4464; pleiotropic pathway modulators, e.g., avadomide (CC-122); amyloid protein-binding protein-1 inhibitors / ubiquitin ligase modulators; FoxM1 inhibitors, e.g., thiostrepton; UBA1 inhibitors, e.g., TAK-243, Src tyrosine kinase inhibitors, e.g., VAL-201;VDAC / HK inhibitors, e.g., VDA-1102; Elf4a inhibitors, e.g., rohitinib, eFT226; TP53 gene stimulators, e.g., ad-p53; retinoic acid receptor agonists, e.g., tretinoin; retinoic acid receptor alpha (RARα) inhibitors, e.g., SY-1425; SIRT3 inhibitors, e.g., YC8-02; stromal cell-derived factor 1 ligand inhibitors, e.g., olaptesed pegol; pegol) (NOX-A12); IL-4 receptor modulators, e.g., MDNA-55; arginase I stimulators, e.g., pegdilaliginase; topoisomerase I inhibitors, e.g., irinotecan hydrochloride, Onivyde; topoisomerase I inhibitors / hypoxia inducible factor-1 alpha inhibitors, e.g., PEG-SN38 (filtecan pegol); hypoxia inducible factor-1 alpha inhibitors, e.g., PT-2977, PT-2385; CD122 (IL-2 receptor IL-2 agonists, e.g., Proleukin (aldesleukin, IL-2); pegylated IL-2 (e.g., NKTR-214); modified variants of IL-2 (e.g., THOR-707); TLR7 / TLR8 agonists, e.g., NKTR-262; TLR7 agonists, e.g., DS-0509, GS-9620, LHC-165, TMX-101 (imiquimod); p53 tumor suppressor protein stimulators, e.g., quevetrin; Mdm4 / Mdm2 p53 binding protein inhibitors, such as ALRN-6924; kinesin spindle protein (KSP) inhibitors, such as filanesib (ARRY-520); CD80-Fc fusion protein inhibitors, such as FPT-155; Menin and mixed lineage leukemia (MLL) inhibitors, such as KO-539; Liver x receptor agonists, such as RGX-104; IL-10 agonists, such as pegilodecakin (AM-0010); VEGFR / PDGFR inhibitors, such as borolanib; IRAK4 inhibitors, such as CA-4948; anti-TLR-2 antibodies, such as OPN-305; calmodulin modulators such as CBP-501;

[0085] glucocorticoid receptor antagonists, e.g., relacorilant (CORT-125134); second mitochondria-derived activator of caspases (SMAC) protein inhibitors, e.g., BI-891065; lactoferrin modulators, e.g., LTX-315; KIT proto-oncogene, receptor tyrosine kinase (KIT) inhibitors, e.g., PLX-9486; platelet-derived growth factor receptor alpha (PDGFRA) / KIT proto-oncogene, receptor tyrosine kinase (KIT) mutant-specific antagonists / inhibitors, e.g., BLU-285, DCC-2618; exportin 1 inhibitors, e.g., Ertanexor; CHST15 gene inhibitors, e.g., STNM-01; somatostatin receptor antagonists, e.g., OPS-201; CEBPA gene stimulators, e.g., MTL-501; DKK3 gene modulators, e.g., MTG-201; chemokine (CXCR1 / CXCR2) inhibitors, e.g., SX-682; p70s6k inhibitors, e.g., MSC2363318A, methionine aminopeptidase 2 (MetAP2) inhibitors, e.g., M8891, APL -1202; arginine N-methyltransferase 5 inhibitors, e.g., GSK-3326595; CD71 modulators, e.g., CX-2029 (ABBV-2029); ATM (ataxia telangiectasia) inhibitors, e.g., AZD0156, AZD1390; CHK1 inhibitors, e.g., GDC-0575, LY2606368 (prexasertib), SRA737, RG7741 (CHK1 / 2); CXCR4 antagonists, e.g., BL-8040, LY25 10924, brixafor (TG-0054), X4P-002, X4P-001-IO, plerixafor; EXH2 inhibitors, such as GSK2816126; KDM1 inhibitors, such as ORY-1001, IMG-7289, INCB-59872, GSK-2879552; CXCR2 antagonists, such as AZD-5069; DNA-dependent protein kinase inhibitors, such as MSC2490484A (nedisertib), VX-984,AsiDNA (DT-01); protein kinase C (PKC) inhibitors, e.g., LXS-196, sotrastaurin; selective estrogen receptor downregulators (SERDs), such as fulvestrant (Faslodex®), RG6046, RG6047, RG6171, elacestrant (RAD-1901), SAR439859, and AZD9496; selective estrogen receptor covalent antagonists (SERCAs), such as H3B-6545; selective androgen modulators (SELs), such as SERCAs, SERs, and SERs. modulators, SARMs), e.g., GTX-024, darolutamide; transforming growth factor-beta (TGF-beta) kinase antagonists, e.g., galunisertib, LY3200882; TGF-beta inhibitors described in WO 2019 / 103203; TGF-beta receptor 1 inhibitors, e.g., PF-06952229; ABT-165 (DLL4 / VEGF), MM-141 (IGF-1 / ErbB3), MM-111 (Erb2 / Erb3), JNJ-64052781 (CD19 / CD3), PRS-343 (CD-137 / HER2), AFM26 (BCMA / CD16A), JNJ-61186372 (EGFR / cMET), AMG-211 (CEA / CD3), RG7 802 (CEA / CD3), ERY-974 (CD3 / GPC3), vancizumab (angiopoietin / VEGF), PF-06671008 (cadherin / CD3), AFM-13 (CD16 / CD30), APVO436 (CD123 / CD3), flotetuzumab (CD123 / CD3), REGN-1979 (CD20 / CD3), MCLA-11 7(CD3 / CLEC12A), MCLA-128(HER2 / HER3), JNJ-0819, JNJ-7564(CD3 / heme), AMG-757(DLL3-CD3), M GD-013 (PD-1 / LAG-3), FS-118 (LAG-3 / PD-L1), MGD-019 (PD-1 / CTLA-4), KN-046 (PD-1 / CTLA-4),MEDI-5752 (CTLA-4 / PD-1), RO-7121661 (PD-1 / TIM-3), XmAb-20717 (PD-1 / CTLA-4), AK-104 (CTLA-4 / PD-1), AMG-420 (BCMA / CD3) , BI-836880(VEFG / ANG2), JNJ-63709178(CD123 / CD3), MGD-007(CD3 / gpA33), MGD-009(CD3 / B7H3), AGEN1223, IMCgp100(CD3 / gp 100), AGEN-1423, ATOR-1015 (CTLA-4 / OX40), LY-3415244 (TIM-3 / PDL1), INHIBRX-105 (4-1BB / PDL1), faricimab (VEGF-A / ANG-2), FAP-4-IBBL (4-1BB / FAP), XmAb-13676 (CD3 / CD20), TAK-252 (PD-1 / OX40L), TG-1801 (CD19 / CD47), XmAb-18087 (SSTR2 / CD3), Katsumakiso Mab (CD3 / EpCAM), SAR-156597 (IL4 / IL13), EMB-01 (EGFR / cMET), REGN-4018 (MUC16 / CD3), REGN-1979 (CD20 / CD3), RG-7828 (CD20 / CD3), CC-93269 (CD3 / BCMA), REGN-5458 (CD3 / BCMA), nabi-cizumab (DLL4 / VEGF), GRB-1302 (CD3 / Erbb2), vanucizumab (VEGF-A / ANG-2), GRB- bispecific antibodies such as 1342 (CD38 / CD3), GEM-333 (CD3 / CD33), IMM-0306 (CD47 / CD20), RG6076, MEDI5752 (PD-1 / CTLA-4), LY3164530 (MET / EGFR); alpha-ketoglutarate dehydrogenase (KGDH) inhibitors, such as CPI-613; XPO1 inhibitors, such as selinexor (KPT-330); isocitrate dehydrogenase 2 (IDH2) inhibitors, such as enasidenib (AG-221); IDH1 inhibitors, such as AG-120 and AG-881 (IDH1 and IDH2), IDH-305, BAY-1436032; IDH1 gene inhibitors, such asivosidenib; interleukin-3 receptor (IL-3R) modulators, e.g., SL-401; arginine deiminase stimulators, e.g., pegalgiminase (ADI-PEG-20); claudin-18 inhibitors, e.g., claudiximab; β-catenin inhibitors, e.g., CWP-291; chemokine receptor 2 (CCR) inhibitors, e.g., PF-04136309, CCX-872, BMS-813160 (CC R2 / CCR5); thymidylate synthase inhibitors, e.g., ONX-0801; ALK / ROS1 inhibitors, e.g., lorlatinib; tankyrase inhibitors, e.g., G007-LK; triggering receptor expressed on myeloid cells 1 (TREM1; NCBI Gene ID: 54210), e.g., PY159; triggering receptor expressed on myeloid cells 2 (TREM2; NCBI Gene ID: 54209), e.g., PY314; Mdm2 p53 binding protein inhibitors, e.g., CMG-097, HDM-201; c-PIM inhibitors, e.g., PIM447; sphingosine kinase-2 (SK2) inhibitors, e.g., Yeliva® (ABC294640); DNA polymerase inhibitors, e.g., sapacitabine; cell cycle / microtubule inhibitors, e.g., eribulin mesylate; c-MET inhibitors, e.g., AMG-337, savolitinib, tivantinib (ARQ-197), capmatinib, and tepotinib. tinib, ABT-700, AG213, AMG-208, JNJ-38877618 (OMO-1), merestinib, HQP-8361; c-Met / VEGFR inhibitors, e.g., BMS-817378, TAS-115; c-Met / RON inhibitors, e.g., BMS-777607; BCR / ABL inhibitors, e.g., revastinib, asciminib, ponatinib (ICLUSIG®); MNK1 / MNK2 inhibitors, e.g., eFT-508; cytochrome P450 11B2 / cytochrome P450 17 / AKT protein kinase inhibitors, such as LAE-201; cytochrome P450 3A4 stimulators, such as mitotane; lysine-specific demethylase-1 (LSD1) inhibitors, such as CC-90011; CSF1R / KIT and FLT3 inhibitors, such aspexidartinib (PLX3397); Flt3 tyrosine kinase / Kit tyrosine kinase inhibitors such as quizartinib dihydrochloride, and PDGF receptor antagonists; kinase inhibitors such as vandetanib; E-selectin antagonists such as GMI-1271; differentiation inducers such as tretinoin; epidermal growth factor receptor (EGFR) inhibitors such as osimertinib (AZD-9291), cetuximab; topoisomerase inhibitors such as adriamycin, doxorubicin, daunorubicin, dactinomycin, DaunoXome, Ca elyx, eniposide, epirubicin, etoposide, idarubicin, irinotecan, mitoxantrone, pixantrone, sobuzoxane, topotecan, irinotecan, MM-398 (liposomal irinotecan), vosaroxin and GPX-150, aldoxorubicin, AR-67, mavereltinib, AST-2818, avitinib (ACEA-0010), irofulven (MGI-114); corticosteroids such as cortisone, dexamethasone, hydrocortisone, methylprednisolone, prednisone, prednisolone; growth factor signaling Kinase inhibitors; nucleoside analogs, e.g., DFP-10917; Axl inhibitors, e.g., BGB-324 (bemcentinib), SLC-0211; Axl / Flt3 inhibitors, e.g., gilteritinib; ABBV-744, inhibitors of bromodomain and extraterminal motif (BET) proteins, including BRD2 (NCBI Gene ID: 6046), BRD3 (NCBI Gene ID: 8019), BRD4 (NCBI Gene ID: 23476), and bromodomain testis-specific protein (BRDT; NCBI Gene ID: 676), e.g., INCB -054329, INCB057643, TEN-010, AZD-5153, ABT-767, BMS-986158, CC-90010, GSK525762 (molybresive), NHWD-870, ODM-207, GSK-2820151, GSK-1210151A, ZBC246, ZBC260, ZEN3694, FT-1101, RG-6146, CC-90010, CC-95775, mibebrexit, BI-894999, PLX-2853, PLX-51107, CPI-0610, GS-5829; PARP inhibitors, e.g., pamiparib,Fuzuloparib, talazoparib tosylate, niraparib tosylate monohydrate, rucaparib camsylate, olaparib, veliparib, ABT-767, BGB-290, bendamustine hydrochloride; PARP / tankyrase inhibitors, e.g., 2X-121 (e-7499); IMP-4297, SC-10914, IDX-1197, HWH-340, CK-102, simimiparib; proteasome inhibitors, e.g., ixazomib (NINLARO®), carfilzomib (Kyprolis®), marizomib, bortezomib; glutaminase inhibitors, e.g., CB-839 (telagrenast), bis-2-(5-phenylacetamido-1,3,4-thiadiazol-2-yl)ethyl sulfide (BPTES); mitochondrial complexes, Complex I inhibitors, e.g. metformin, phenformin; vaccines such as peptide vaccines TG-01 (RAS), GALE-301, GALE-302, neripepimut-s, SurVaxM, DSP-7888, TPIV-200, PVX-410, VXL-100, DPX-E7, ISA-101, 6MHP, OSE-2101, galipepimut-S, SVN53-67 / M57-KLH, IMU-131, peptide subunit vaccine (acute lymphoblastic leukemia, University Children's Hospital Tuebingen); bacterial vector vaccines, e.g. CRS-207 / GVAX, axalimogene filolisbac (ADXS11-001); adenovirus vector vaccines, e.g. nadofaragene filolisbac (ADXS11-001); firadenovec; autologous Gp96 vaccines; dendritic cell vaccines, e.g., CVactm, stapuldencel-T, eltrapuldencel-T, rocapuldencel-T (AGS-003), DCVAC, SL-701, BSK01TM, ADXS31-142, autologous dendritic cell vaccines (metastatic melanoma, intradermal / intravenous, Universitatsklinikum Erlangen); oncolytic vaccines, e.g., talimogene laherparepvec, pexastimogene devasilepvec devacirepvec), GL-ONC1, MG1-MA3, Parvovirus H-1, ProstAtak, enadenotucirev, MG1MA3, ASN-002 (TG-1042); therapeutic vaccines, e.g., CVAC-301, CMP-001, CreaVax-BC, PF-06753512, VBI-1901, TG-4010, ProscaVax™; tumor cell vaccines, e.g., Vigil® (IND-14205), Oncoquest-L vaccine; attenuated recombinant serotype 1 poliovirus vaccines, e.g., PVS-RIPO; Adagloxad simolenin; MEDI-0457;DPV-001, a tumor-derived autophagosome-enriched cancer vaccine; RNA vaccines, e.g., CV-9209, LV-305; DNA vaccines, e.g., MEDI-0457, MVI-816, INO-5401; modified vaccinia virus expressing p53, Ankara vaccine, e.g., MVA-p53; DPX-Survivac; BriaVax™; GI-6301; GI-6 207; GI-4000; IO-103; Neo-antigen peptide vaccines, e.g., AGEN-2017, GEN-010, NeoVax, RG-6180, GEN-009, PGV-001 (TLR-3 agonist), GRANITE-001, NEO-PV-01; PhosphoSynVax™; Vitespen (HSPPC-96-C), NANT colorectal cancer vaccines containing aldoxorubicin Chin, autologous tumor cell vaccine + systemic CpG-B + IFN-alpha (cancer), IO-120 + IO-103 (PD-L1 / PD-L2 vaccine), peptide vaccines targeting heat shock proteins such as HB-201, HB-202, HB-301, TheraT®-based vaccines; TLR-3 agonists / interferon inducers, e.g., poly-ICLC (NSC-301463); TAT-3 inhibitors, such as napabucasin (BBI-608); ATPase p97 inhibitors, such as CB-5083; Smoothened (SMO) receptor inhibitors, such as Odomzo® (sonidegib, formerly LDE-225), LEQ506, vismodegib (GDC-0449), BMS-833923, glasdegib (PF-04449913), LY2940680, and itraconazole;Interferon alpha ligand modulators, such as interferon alpha-2b, interferon alpha-2a biosimilars (Biogenomics), PEG interferon alpha-2b (AOP-2014, P-1101, PEG IFN alpha-2b), multiferon (Alpha Nativ, Viragen), interferon alpha 1b, Roferon-A (Camferon, Ro-25-3036), interferon alpha-2a post-development (Biosidus) (Inmutag, Inter 2A), interferon alpha-2b post-development (Biosidus-Bioferon, Citoferon, Ganapar, Beijing Kawin Technology-Kaferon), alphaferon, pegylated interferon alpha-1b, pegylated interferon alpha-2b post-development formulation (Amega), recombinant human interferon alpha-1b, recombinant human interferon alpha-2a, recombinant human interferon alpha-2b, veltuzumab-IFN alpha 2b conjugate, Dynavax (SD-101), and interferon alpha-n1 (Humoferon, SM-10500, Sumiferon); interferon gamma ligand modulators, e.g., interferon gamma (OH-6000, Ogam ma100; telomerase modulators such as tertomotide (GV-1001, HR-2802, Riavax) and imetelstat (GRN-163, JNJ-63935937); DNA methyltransferase inhibitors such as temozolomide (CCRG-81045), decitabine, oral decitabine and cedazuridine (ASTX727), guadecitabine (S-110, SGI-110), KRX-0402, RX-3117, RRx-001, and azacitidine (CC-486); DNA gyrase inhibitors such as pixantrone and sobuzoxane; DNA gyrase inhibitors / topoisomerase II inhibitors such as amrubicin;Bcl-2 family protein inhibitors, such as ABT-263, venetoclax (ABT-199), obatoclax mesylate, pelcitoclax, ABT-737, RG7601, and AT-101; Bcl-2 / Bcl-XL inhibitors, such as navitoclax (ABT-263; RG-7433); Notch inhibitors, such as LY3039478 (crenigacestat), tarexuzumab (anti-Notch2 / 3), BMS-906024; hyaluronidase stimulators, such as PEGPH-20; Erbb2 tyrosine kinase receptor inhibitors / hyaluronidase stimulators, e.g., Herceptin Hylecta; Wnt pathway inhibitors, e.g., SM-04755, PRI-724, WNT-974; gamma secretase inhibitors, e.g., PF-03084014, MK-0752, RO-4929097; Grb-2 (growth factor receptor-bound protein-2) inhibitors, e.g., BP1001; TRAIL pathway inducer compounds, e.g., ONC201, ABBV-621; TRAIL modulators, e.g., SCB- 313; focal adhesion kinase inhibitors, e.g., VS-4718, defactinib, GSK2256098; hedgehog inhibitors, e.g., salidegib, sonidegib (LDE225), glasdegib; aurora kinase inhibitors, e.g., alisertib (MLN-8237), and AZD-2811, AMG-900, barasertib, ENMD-2076; HSPB1 modulators (heat shock protein 27, HSP27), e.g., brivudine, apatorsen; ATR inhibitors, e.g., BAY-937, AZD6738, AZD6 783, VX-803, VX-970 (berzosertib), and VX-970; Hsp90 inhibitors, e.g., AUY922, onarespib (AT13387), SNX-2112, SNX5422; mouse double minute chromosome (mdm2) oncogene inhibitors, such as DS-3032b, RG7775, AMG-232, HDM201, and idazanutulin (RG7388); CD137 agonists, such as urelumab, utomilumab (PF-05082566), AGEN2373, ADG-106, BT-7480, and QL1806;STING agonists such as ADU-S100 (MIW-815), SB-11285, MK-1454, SR-8291, AdVCA0848, GSK-532, SYN-STING, MSA-1, SR-8291, GSK3745417; FGFR inhibitors, such as FGF-401, INCB-054828, BAY-1163877, AZD4547, JNJ-42756493, LY2874455, Debio-1347; fatty acid synthase (FASN) inhibitors, such as , TVB-2640; CD44 binding agents, e.g., A6; protein phosphatase 2A (PP2A) inhibitors, e.g., LB-100; CYP17 inhibitors, e.g., ceviteronel (VT-464), ASN-001, ODM-204, CFG920, abiraterone acetate; RXR agonists, e.g., IRX4204; hedgehog / smoothened (hh / Smo) antagonists, e.g., taladegib, pachidegib, vismodegib; complement C3 modulators, e.g., Imprime PGG; IL-15 agonists, e.g., ALT-803, NKTR-255, interleukin-15 / Fc fusion protein, AM-0015, NIZ-985, and hetIL-15; EZH2 (enhancer of zeste homolog 2) inhibitors, e.g., tazemetostat, CPI-1205, GSK-2816126, PF-06821497; pelareorep, CG-0070, MV-NIS therapy, HSV-1716, DS-1647, VCN-01, ONCOS-102, TBI-1401, tasadenoturev (DNX-2401), vocimagene oncolytic viruses such as amiretrorepvec, RP-1, CVA21, Celyvir, LOAd-703, OBP-301, IMLYGIC®; DOT1L (histone methyltransferase) inhibitors such as pinometostat (EPZ-5676); toxins such as cholera toxin, ricin, Pseudomonas exotoxin, Bordetella pertussis adenylate cyclase toxin, diphtheria toxin, and caspase activators; DNA plasmids such as BC-819; PLK inhibitors of PLK1, 2, and 3, such as volasertib (PLK1); WEE1 inhibitors such as AZD-1775 (adavosertib);Rho kinase (ROCK) inhibitors, e.g., AT13148, KD025; inhibitor of apoptosis protein (IAP) inhibitors, e.g., ASTX660, debio-1143, birinapant, APG-1387, LCL-161; RNA polymerase inhibitors, e.g., lurbinectedin (PM-1183), CX-5461; PM-184, BAL-101553 (risabumbulin), and OXI-4503, tubulin inhibitors such as fluorapasin (AC-0001), plinabulin, and vinflunine; Toll-like receptor 4 (TLR-4) agonists, e.g., G100, GSK1795091, and PEPA-10; elongation factor 1 alpha 2 inhibitors, e.g., plitidepsin; elongation factor 2 inhibitors / interleukin-2 ligand / NAD ADP-ribosyltransferase stimulators, such as denileukin diftitox; CD95 inhibitors, such as APG-101, APO-010, asnercept; WT1 inhibitors, such as DSP-7888; splicing factor 3B subunit 1 (SF3B1) inhibitors, such as H3B-8800; retinoid Z receptor gamma (RORγ) agonists, such as LYC-55716; and microbiome modulators, such as SER-401, EDP-1503, MRx-0518.

[0086] In various embodiments, the agents that inhibit the binding between CD47 and SIRPα (e.g., magrolimab) and VEGFA / VEGFR inhibitors (e.g., bevacizumab) described herein are further combined with one or more additional therapeutic agents, including inhibitors or antagonists of the following: myeloid cell leukemia sequence 1 (MCL1) apoptosis regulator (NCBI Gene ID: 4170); mitogen-activated protein kinase 1 (MAP4K1) (also referred to as hematopoietic progenitor kinase 1 (HPK1), NCBI Gene ID: 11184); diacylglutaminidase inhibitors (DGR1, D ... Lyserol kinase alpha (DGKA, DAGK, DAGK1, or DGK-alpha; NCBI Gene ID: 1606); ecto-5'-nucleotidase (NT5E or CD73; NCBI Gene ID: 4907); ectonucleoside triphosphate diphosphohydrolase 1 (ENTPD1 or CD39; NCBI Gene ID: 593); transforming growth factor beta 1 (TGFB1 or TGFβ; NCBI Gene ID: 7040); heme oxygenase 1 (HMOX1, HO-1, or HO1; NCBI Gene ID: 3162); heme oxygenase endothelial growth factor A (VEGFA or VEGF; NCBI Gene ID: 7422); erb-b2 receptor tyrosine kinase 2 (ERBB2, HER2, HER2 / neu, or CD340; NCBI Gene ID: 2064), epidermal growth factor receptor (EGFR, ERBB, ERBB1, or HER1; NCBI Gene ID: 1956); ALK receptor tyrosine kinase (ALK, CD246; NCBI Gene ID: 238); poly(ADP-ribose) polymerase 1 ( PARP1; NCBI Gene ID: 142; poly(ADP-ribose) polymerase 2 (PARP2; NCBI Gene ID: 10038); TCDD-inducible poly(ADP-ribose) polymerase (TIPARP, PARP7; NCBI Gene ID: 25976); cyclin-dependent kinase 4 (CDK4; NCBI Gene ID: 1019); cyclin-dependent kinase 6 (CDK6; NCBI Gene ID: 1021); TNF receptor superfamily member 14 (TNFRSF14, HVEM, CD270; NCBI Gene ID: 8764);T cell immunoreceptor with Ig and ITIM domains (TIGIT; NCBI Gene ID: 201633); X-linked inhibitor of apoptosis (XIAP, BIRC4, IAP-3; NCBI Gene ID: 331); baculovirus IAP repeat-containing 2 (BIRC2, cIAP1; NCBI Gene ID: 329); baculovirus IAP repeat-containing 3 (BIRC3, cIAP2; NCBI Gene ID: 330); baculovirus IAP repeat-containing 5 (BIRC5, survivin; NCBI Gene ID: 332); CC motif chemokine receptor 2 (CCR2, CD192; NCBI gene ID: 729230); CC motif chemokine receptor 5 (CCR5, CD195; NCBI gene ID: 1234); CC motif chemokine receptor 8 (CCR8, CDw198; NCBI gene ID: 1237); CXC motif chemokine receptor 2 (CXCR2, CD182; NCBI gene ID: 3579); CXC motif chemokine receptor 3 (CXCR3, CD182, CD183; NCBI gene ID: 2833); CXC motif chemokine receptor 4 (CXCR4, CD184; NCBI gene ID: 7852); arginase (ARG1 (NCBI gene ID: 383), ARG2 (NCBI gene ID: 384)), carbonic anhydrase (CA1 (NCBI gene ID: 759), CA2 (NCBI gene ID: 760), CA3 (NCBI gene ID: 761), CA4 (NCBI gene ID: 762), CA5A (NCBI gene ID: 763), CA5B (NCBI gene ID: 11238), CA6 (NCBI gene ID: 765), CA7 (NCBI gene ID: 766), 66), CA8 (NCBI Gene ID: 767), CA9 (NCBI Gene ID: 768), CA10 (NCBI Gene ID: 56934), CA11 (NCBI Gene ID: 770), CA12 (NCBI Gene ID: 771), CA13 (NCBI Gene ID: 377677), CA14 (NCBI Gene ID: 23632)), prostaglandin endoperoxide synthase 1 (PTGS1, COX-1; NCBI Gene ID: 5742), prostaglandin endoperoxide synthase 2 (PTGS2, COX-2;NCBI Gene ID: 5743), secretory phospholipase A2, prostaglandin E synthase (PTGES, PGES; Gene ID: 9536), arachidonate 5-lipoxygenase (ALOX5, 5-LOX; NCBI Gene ID: 240), and / or soluble epoxide hydrolase 2 (EPHX2, SEH; NCBI Gene ID: 2053); secretory phospholipase A2 (e.g., PLA2G1B (NCBI Gene ID: 5319); PLA2G7 (NCBI Gene ID: 7941), PLA2G3 (NCBI Gene ID: 50487), PLA2G2A (NCBI Gene ID: 5320); PLA2G4A (NCBI Gene ID: 5321); PLA2G12A (NCBI Gene ID: 81579); PLA2G12B (NCBI Gene ID: 84647); PLA2G10 (NCBI Gene ID: 8399); PLA2G5 (NCBI Gene ID: 5322); PLA2G 2D (NCBI Gene ID: 26279); PLA2G15 (NCBI Gene ID: 23659); indoleamine-2,3-dioxygenase 1 (IDO1; NCBI Gene ID: 3620); indoleamine-2,3-dioxygenase 2 (IDO2; NCBI Gene ID: 169355); hypoxia-inducible factor 1 subunit alpha (HIF1A; NCBI Gene ID: 3091); angiopoietin 1 (ANGPT1; NCBI Gene ID: 23659); gene ID: 284); endothelial TEK tyrosine kinase (TIE-2, TEK, CD202B; NCBI gene ID: 7010); Janus kinase 1 (JAK1; NCBI gene ID: 3716); catenin beta 1 (CTNNB1; NCBI gene ID: 1499); histone deacetylase 9 (HDAC9; NCBI gene ID: 9734), and / or 5'-3' exoribonuclease 1 (XRN1; NCBI gene ID: 54464).

[0087] In various embodiments, the agents that inhibit the binding between CD47 and SIRPα (e.g., magrolimab) and VEGFA / VEGFR inhibitors (e.g., bevacizumab) described herein are further combined with agonists of fms-related receptor tyrosine kinase 3 (FLT3); FLK2; STK1; CD135; FLK-2; NCBI gene ID: 2322). Examples of FLT3 agonists include, but are not limited to, CDX-301 and GS-3583. GS-3583 is described, for example, in International Publication No. WO 2020 / 263830, which is incorporated herein by reference in its entirety for all purposes.

[0088] In various embodiments, the agents that inhibit the binding between CD47 and SIRPα (e.g., magrolimab) and VEGFA / VEGFR inhibitors (e.g., bevacizumab) described herein are further combined with an anti-CD19 agent or antibody. Examples of anti-CD19 agents or antibodies that may be co-administered include, but are not limited to, blinatumomab, tafasitamab, XmAb5574 (Xencor), AFM-11, inebilizumab, loncastuximab, MEDI 551 (Cellective Therapeutics); and MDX-1342 (Medarex).

[0089] In various embodiments, the agents that inhibit the binding between CD47 and SIRPα (e.g., magrolimab) and VEGFA / VEGFR inhibitors (e.g., bevacizumab) described herein are further combined with an anti-CD20 agent or antibody. Examples of anti-CD20 agents or antibodies that may be co-administered include, but are not limited to, IGN-002, PF-05280586; rituximab (Rituxan / Biogen Idec), ofatumumab (Arzerra / Genmab), obinutuzumab (Gazyva / Roche Glycart Biotech), alemtuzumab, veltuzumab, ocrelizumab (Ocrevus / Biogen Idec; Genentech), ocaratuzumab and ublituximab, and LFB-R603 (LFB Biotech.; rEVO Biologics).

[0090] In various embodiments, the agents that inhibit the binding between CD47 and SIRPα (e.g., magrolimab) and VEGFA / VEGFR inhibitors (e.g., bevacizumab) described herein are further combined with an anti-CD22 agent or antibody. Examples of anti-CD22 agents or antibodies that may be co-administered include, but are not limited to, epratuzumab, AMG-412, IMMU-103 (Immunomedics).

[0091] In various embodiments, the agents that inhibit the binding between CD47 and SIRPα (e.g., magrolimab) and VEGFA / VEGFR inhibitors (e.g., bevacizumab) described herein are further combined with an anti-CD30 agent or antibody. Examples of anti-CD30 agents or antibodies that may be co-administered include, but are not limited to, brentuximab vedotin (Seattle Genetics).

[0092] In various embodiments, the agents that inhibit the binding between CD47 and SIRPα (e.g., magrolimab) and VEGFA / VEGFR inhibitors (e.g., bevacizumab) described herein are further combined with an anti-CD33 agent or antibody. Examples of anti-CD33 agents or antibodies that may be co-administered include, but are not limited to, gemtuzumab, lintuzumab, vadastuximab, CIK-CAR.CD33;CD33CART, AMG-330 (CD33 / CD3), AMG-673 (CD33 / CD3), and GEM-333 (CD3 / CD33), and IMGN-779.

[0093] In various embodiments, the agents that inhibit the binding between CD47 and SIRPα (e.g., magrolimab) and VEGFA / VEGFR inhibitors (e.g., bevacizumab) described herein are further combined with an anti-CD37 agent or antibody. Examples of anti-CD37 agents or antibodies that may be co-administered include, but are not limited to, BI836826 (Boehringer Ingelheim), Otlertuzumab, and TRU-016 (Trubion Pharmaceuticals).

[0094] In various embodiments, the agents that inhibit the binding between CD47 and SIRPα (e.g., magrolimab) and VEGFA / VEGFR inhibitors (e.g., bevacizumab) described herein are further combined with an anti-CD38 agent or antibody. Exemplary anti-CD38 agents or antibodies that may be co-administered include, but are not limited to, CD38, such as T-007, UCART-38; Darzalex (Genmab), daratumumab, JNJ-54767414 (Darzalex / Genmab), isatuximab, SAR650984 (ImmunoGen), MOR202, MOR03087 (MorphoSys), TAK-079; and anti-CD38-attenukines, such as TAK573.

[0095] In various embodiments, the agents that inhibit the binding between CD47 and SIRPα (e.g., magrolimab) and VEGFA / VEGFR inhibitors (e.g., bevacizumab) described herein are further combined with an anti-CD52 agent or antibody. Examples of anti-CD52 agents or antibodies that may be co-administered include, but are not limited to, anti-CD52 antibodies, such as alemtuzumab (Campath / University of Cambridge).

[0096] In various embodiments, the agents that inhibit the binding between CD47 and SIRPα (e.g., magrolimab) and VEGFA / VEGFR inhibitors (e.g., bevacizumab) described herein are further combined with an anti-CD98 (4F2, FRP-1) agent or antibody. Examples of anti-CD98 agents or antibodies that may be co-administered include, but are not limited to, IGN523 (Igenica).

[0097] In various embodiments, the agents that inhibit the binding between CD47 and SIRPα (e.g., magrolimab) and VEGFA / VEGFR inhibitors (e.g., bevacizumab) described herein are further combined with an anti-CD157 (BST-1) agent or antibody. Examples of anti-CD157 agents or antibodies that may be co-administered include, but are not limited to, OBT357, MEN1112 (Menarini; Oxford BioTherapeutics).

[0098] In various embodiments, the agents that inhibit the binding between CD47 and SIRPα (e.g., magrolimab) and VEGFA / VEGFR inhibitors (e.g., bevacizumab) described herein are further combined with an anti-DKK-1 agent or antibody. Examples of anti-DKK-1 agents or antibodies that may be co-administered include, but are not limited to, BHQ880 (MorphoSys; Novartis) and DKN-01, LY-2812176 (Eli Lilly).

[0099] In various embodiments, the agents that inhibit the binding between CD47 and SIRPα (e.g., magrolimab) and VEGFA / VEGFR inhibitors (e.g., bevacizumab) described herein are further combined with an anti-GRP78 (BiP) agent or antibody. Examples of anti-GRP78 agents or antibodies that may be co-administered include, but are not limited to, PAT-SM6 (OncoMab GmbH).

[0100] In various embodiments, the agents that inhibit the binding between CD47 and SIRPα (e.g., magrolimab) and VEGFA / VEGFR inhibitors (e.g., bevacizumab) described herein are further combined with anti-NOTCH1 agents or antibodies. Examples of anti-NOTCH1 agents or antibodies that may be co-administered include, but are not limited to, Brontictuzumab, OMP-52M51 (OncoMed Pharmaceuticals).

[0101] In various embodiments, the agents that inhibit the binding between CD47 and SIRPα (e.g., magrolimab) and VEGFA / VEGFR inhibitors (e.g., bevacizumab) described herein are further combined with an anti-ROR1 agent or antibody. Examples of anti-ROR1 agents or antibodies that may be co-administered include, but are not limited to, mapatuzumab, TRM1, HGS-1012 (Cambridge Antibody Technology).

[0102] In various embodiments, the agents that inhibit the binding between CD47 and SIRPα (e.g., magrolimab) and VEGFA / VEGFR inhibitors (e.g., bevacizumab) described herein are further combined with an anti-SLAMF7 (CS1, CD319) agent or antibody. Examples of anti-SLAMF7 agents or antibodies that may be co-administered include, but are not limited to, elotuzumab, HuLuc63, BMS-901608 (Empliciti / PDL BioPharma), mogamulizumab (KW-0761).

[0103] In various embodiments, the agents that inhibit the binding between CD47 and SIRPα (e.g., magrolimab) and VEGFA / VEGFR inhibitors (e.g., bevacizumab) described herein are further combined with anti-TNFRSF10A (DR4; APO2; CD261; TRAILR1; TRAILR-1) agents or antibodies. Examples of anti-TNFRSF10A agents or antibodies that may be co-administered include, but are not limited to, mapatuzumab, TRM1, HGS-1012 (Cambridge Antibody Technology).

[0104] In various embodiments, the agents that inhibit the binding between CD47 and SIRPα (e.g., magrolimab) and VEGFA / VEGFR inhibitors (e.g., bevacizumab) described herein are further combined with an anti-transferrin receptor (TFRC; CD71) agent or antibody. Examples of anti-transferrin receptor agents or antibodies that may be co-administered include, but are not limited to, E2.3 / A27.15 (University of Arizona).

[0105] In various embodiments, the agent that inhibits the binding between CD47 and SIRPα (e.g., magrolimab) and the VEGFA / VEGFR inhibitor (e.g., bevacizumab) described herein are further combined with an anti-EPHA3 agent or antibody. Examples of anti-EPHA3 agents or antibodies that can be co-administered include, but are not limited to, Ifabotuzumab, KB004 (Ludwig Institute for Cancer Research).

[0106] In various embodiments, the agents that inhibit the binding between CD47 and SIRPα (e.g., magrolimab) and VEGFA / VEGFR inhibitors (e.g., bevacizumab) described herein are further combined with an anti-CCR4 agent or antibody. Examples of anti-CCR4 agents or antibodies that may be co-administered include, but are not limited to, mogamulizumab, KW-0761 (Poteligeo / Kyowa Hakko Kirin Co.).

[0107] In various embodiments, the agents that inhibit the binding between CD47 and SIRPα (e.g., magrolimab) and VEGFA / VEGFR inhibitors (e.g., bevacizumab) described herein are further combined with an anti-CXCR4 agent or antibody. Examples of anti-CXCR4 agents or antibodies that may be co-administered include, but are not limited to, BMS-936564, MDX-1338 (Medarex), and PF-06747143 (Pfizer).

[0108] In various embodiments, the agents that inhibit the binding between CD47 and SIRPα (e.g., magrolimab) and VEGFA / VEGFR inhibitors (e.g., bevacizumab) described herein are further combined with an anti-BAFF agent or antibody. Examples of anti-BAFF agents or antibodies that may be co-administered include, but are not limited to, tabalumab, LY2127399 (Eli Lilly).

[0109] In various embodiments, the agents that inhibit the binding between CD47 and SIRPα (e.g., magrolimab) and VEGFA / VEGFR inhibitors (e.g., bevacizumab) described herein are further combined with an anti-BAFF receptor (BAFF-R) agent or antibody. Examples of anti-BAFF-R agents or antibodies that may be co-administered include, but are not limited to, VAY736 (MorphoSys; Novartis).

[0110] In various embodiments, the agents that inhibit the binding between CD47 and SIRPα (e.g., magrolimab) and VEGFA / VEGFR inhibitors (e.g., bevacizumab) described herein are further combined with an anti-RANKL agent or antibody. Examples of anti-RANKL agents or antibodies that may be co-administered include, but are not limited to, denosumab, AMG-162 (Prolia; Ranmark; Xgeva / Amgen).

[0111] In various embodiments, the agents that inhibit the binding between CD47 and SIRPα (e.g., magrolimab) and VEGFA / VEGFR inhibitors (e.g., bevacizumab) described herein are further combined with an anti-IL-6 agent or antibody. Examples of anti-IL-6 agents or antibodies that may be co-administered include, but are not limited to, siltuximab, CNTO-328 (Sylvant / Centocor).

[0112] In various embodiments, the agents that inhibit the binding between CD47 and SIRPα (e.g., magrolimab) and VEGFA / VEGFR inhibitors (e.g., bevacizumab) described herein are further combined with anti-IL-6 receptor (IL-6R) agents or antibodies. Examples of anti-IL-6R agents or antibodies that may be co-administered include, but are not limited to, tocilizumab, R-1569 (Actemra / Chugai Pharmaceutical; Osaka University) or AS-101 (CB-06-02, IVX-Q-101).

[0113] In various embodiments, the agents that inhibit the binding between CD47 and SIRPα (e.g., magrolimab) and VEGFA / VEGFR inhibitors (e.g., bevacizumab) described herein are further combined with an anti-IL3RA (CD123) agent or antibody. Examples of anti-IL3RA (CD123) agents or antibodies that may be co-administered include tagraxofusp, talacoutuzumab (JNJ-56022473; CSL362 (CSL)), pivekimab sunirine (IMGN632), MB-102 (Mustang Bio), CSL360 (CSL); vibecotamab (XmAb14045; Xencor); KHK2823 (Kyowa Hakko Kirin Co.); MGD-024 (CD123 / CD3; Macrogenics), APVO436 (CD123 / CD3); flotetuzumab (CD123 / CD3); JNJ-63709178 (CD123, CD3); and XmAb-14045 (CD123 / CD3) (Xencor).

[0114] In various embodiments, the agents that inhibit the binding between CD47 and SIRPα (e.g., magrolimab) and VEGFA / VEGFR inhibitors (e.g., bevacizumab) described herein are further combined with an anti-IL2RA (CD25) agent or antibody. Examples of anti-IL2RA agents or antibodies that may be co-administered include, but are not limited to, basiliximab, SDZ-CHI-621 (Simulect / Novartis), and daclizumab.

[0115] In various embodiments, the agents that inhibit the binding between CD47 and SIRPα (e.g., magrolimab) and VEGFA / VEGFR inhibitors (e.g., bevacizumab) described herein are further combined with an anti-IGF-1R (CD221) agent or antibody. Examples of anti-IGF-1R agents or antibodies that may be co-administered include, but are not limited to, ganitumab, AMG-479 (Amgen); ganitumab, AMG-479 (Amgen), dalotuzumab, MK-0646 (Pierre Fabre), and AVE1642 (ImmunoGen).

[0116] In various embodiments, the agents that inhibit the binding between CD47 and SIRPα (e.g., magrolimab) and VEGFA / VEGFR inhibitors (e.g., bevacizumab) described herein are further combined with an anti-GM-CSF (CSF2) agent or antibody. Examples of anti-GM-CSF agents or antibodies that may be co-administered include, but are not limited to, lenzilumab (aka KB003; KaloBios Pharmaceuticals).

[0117] In various embodiments, the agents that inhibit the binding between CD47 and SIRPα (e.g., magrolimab) and VEGFA / VEGFR inhibitors (e.g., bevacizumab) described herein are further combined with anti-HGF agents or antibodies. Examples of anti-HGF agents or antibodies that can be co-administered include, but are not limited to, ficlatuzumab, AV-299 (AVEO Pharmaceuticals).

[0118] In various embodiments, the agents that inhibit the binding between CD47 and SIRPα (e.g., magrolimab) and VEGFA / VEGFR inhibitors (e.g., bevacizumab) described herein are further combined with an anti-CD44 agent or antibody. Examples of anti-CD44 agents or antibodies that may be co-administered include, but are not limited to, RG7356, RO5429083 (Chugai Biopharmaceuticals; Roche).

[0119] In various embodiments, the agents that inhibit the binding between CD47 and SIRPα (e.g., magrolimab) and VEGFA / VEGFR inhibitors (e.g., bevacizumab) described herein are further combined with an anti-VLA-4 (CD49d) agent or antibody. Examples of anti-VLA-4 agents or antibodies that may be co-administered include, but are not limited to, natalizumab, BG-0002-E (Tysabri / Elan Corporation).

[0120] In various embodiments, the agents that inhibit the binding between CD47 and SIRPα (e.g., magrolimab) and VEGFA / VEGFR inhibitors (e.g., bevacizumab) described herein are further combined with an anti-ICAM-1 (CD54) agent or antibody. Examples of anti-ICAM-1 agents or antibodies that may be co-administered include, but are not limited to, BI-505 (BioInvent International).

[0121] In various embodiments, the agents that inhibit the binding between CD47 and SIRPα (e.g., magrolimab) and VEGFA / VEGFR inhibitors (e.g., bevacizumab) described herein are further combined with an anti-VEGF-A agent or antibody. Examples of anti-VEGF-A agents or antibodies that may be co-administered include, but are not limited to, bevacizumab (Avastin / Genentech; Hackensack University Medical Center).

[0122] In various embodiments, the agents that inhibit the binding between CD47 and SIRPα (e.g., magrolimab) and VEGFA / VEGFR inhibitors (e.g., bevacizumab) described herein are further combined with an anti-endosialin (CD248, TEM1) agent or antibody. Examples of anti-endosialin agents or antibodies that may be co-administered include, but are not limited to, ontecizumab, MORAB-004 (Ludwig Institute for Cancer Research; Morphotek).

[0123] In various embodiments, the agents that inhibit the binding between CD47 and SIRPα (e.g., magrolimab) and VEGFA / VEGFR inhibitors (e.g., bevacizumab) described herein are further combined with an anti-CD79 agent or antibody. Examples of anti-CD79 agents or antibodies that may be co-administered include, but are not limited to, polatuzumab, DCDS4501A, RG7596 (Genentech).

[0124] In various embodiments, the agents that inhibit the binding between CD47 and SIRPα (e.g., magrolimab) and VEGFA / VEGFR inhibitors (e.g., bevacizumab) described herein are further combined with an anti-isocitrate dehydrogenase (IDH) agent or antibody. Examples of anti-IDH agents or antibodies that may be co-administered include, but are not limited to, the IDH1 inhibitor ivosidenib (Tibsovo; Agios) and the IDH 2 inhibitor enasidenib (Idhifa; Celgene / Agios).

[0125] In various embodiments, the agents described herein that inhibit the binding between CD47 and SIRPα (e.g., magrolimab) and VEGFA / VEGFR inhibitors (e.g., bevacizumab) are further combined with an antibody targeting tumor-associated calcium signal transducer 2 (TACSTD2) (NCBI Gene ID: 4070; EGP-1, EGP1, GA733-1, GA7331, GP50, M1S1, TROP2), e.g., sacituzumab, e.g., sacituzumab govitecan (TRODELVY™).

[0126] In various embodiments, the agents described herein that inhibit the binding between CD47 and SIRPα (e.g., magrolimab) and VEGFA / VEGFR inhibitors (e.g., bevacizumab) are further combined with an anti-major histocompatibility complex, class I, G (HLA-G; NCBI gene ID: 3135) antibody, such as TTX-080.

[0127] In various embodiments, the agents described herein that inhibit the binding between CD47 and SIRPα (e.g., magrolimab) and VEGFA / VEGFR inhibitors (e.g., bevacizumab) are further combined with an anti-leukocyte immunoglobulin-like receptor B2 (LILRB2, also known as CD85D, ILT4; NCBI Gene ID: 10288) antibody, such as JTX-8064 or MK-4830.

[0128] Agonists or activators of members of the TNF Receptor Superfamily (TNFRSF) In various embodiments, the agents that inhibit the binding between CD47 and SIRPα (e.g., magrolimab) and VEGFA / VEGFR inhibitors (e.g., bevacizumab) described herein inhibit one or more TNF receptor superfamily (TNFRSF) members, such as TNFRSF1A (NCBI Gene ID: 7132), TNFRSF1B (NCBI Gene ID: 7133), TNFRSF4 (OX40, CD134; NCBI Gene ID; 7293), TNFRSF5 (CD40; NCBI Gene ID; 7294), TNFRSF6 (OX40, CD134; NCBI Gene ID; 7295), TNFRSF7 (OX40, CD134; NCBI Gene ID; 7296), TNFRSF8 (OX40, CD134; NCBI Gene ID; 7297), TNFRSF9 (OX40, CD134; NCBI Gene ID; 7298), TNFRSF10 (OX40, CD134; NCBI Gene ID; 7299), TNFRSF11 (OX40, CD134; NCBI Gene ID; 7299), TNFRSF12 (OX40, CD134; NCBI Gene ID; 7299), TNFRSF13 (OX40, CD134; NCBI Gene ID; 7297), TNFRSF14 (OX40, CD134; NCBI Gene ID; 7298), TNFRSF15 (OX40, CD134; NCBI Gene ID; 7299), TNFRSF16 (OX40, CD134; NCBI Gene ID; 7299), TNFRSF17 (OX40, CD134; NCBI Gene ID; 7299), TNFRSF18 (OX40, CD134; NCBI Gene ID; Gene ID: 958), TNFRSF6 (FAS, NCBI Gene ID: 355), TNFRSF7 (CD27, NCBI Gene ID: 939), TNFRSF8 (CD30, NCBI Gene ID: 943), TNFRSF9 (4-1BB, CD137, NCBI Gene ID: 3604), TNFRSF10A (CD261, DR4, TRAILR1, NCBI Gene ID: 8797), TNFRSF10B (CD262, DR5, TRAILR2, NCBI Gene ID: 8795), TNFRSF10C (C D263, TRAILR3, NCBI gene ID; 8794), TNFRSF10D (CD264, TRAILR4, NCBI gene ID; 8793), TNFRSF11A (CD265, RANK, NCBI gene ID; 8792), TNFRSF11B (NCBI gene ID; 4982), TNFRSF12A (CD266, NCBI gene ID; 51330), TNFRSF13B (CD267, NCBI gene ID; 23495), TNFRSF13C (CD268, NCBI gene ID; 1156 50), TNFRSF16 (NGFR, CD271, NCBI Gene ID; 4804), TNFRSF17 (BCMA, CD269, NCBI Gene ID; 608), TNFRSF18 (GITR, CD357, NCBI Gene ID; 8784), TNFRSF19 (NCBI Gene ID; 55504), TNFRSF21 (CD358, DR6, NCBI Gene ID; 27242), and TNFRSF25 (DR3, NCBI Gene ID; 8718).

[0129] Exemplary anti-TNFRSF4 (OX40) antibodies that may be co-administered include, but are not limited to, MEDI6469, MEDI6383, MEDI0562 (tabolixizumab), MOXR0916, PF-04518600, RG-7888, GSK-3174998, INCAGN1949, BMS-986178, GBR-8383, ABBV-368, and antibodies described in WO2016179517, WO2017096179, WO2017096182, WO2017096281, and WO2018089628, each of which is incorporated by reference in its entirety.

[0130] Exemplary anti-TNF receptor superfamily member 10b (TNFRSF10B, DR5, TRAILR2) antibodies that may be co-administered include, but are not limited to, DS-8273, CTB-006, INBRX-109, and GEN-1029.

[0131] Anti-TNFRSF5 (CD40) antibodies that may be co-administered include, but are not limited to, celicrelumab (RO7009789), mitazalimab (also known as banalimab, ADC-1013, JNJ-64457107), RG7876, SEA-CD40, APX-005M, and ABBV-428, ABBV-927, and JNJ-64457107.

[0132] Examples of anti-TNFRSF7 (CD27) agents that may be co-administered include, but are not limited to, valilumab (CDX-1127).

[0133] Examples of anti-TNFRSF9 (4-1BB, CD137) antibodies that may be co-administered include, but are not limited to, urelumab, utomilumab (PF-05082566), AGEN2373, and ADG-106, BT-7480, and QL1806.

[0134] Examples of anti-TNFRSF17 (BCMA) agents that may be co-administered include, but are not limited to, GSK-2857916.

[0135] Examples of anti-TNFRSF18 (GITR) antibodies that may be co-administered include, but are not limited to, MEDI1873, FPA-154, INCAGN-1876, TRX-518, BMS-986156, MK-1248, GWN-323, and those described in WO 2017096179, WO 2017096276, WO 2017096189, and WO 2018089628. In some embodiments, an antibody or fragment thereof that simultaneously targets TNFRSF4 (OX40) and TNFRSF18 (GITR) is co-administered. Such antibodies are described, for example, in WO 2017096179 and WO 2018089628, each of which is incorporated herein by reference in its entirety.

[0136] Exemplary anti-TRAILR1, anti-TRAILR2, anti-TRAILR3, anti-TRAILR4 antibodies that may be co-administered include, but are not limited to, ABBV-621.

[0137] Examples of bispecific antibodies targeting TNFRSF family members that can be co-administered include, but are not limited to, PRS-343 (CD-137 / HER2), AFM26 (BCMA / CD16A), AFM-13 (CD16 / CD30), REGN-1979 (CD20 / CD3), AMG-420 (BCMA / CD3), INHIBRX-105 (4-1BB / PDL1), FAP-4-IBBL (4-1BB / FAP), XmAb-13676 (CD3 / CD20), RG-7828 (CD20 / CD3), CC-93269 (CD3 / BCMA), REGN-5458 (CD3 / BCMA), and IMM-0306 (CD47 / CD20), and AMG-424 (CD38.CD3).

[0138] Examples of PVR-related immunoglobulin domain-containing (PVRIG, CD112R) inhibitors that may be co-administered include, but are not limited to, COM-701.

[0139] Examples of inhibitors of T cell immunoreceptor with Ig and ITIM domains (TIGIT; NCBI Gene ID: 201633) that may be co-administered include, but are not limited to, BMS-986207, RG-6058, AGEN-1307, and COM-902, etigilimab, tiragolumab (also known as MTIG-7192A; RG-6058; RO7092284), AGEN1777, IBI-939, AB154, MG1131, and EOS884448 (EOS-448).

[0140] Examples of inhibitors of Hepatitis A Virus Cellular Receptor 2 (HAVCR2, TIMD3, TIM-3) that may be co-administered include, but are not limited to, covolimab (TSR-022), LY-3321367, sabatolimab (MBG-453), INCAGN-2390, RO-7121661 (PD-1 / TIM-3), LY-3415244 (TIM-3 / PDL1), and RG7769 (PD-1 / TIM-3).

[0141] Examples of inhibitors of lymphocyte activation 3 (LAG-3, CD223) that may be co-administered include, but are not limited to, leratolimab (ONO-4482), LAG-525, MK-4280, REGN-3767, INCAGN2385, TSR-033, MGD-013 (PD-1 / LAG-3), and FS-118 (LAG-3 / PD-L1).

[0142] Examples of anti-killer cell immunoglobulin-like receptor, three Ig domains, and long cytoplasmic tail 1 (KIR3DL1; KIR; NCBI Gene ID: 3811) monoclonal antibodies include lirilumab (IPH-2102), IPH-4102, etc.

[0143] An example of an anti-NKG2a antibody that may be co-administered includes, but is not limited to, monalizumab.

[0144] Examples of anti-V-set immunoregulatory receptor (VSIR, B7H5, VISTA) antibodies that may be co-administered include, but are not limited to, HMBD-002, and CA-170 (PD-L1 / VISTA).

[0145] Examples of anti-CD70 antibodies that may be co-administered include, but are not limited to, AMG-172.

[0146] Examples of anti-ICOS antibodies that may be co-administered include, but are not limited to, JTX-2011, GSK3359609.

[0147] Examples of ICOS agonists that may be co-administered include, but are not limited to, ICOS-L.COMP (Gariepy, et al. 106th Annu Meet Am Assoc Immunologists (AAI) (May 9-13, San Diego) 2019, Abst 71.5).

[0148] Immune checkpoint inhibitors In various embodiments, the agents that inhibit the binding between CD47 and SIRPα (e.g., magrolimab) and VEGFA / VEGFR inhibitors (e.g., bevacizumab) described herein are further combined with one or more immune checkpoint inhibitors. In some embodiments, the one or more immune checkpoint inhibitors are proteinaceous (e.g., antibodies or fragments thereof, or antibody mimetics) inhibitors of PD-L1 (CD274), PD-1 (PDCD1), or CTLA4. In some embodiments, the one or more immune checkpoint inhibitors include small organic molecule inhibitors of PD-L1 (CD274), PD-1 (PDCD1), or CTLA4.

[0149] Examples of CTLA4 inhibitors that may be co-administered include, but are not limited to, ipilimumab, tremelimumab, BMS-986218, AGEN1181, AGEN1884, BMS-986249, MK-1308, REGN-4659, ADU-1604, CS-1002, BCD-145, APL-509, JS-007, BA-3071, ONC-392, AGEN-2041, JHL-1155, KN-044, CG-0161, ATOR- 1144, PBI-5D3H5, BPI-002, HBM-4003, and the multispecific inhibitors FPT-155 (CTLA4 / PD-L1 / CD28), PF-06936308 (PD-1 / CTLA4), MGD-019 (PD-1 / CTLA4), KN-046 (PD-1 / CTLA4), MEDI-5752 (CTLA4 / PD-1), XmAb-20717 (PD-1 / CTLA4), and AK-104 (CTLA4 / PD-1).

[0150] Examples of PD-L1 (CD274) or PD-1 (PDCD1) inhibitors / antibodies that may be co-administered include zimberelimab, pembrolizumab (KEYTRUDA®, MK-3477), nivolumab (OPDIVO®, BMS-936558, MDX-1106), cemiplimab, pidilizumab, spartalizumab (PDR-001), atezolizumab (RG-7446; TECENTRIQ, MPDL3280A), durvalumab (MEDI-4736), avelumab (MSB0010718C), tislelizumab (BGB -A317), toripalimab (JS-001), genolimuzumab (CBT-501), camrelizumab (SHR-1210), dostallimab (TSR-042), sintilimab (IBI-308), tislelizumab (BGB-A317), cemiplimab (REGN-2810), lambrolizumab (CAS Registry Number 1374853-91-4), AMG-404, AMP-224, MEDI0680 (AMP-514), BMS-936559, CK-301, PF-06801591, GEN-1046 (PD-L1 / 4-1BB), GLS-01 0(WBP-3055), AK-103(HX-008), AK-105, CS-1003, HLX-10, MGA-012, BI-754091, AGEN-2034, JNJ-63723283, LZM-009, BCD-100, LY-3300054, SHR-12 01, Sym-021, ABBV-181, PD1-PIK, BAT-1306, CX-072, CBT-502, MSB-2311, JTX-4014, BGB-A333, SHR-1316, CS-1001(WBP-3155, KN-035, HLX-20, KL-A1 67, STI-A1014, STI-A1015 (IMC-001), BCD-135, FAZ-053, TQB-2450, MDX1105-01, GS-4224, GS-4416, INCB086550, MAX10181, and multispecific inhibitors FPT-155 (CTLA4 / PD-L1 / CD28), PF-06936308 (PD-1 / CTLA4), MGD-013 (PD-1 / LAG-3), RO-7247669 (PD-1 / LAG-3), FS-118 (LAG-3 / PD-L1) MGD-019 (PD-1 / CTLA4),KN-046(PD-1 / CTLA4), MEDI-5752(CTLA4 / PD-1), RO-7121661(PD-1 / TIM-3), XmAb-20717(PD-1 / CTLA4), AK-104(CTLA4 / PD-1), M7824(PD-L1 / G NS-1480 (PD-L1 / EGFR), SCH-900475, PF-06801591, AGEN-2034, AK-105, PD1-PIK, BAT-1306, BMS-936559, CK-301, MEDI-0680, PDR001+Tafinlar®+Mekinist®, and those described in, for example, WO2018195321, WO2020014643, WO2019160882, and WO2018195321, but are not limited thereto.

[0151] In various embodiments, the anti-CD47 agents described herein are further combined with MCL1 apoptosis regulators, BCL2 family members (MCL1, TM; EAT; MCL1L; MCL1S; Mcl-1; BCL2L3; MCL1-ES; bcl2-L-3; mcl1 / EAT; NCBI gene ID: 4170). Examples of MCL1 inhibitors include AMG-176, AMG-397, S-64315 and AZD-5991, 483-LM, A-1210477, UMI-77, JKY-5-037, and those described in WO 2018183418, WO 2016033486, and WO 2017147410.

[0152] Toll-like receptor (TLR) agonists In various embodiments, an anti-CD47 agent or an anti-SIRPα agent described herein is combined with an agonist of a toll-like receptor (TLR), such as an agonist of TLR1 (NCBI Gene ID: 7096), TLR2 (NCBI Gene ID: 7097), TLR3 (NCBI Gene ID: 7098), TLR4 (NCBI Gene ID: 7099), TLR5 (NCBI Gene ID: 7100), TLR6 (NCBI Gene ID: 10333), TLR7 (NCBI Gene ID: 51284), TLR8 (NCBI Gene ID: 51311), TLR9 (NCBI Gene ID: 54106), and / or TLR10 (NCBI Gene ID: 81793).Exemplary TLR7 agonists that may be co-administered include, but are not limited to, DS-0509, GS-9620, LHC-165, TMX-101 (imiquimod), GSK-2245035, resiquimod, DSR-6434, DSP-3025, IMO-4200, MCT-465, MEDI-9197, 3M-051, SB-9922, 3M-052, Limtop, TMX-30X, TMX-202, RG-7863, RG-7795, and the TLR7 agonists described in U.S. Patent Application Publication Nos. 20100143301 (Gilead Sciences), 20110098248 (Gilead Sciences), and 20090047249 (Gilead Sciences). Sciences), 20140045849 (Janssen), 20140073642 (Janssen), WO 2014 / 056953 (Janssen), WO 2014 / 076221 (Janssen), WO 2014 / 128189 (Janssen), U.S. Patent Application Publication No. 20140350031 (Janssen), WO 2014 / 023813 (Janssen), U.S. Patent Application Publication No. 20080234251 (Array Biopharma), U.S. Patent Application Publication No. 20080306050 (Array Biopharma), U.S. Patent Application Publication No. 20100029585 (Ventirx Pharma), U.S. Patent Application Publication No. 20110092485 (Ventirx Examples of TLR7 / TLR8 agonists that may be co-administered include those disclosed in Ventirx Pharma, No. 20110118235 (Ventirx Pharma), No. 20120082658 (Ventirx Pharma), No. 20120219615 (Ventirx Pharma), No. 20140066432 (Ventirx Pharma), No. 20140088085 (Ventirx Pharma), No. 20140275167 (Novira Therapeutics), and No. 20130251673 (Novira Therapeutics). A TLR7 / TLR8 agonist that may be co-administered is NKTR-262.Examples of TLR8 agonists that may be co-administered include, but are not limited to, E-6887, IMO-4200, IMO-8400, IMO-9200, MCT-465, MEDI-9197, motolimod, resiquimod, GS-9688, VTX-1463, VTX-763, 3M-051, 3M-052, and the TLR8 agonists described in U.S. Patent Application Publication No. 20140045849 (Janssen), ... No. 40073642 (Janssen), WO 2014 / 056953 (Janssen), WO 2014 / 076221 (Janssen), WO 2014 / 128189 (Janssen), U.S. Patent Application Publication No. 20140350031 (Janssen), WO 2014 / 023813 (Janssen), U.S. Patent Application Publication No. 20080234251 (Array and compounds disclosed in Array Biopharma, No. 20080306050 (Array Biopharma), No. 20100029585 (Ventirx Pharma), No. 20110092485 (Ventirx Pharma), No. 20110118235 (Ventirx Pharma), No. 20120082658 (Ventirx Pharma), No. 20120219615 (Ventirx Pharma), No. 20140066432 (Ventirx Pharma), No. 20140088085 (Ventirx Pharma), No. 20140275167 (Novira Therapeutics), and No. 20130251673 (Novira Therapeutics). Exemplary TLR9 agonists that may be co-administered include, but are not limited to, AST-008, CMP-001, IMO-2055, IMO-2125, ritenimod, MGN-1601, BB-001, BB-006, IMO-3100, IMO-8400, IR-103, IMO-9200, agatolimod, DIMS-9054, DV-1079, DV-1179, AZD-1419, lefitolimod (MGN-1703), CYT-003, CYT-003-QbG10, and PUL-042.Examples of TLR3 agonists include lintatorimod, poly-ICLC, RIBOXXON®, Apoxxim, RIBOXXIM®, IPH-33, MCT-465, MCT-475, and ND-1.1.

[0153] Examples of TLR8 inhibitors include, but are not limited to, E-6887, IMO-8400, IMO-9200, and VTX-763.

[0154] Examples of TLR8 agonists include, but are not limited to, MCT-465, motolimod, GS-9688, and VTX-1463.

[0155] Examples of TLR9 agonists include, but are not limited to, AST-008, IMO-2055, IMO-2125, lefitolimod, ritenimod, MGN-1601, and PUL-042.

[0156] Examples of TLR7 / TLR8 agonists include, but are not limited to, NKTR-262, IMO-4200, MEDI-9197 (telluratolimod), and resiquimod.

[0157] Examples of TLR agonists include, but are not limited to, lefitolimod, tilsotolimod, lintatolimod, DSP-0509, AL-034, G-100, cobitolimod, AST-008, motolimod, GSK-1795091, GSK-2245035, VTX-1463, GS-9688, LHC-165, BDB-001, RG-7854, tellulatorimod.

[0158] In some embodiments, the therapeutic agent is a stimulator of interferon genes (STING). In some embodiments, the STING receptor agonist or activator is selected from ADU-S100 (MIW-815), SB-11285, MK-1454, SR-8291, AdVCA0848, GSK-532, SYN-STING, MSA-1, SR-8291, 5,6-dimethylxanthenone-4-acetic acid (DMXAA), cyclic GAMP (cGAMP), and cyclic-di-AMP.

[0159] TCR Signaling Modulators In various embodiments, the agents described herein that inhibit the binding between CD47 and SIRPα (e.g., magrolimab) and VEGFA / VEGFR inhibitors (e.g., bevacizumab) are further combined with one or more agonists or antagonists of T cell receptor (TCR) signaling modulators. Activation of T cells via TCR is essential for thymocyte development and effector T cell function. TCR activation promotes signaling cascades that ultimately determine cell fate by regulating cytokine production, cell survival, proliferation, and differentiation. Examples of TCR signaling modulators include, but are not limited to, CD2 (cluster of differentiation 2, LFA-2, T11, LFA-3 receptor), CD3 (cluster of differentiation 3), CD4 (cluster of differentiation 4), CD8 (cluster of differentiation 8), CD28 (cluster of differentiation 28), CD45 (PTPRC, B220, GP180), LAT (linker for T cell activation, LAT1), Lck, LFA-1 (ITGB2, CD18, LAD, LCAMB), Src, Zap-70, SLP-76, DGK alpha, CBL-b, CISH, HPK1. Examples of cluster of differentiation 3 (CD3) agonists that may be co-administered include, but are not limited to, MGD015.

[0160] In various embodiments, the agents that inhibit the binding between CD47 and SIRPα (e.g., magrolimab) and VEGFA / VEGFR inhibitors (e.g., bevacizumab) described herein are further combined with one or more blockers or inhibitors of inhibitory immune checkpoint proteins or receptors, and / or one or more stimulators, activators, or agonists of one or more stimulatory immune checkpoint proteins or receptors. Blocking or inhibiting an inhibitory immune checkpoint can positively regulate T cell or NK cell activation and prevent immune evasion of cancer cells in the tumor environment. Activating or stimulating a stimulatory immune checkpoint can enhance the effect of immune checkpoint inhibitors in cancer treatment. In various embodiments, an immune checkpoint protein or receptor regulates T cell responses (e.g., as reviewed in Xu, et al., J Exp Clin Cancer Res. (2018) 37:110). In various embodiments, immune checkpoint proteins or receptors regulate NK cell responses (reviewed, e.g., in Davis, et al., Semin Immunol. (2017) 31:64-75, and Chiossone, et al., Nat Rev Immunol. (2018) 18(11):671-688).

[0161] Examples of immune checkpoint proteins or receptors include, but are not limited to, CD27, CD70; CD40, CD40LG; CD47, CD48 (SLAMF2), transmembrane and immunoglobulin domain containing 2 (TMIGD2, CD28H), CD84 (LY9B, SLAMF5), CD96, CD160, MS4A1 (CD20), CD244 (SLAMF4); CD276 (B7H3); V-set domain-containing inhibitor of T-cell activation 1 (VTCN1, B7H4); V-set immunoregulatory receptor (VSIR, B7H5, VISTA); immunoglobulin superfamily member 11 (IGSF11, VSIG3); natural killer cytotoxicity receptor 3 ligand 1 (NCR3LG1, B7H6); HERV-H LTR-associated 2 (HHLA2, B7H7); inducible T cell costimulatory factor (ICOS, CD278); inducible T cell costimulatory factor ligand (ICOSLG, B7H2); TNF receptor superfamily member 4 (TNFRSF4, OX40); TNF superfamily member 4 (TNFSF4, OX40L); TNFRSF8 (CD30), TNFSF8 (CD30L); TNFRSF10A (CD261, DR4, TRAILR1), TNFRSF9 (CD137), TNFSF9 (CD137L); TNFRSF10B (CD262, DR5, TRAILR2), TNFRSF10 (TRAIL); TNFRSF14 (HVEM, CD270), TNFSF14 (HVEML); CD272 (B and T lymphocyte associated associated, BTLA);TNFRSF17 (BCMA, CD269), TNFSF13B (BAFF);TNFRSF18 (GITR), TNFSF18 (GITRL);MHC class I polypeptide-associated sequence A (MICA);MHC class I polypeptide-associated sequence B (MICB);CD274 (PDL1, PD-L1);programmed cell death 1 (PDCD1, PD-1, PD-1);cytotoxic T lymphocyte-associated protein 4 (CTLA4, CD152);CD80 (B7-1), CD28;nectin cell adhesion molecule 2 (NECTIN2, CD112);CD226 (DNAM-1);poliovirus receptor (PVR) cell adhesion molecule (PVR, CD155);T cell immunoreceptor with Ig and ITIM domains (TIGIT); T cell immunoglobulin and mucin domain containing 4 (TIMD4; TIM4); Hepatitis A virus cellular receptor 2 (HAVCR2, TIMD3, TIM-3); Galectin 9 (LGALS9); Lymphocyte activation 3 (LAG-3, CD223); Signaling lymphocyte activation molecule family member 1 (SLAMF1, SLAM, CD150); Lymphocyte antigen 9 (LY9, CD229, SLAMF3); SLAM family member 6 (SLAMF6, CD352); SLAM family member 7 (SLAM family member 7, SLAMF7, CD319); UL16 binding protein 1 (ULBP1); UL16 binding protein 2 (ULBP2); UL16 binding protein 3 (ULBP3); retinoic acid early transcript 1E (retinoic acid early transcript 1E) 1E, RAET1E; ULBP4; retinoic acid early transcript 1G, RAET1G; ULBP5; retinoic acid early transcript 1L, RAET1L; ULBP6; lymphocyte activation 3 (CD223); killer cell immunoglobulin-like receptor (KIR); killer cell lectin like receptor C1, KLRC1, NKG2A, CD159A; killer cell lectin like receptor K1, KLRK1, NKG2D, CD314; killer cell lectin like receptor C2, KLRC2, CD159c, NKG2C; killer cell lectin like receptor C3 C3, KLRC3, NKG2E); killer cell lectin like receptor C4 (KLRC4, NKG2F);Killer cell immunoglobulin-like receptor, one Ig domain and long cytoplasmic tail 2 (KIR2DL1); Killer cell immunoglobulin-like receptor, two Ig domains and long cytoplasmic tail 2 (KIR2DL2); Killer cell immunoglobulin-like receptor, three Ig domains and long cytoplasmic tail 2 (KIR2DL3); Killer cell immunoglobulin-like receptor, three Ig domains and long cytoplasmic tail 1 (KIR3DL1); Killer cell lectin like receptor D1 (KLRD1);

[0162] In various embodiments, the agents described herein that inhibit the binding between CD47 and SIRPα (e.g., magrolimab) and VEGFA / VEGFR inhibitors (e.g., bevacizumab) are further combined with one or more blockers or inhibitors of one or more T cell inhibitory immune checkpoint proteins or receptors. Exemplary T cell inhibitory immune checkpoint proteins or receptors include, but are not limited to, CD274 (PDL1, PD-L1); programmed cell death 1 ligand 2 (PDCD1LG2, PD-L2, CD273); programmed cell death 1 (PDCD1, PD1, PD-1); cytotoxic T lymphocyte-associated protein 4 (CTLA4, CD152); CD276 (B7H3); V-set domain-containing inhibitor of T cell activation 1 (VTCN1, B7H4); V-set immunoregulatory receptor (VSIR, B7H5, VISTA); immunoglobulin superfamily member 11 (IGSF11, VSIG3); TNFRSF14 (HVEM, CD270), TNFSF14 (HVEML); CD272 (B and T lymphocyte-associated (BTLA)); PVR-associated immunoglobulin domain-containing (PVRIG, CD112R); T cell immunoreceptor with Ig and ITIM domains (TIGIT); lymphocyte activation 3 (LAG-3, CD223); Hepatitis A virus cell receptor 2 (HAVCR2, TIMD3, TIM-3); galectin 9 (LGALS9); killer cell immunoglobulin-like receptor (KIR); killer cell immunoglobulin-like receptor, one Ig domain, and long cytoplasmic tail 2 (KIR2DL1); killer cell immunoglobulin-like receptor, two Ig domains, and long cytoplasmic tail 2 (KIR2DL2); killer cell immunoglobulin-like receptor, three Ig domains, and long cytoplasmic tail 2 (KIR2DL3); and killer cell immunoglobulin-like receptor, three Ig domains, and long cytoplasmic tail 1 (KIR3DL1).

[0163] In various embodiments, the agents described herein that inhibit the binding between CD47 and SIRPα (e.g., magrolimab) and VEGFA / VEGFR inhibitors (e.g., bevacizumab) are further combined with one or more agonists or activators of one or more T cell stimulatory immune checkpoint proteins or receptors. Exemplary T cell stimulatory immune checkpoint proteins or receptors include, but are not limited to, CD27, CD70; CD40, CD40LG; inducible T cell costimulator (ICOS, CD278); inducible T cell costimulator ligand (ICOSLG, B7H2); TNF receptor superfamily member 4 (TNFRSF4, OX40); TNF superfamily member 4 (TNFSF4, OX40L); TNFRSF9 (CD137), TNFSF9 (CD137L); TNFRSF18 (GITR), TNFSF18 (GITRL); CD80 (B7-1), CD28; nectin cell adhesion molecule 2 (NECTIN2, CD112); CD226 (DNAM-1); CD244 (2B4, SLAMF4), poliovirus receptor (PVR) cell adhesion molecule (PVR, CD155). See, e.g., Xu, et al., J Exp Clin Cancer Res. (2018) 37:110.

[0164] In various embodiments, the agents described herein that inhibit the binding between CD47 and SIRPα (e.g., magrolimab) and VEGFA / VEGFR inhibitors (e.g., bevacizumab) are further combined with one or more blockers or inhibitors of one or more NK cell inhibitory immune checkpoint proteins or receptors. Exemplary NK cell inhibitory immune checkpoint proteins or receptors include, but are not limited to, killer cell immunoglobulin-like receptor, three Ig domains and long cytoplasmic tail 1 (KIR, CD158E1); killer cell immunoglobulin-like receptor, one Ig domain and long cytoplasmic tail 2 (KIR2DL1); killer cell immunoglobulin-like receptor, two Ig domains and long cytoplasmic tail 2 (KIR2DL2); killer cell immunoglobulin-like receptor, three Ig domains and long cytoplasmic tail 2 (KIR2DL3); killer cell immunoglobulin-like receptor, three Ig domains and long cytoplasmic tail 1 (KIR3DL1); killer cell lectin-like receptor C1 (KLRC1, NKG2A, CD159A); and killer cell lectin-like receptor D1 (KLRD1, CD94).

[0165] In various embodiments, the agents described herein that inhibit the binding between CD47 and SIRPα (e.g., magrolimab) and VEGFA / VEGFR inhibitors (e.g., bevacizumab) are further combined with one or more agonists or activators of one or more NK cell stimulatory immune checkpoint proteins or receptors. Exemplary NK cell stimulatory immune checkpoint proteins or receptors include, but are not limited to: CD16, CD226 (DNAM-1); CD244 (2B4, SLAMF4); Killer cell lectin-like receptor K1 (KLRK1, NKG2D, CD314); SLAM family member 7 (SLAMF7). See, e.g., Davis, et al., Semin Immunol. (2017) 31:64-75; Fang, et al., Semin Immunol. (2017) 31:37-54, and Chiossone, et al., Nat Rev Immunol. (2018) 18(11):671-688.

[0166] Adenosine Generation and Signaling In various embodiments, the agents that inhibit the binding between CD47 and SIRPα (e.g., magrolimab) and VEGFA / VEGFR inhibitors (e.g., bevacizumab) described herein are selected from the group consisting of agonists or antagonists of A1R, A2AR, A2BR, A3R, CD73, CD39, CD26; adenosine A3 receptor (A3R) agonists such as namodenoson (CF102); A2aR / A2bR antagonists such as AB928; MEDI-9447 (oleculab), CPX-006, IPH-53, BMS-986179, NZ Further combined with anti-CD73 antibodies such as V-930, CPI-006; CD73 inhibitors such as AB-680, PSB-12379, PSB-12441, PSB-12425, CB-708, and those described in WO 19173692; CD39 / CD73 inhibitors such as PBF-1662; anti-CD39 antibodies, e.g., adenosine A2A receptor antagonists such as TTX-030, CPI-444, AZD-4635, preladenant, PBF-509; and adenosine deaminase inhibitors such as pentostatin, cladribine.

[0167] Bispecific T cell engagers In various embodiments, the agents described herein that inhibit the binding between CD47 and SIRPα (e.g., magrolimab) and VEGFA / VEGFR inhibitors (e.g., bevacizumab) are further combined with a bispecific T cell engager (e.g., without Fc) or an anti-CD3 bispecific antibody (e.g., with Fc).Exemplary anti-CD3 bispecific antibodies or BiTEs that may be co-administered include AMG-160 (PSMA / CD3), AMG-212 (PSMA / CD3), AMG-330 (CD33 / CD3), AMG-420 (BCMA / CD3), AMG-427 (FLT3 / CD3), AMG-562 (CD19 / CD3), AMG-596 (EGFRvIII / CD3), AMG-701 (BCMA / CD3), AMG-757 (DLL3 / CD3), JNJ-64052781 (CD 19 / CD3), AMG-211 (CEA / CD3), BLINCYTO® (CD19 / CD3), RG7802 (CEA / CD3), ERY-974 (CD3 / GPC3), huGD2-BsAb (CD3 / GD2), PF-06671008 (cadherin / CD3), APVO436 (CD123 / CD3), ERY974, flotetuzumab (CD123 / CD3), GEM333 (CD3 / CD33), GEMoab (CD3 / PSCA), REGN-1979 ( CD20 / CD3), REGN-5678(PSMA / CD28), MCLA-117(CD3 / CLEC12A), JNJ-0819, JNJ-7564(CD3 / hem), JNJ-63709178(CD123 / CD3), MGD-0 07(CD3 / gpA33), MGD-009(CD3 / B7H3), IMCgp100(CD3 / gp100), XmAb-14045(CD123 / CD3), XmAb-13676(CD3 / CD20), XmAb-18087(SS TR2 / CD3), catumaxomab (CD3 / EpCAM), REGN-4018 (MUC16 / CD3), RG6026, RG6076, RG6194, RG-7828 (CD20 / CD3), CC-93269 (CD3 / BCMA), REGN-5458 (CD3 / BCMA), GRB-1302 (CD3 / Erbb2), GRB-1342 (CD38 / CD3), PF-06863135 (BCMA / CD3), SAR440234 (CD3 / CDw123). Optionally, the anti-CD3 binding bispecific molecule may or may not have an Fc.Exemplary bispecific T cell engagers that may be co-administered target CD3 and tumor associated antigens described herein, including, for example, CD19 (e.g., blinatumomab); CD33 (e.g., AMG330); CEA (e.g., MEDI-565); receptor tyrosine kinase-like orphan receptor 1 (ROR1) (Gohil, et al., Oncoimmunology. (2017) May 17; 6(7): e1326437); PD-L1 (Horn, et al., Oncotarget. 2017 Aug 3; 8(35): 57964-57980); and EGFRvIII (Yang, et al., Cancer Lett. 2017 Sep 10; 403: 224-230).

[0168] Bispecific and Trispecific Natural Killer (NK) Cell Engagers In various embodiments, agents that inhibit the binding between CD47 and SIRPα (e.g., magrolimab) and VEGFA / VEGFR inhibitors (e.g., bevacizumab) described herein are used to inhibit the binding between CD47 and SIRPα and to inhibit the binding between CD47 and SIRPα and to inhibit the binding between VEGFA / VEGFR inhibitors (e.g., bevacizumab). In various embodiments, agents that inhibit the binding between CD47 and SIRPα (e.g., magrolimab) and VEGFA / VEGFR inhibitors (e.g., bevacizumab) described herein are used to inhibit the binding between CD47 and SIRPα and to inhibit the binding between VEGFA / VEGFR inhibitors (e.g., bevacizumab), as well as ... The anti-CD16 binding bispecific molecule may be further combined with a bispecific NK cell engager (BiKE) or tri-specific NK-cell engager (TriKE) (e.g., without Fc) or a bispecific antibody (e.g., with Fc). Exemplary anti-CD16 bispecific antibodies, BiKE, or TriKE that may be co-administered include AFM26 (BCMA / CD16A) and AFM-13 (CD16 / CD30). Optionally, the anti-CD16 binding bispecific molecule may or may not have an Fc. Exemplary bispecific NK cell engagers that may be co-administered target CD16 and one or more tumor-associated antigens described herein, including, for example, CD19, CD20, CD22, CD30, CD33, CD123, EGFR, EpCAM, ganglioside GD2, HER2 / neu, HLA class II, and FOLR1. BiKE and TriKE are described, for example, in Felices, et al., Methods Mol Biol. (2016) 1441:333-346; Fang, et al., Semin Immunol. (2017) 31:37-54.

[0169] Hematopoietic progenitor kinase 1 (HPK1) inhibitors In various embodiments, the agents described herein that inhibit the binding between CD47 and SIRPα (e.g., magrolimab) and VEGFA / VEGFR inhibitors (e.g., bevacizumab) are further combined with an inhibitor of mitogen-activated protein kinase kinase kinase kinase 1 (MAP4K1, HPK1; NCBI Gene ID: 11184). Examples of inhibitors of hematopoietic progenitor kinase 1 (HPK1) include, but are not limited to, those described in WO 2018183956, WO 2018183964, WO 2018167147, WO 2018183964, WO 2016205942, WO 2018049214, WO 2018049200, WO 2018049191, WO 2018102366, WO 2018049152, WO 2020092528, WO 2020092621, and WO 2016090300.

[0170] Apoptosis signal-regulating kinase (ASK) inhibitors In various embodiments, the agents that inhibit binding between CD47 and SIRPα (e.g., magrolimab) and VEGFA / VEGFR inhibitors (e.g., bevacizumab) described herein are further combined with an ASK inhibitor, such as an inhibitor of mitogen-activated protein kinase kinase kinase 5 (MAP3K5; ASK1, MAPKKK5, MEKK5; NCBI gene ID: 4217). Examples of ASK1 inhibitors include, but are not limited to, those described in WO 2011 / 008709 (Gilead Sciences) and WO 2013 / 112741 (Gilead Sciences).

[0171] Bruton's tyrosine kinase (BTK) inhibitors In various embodiments, the agents described herein that inhibit the binding between CD47 and SIRPα (e.g., magrolimab) and VEGFA / VEGFR inhibitors (e.g., bevacizumab) are further combined with an inhibitor of Bruton's tyrosine kinase (BTK, AGMX1, AT, ATK, BPK, IGHD3, IMD1, PSCTK1, XLA; NCBI Gene ID: 695). Examples of BTK inhibitors include, but are not limited to, (S)-6-amino-9-(1-(but-2-ynoyl)pyrrolidin-3-yl)-7-(4-phenoxyphenyl)-7H-purin-8(9H)-one, acalabrutinib (ACP-196), BGB-3111, CB988, HM71224, ibrutinib (Imbruvica), M-2951 (evobrutinib), M7583, tirabrutinib (ONO-4059), PRN-1008, spebrutinib (CC-292), TAK-020, becabrutinib, ARQ-531, SHR-1459, DTRMWXHS-12, TAS-5315, Calquence+AZD6738, Calquence+danvatirsen.

[0172] Cyclin-dependent kinase (CDK) inhibitors In various embodiments, the agents that inhibit the binding between CD47 and SIRPα (e.g., magrolimab) and VEGFA / VEGFR inhibitors (e.g., bevacizumab) described herein are selected from the group consisting of cyclin-dependent kinase 1 (CDK1, CDC2; CDC28A; P34CDC2; NCBI Gene ID: 983); cyclin-dependent kinase 2 (CDK2, CDKN2; p33(CDK2); NCBI Gene ID: 1017); cyclin-dependent kinase 3 (CDK3; NCBI Gene ID: 1018); cyclin-dependent kinase 4 (CDK5; NCBI Gene ID: 1020); cyclin-dependent kinase 5 (CDK6; NCBI Gene ID: 1022); cyclin-dependent kinase 6 (CDK7; NCBI Gene ID: 1024); cyclin-dependent kinase 7 (CDK8; NCBI Gene ID: 1026); cyclin-dependent kinase 8 (CDK9; NCBI Gene ID: 1028); cyclin-dependent kinase 9 (CDK1; NCBI Gene ID: 1029); cyclin-dependent kinase 10 (CDK1; CDC2; CDC28A; P34CDC2; NCBI Gene ID: 983); cyclin-dependent kinase 2 (CDK2, CDKN2; p33(CDK2); NCBI Gene ID: 1017); cyclin-dependent kinase 3 (CDK3; NCBI Gene ID: 1026); cyclin-dependent kinase 11 (CDK1; CDC2; CDC28A; P34CDC2; NCBI Gene ID: 983); cyclin-dependent kinase 12 (CDK2; CDKN2; p33(CDK2); NCBI Gene ID: 1028); cyclin-dependent kinase 13 (CDK1 and further combined with an inhibitor of cyclin-dependent kinase 4 (CDK4, CMM3; PSK-J3; NCBI Gene ID: 1019); cyclin-dependent kinase 6 (CDK6, MCPH12; PLSTIRE; NCBI Gene ID: 1021); cyclin-dependent kinase 7 (CDK7, CAK; CAK1; HCAK; MO15; STK1; CDKN7; p39MO15; NCBI Gene ID: 1022); or cyclin-dependent kinase 9 (CDK9, TAK; C-2k; CTK1; CDC2L4; PITALRE; NCBI Gene ID: 1025). Inhibitors of CDK1, 2, 3, 4, 6, 7, and / or 9 include, but are not limited to, abemaciclib, alvocidib (HMR-1275, flavopiridol), AT-7519, dinaciclib, ibrance, FLX-925, LEE001, palbociclib, ribociclib, rigosertib, selinexor, UCN-01, SY1365, CT-7001, SY-1365, G1T38, mirciclib, trilaciclib, PF-06873600, AZD4573, and TG-02.

[0173] Discoidin domain receptor (DDR) inhibitor. In various embodiments, the agents described herein that inhibit the binding between CD47 and SIRPα (e.g., magrolimab) and VEGFA / VEGFR inhibitors (e.g., bevacizumab) are further combined with inhibitors of discoidin domain receptor tyrosine kinase 1 (DDR1, CAK, CD167, DDR, EDDR1, HGK2, MCK10, NEP, NTRK4, PTK3, PTK3A, RTK6, TRKE; NCBI Gene ID: 780); and / or discoidin domain receptor tyrosine kinase 2 (DDR2, MIG20a, NTRKR3, TKT, TYRO10, WRCN; NCBI Gene ID: 4921). Examples of DDR inhibitors include, but are not limited to, dasatinib, and those disclosed in WO 2014 / 047624 (Gilead Sciences), U.S. Patent Application Publication No. 2009 / 0142345 (Takeda Pharmaceutical), U.S. Patent Application Publication No. 2011 / 0287011 (Oncomed Pharmaceuticals), WO 2013 / 027802 (Chugai Pharmaceutical), and WO 2013 / 034933 (Imperial Innovations).

[0174] Histone deacetylase (HDAC) inhibitors In various embodiments, the agents described herein that inhibit the binding between CD47 and SIRPα (e.g., magrolimab) and VEGFA / VEGFR inhibitors (e.g., bevacizumab) are further combined with inhibitors of histone deacetylase, e.g., histone deacetylase 9 (HDAC9, HD7, HD7b, HD9, HDAC, HDAC7, HDAC7B, HDAC9B, HDAC9FL, HDRP, MITR; Gene ID: 9734). Examples of HDAC inhibitors include, but are not limited to, abexinostat, ACY-241, AR-42, BEBT-908, belinostat, CKD-581, CS-055 (HBI-8000), CUDC-907 (fimepinostat), entinostat, gibinostat, mocetinostat, panobinostat, pracinostat, xinostat (JNJ-26481585), resminostat, ricolinostat, SHP-141, valproic acid (VAL-001), vorinostat, tinostamustine, remetinostat, entinostat, romidepsin, and tucidinostat.

[0175] Indoleamine-pyrrole-2,3-dioxygenase (IDO1) inhibitors In various embodiments, the agents described herein that inhibit the binding between CD47 and SIRPα (e.g., magrolimab) and VEGFA / VEGFR inhibitors (e.g., bevacizumab) are further combined with an inhibitor of indoleamine 2,3-dioxygenase 1 (IDO1; NCBI Gene ID: 3620). Examples of IDO1 inhibitors include, but are not limited to, BLV-0801, epacadostat, F-001287, GBV-1012, GBV-1028, GDC-0919, indoximod, NKTR-218, NLG-919-based vaccines, PF-06840003, pyranonaphthoquinone derivatives (SN-35837), resminostat, SBLK-200802, BMS-986205, and shIDO-ST, EOS-200271, KHK-2455, LY-3381916.

[0176] Janus kinase (JAK) inhibitors In various embodiments, the agents that inhibit binding between CD47 and SIRPα (e.g., magrolimab) and VEGFA / VEGFR inhibitors (e.g., bevacizumab) described herein are further combined with inhibitors of Janus kinase 1 (JAK1, JAK1A, JAK1B, JTK3; NCBI Gene ID: 3716); Janus kinase 2 (JAK2, JTK10, THCYT3; NCBI Gene ID: 3717); and / or Janus kinase 3 (JAK3, JAK-3, JAK3_HUMAN, JAKL, L-JAK, LJAK; NCBI Gene ID: 3718). Examples of JAK inhibitors include, but are not limited to, AT9283, AZD1480, baricitinib, BMS-911543, fedratinib, filgotinib (GLPG0634), gandotinib (LY2784544), INCB039110 (itacitinib), restortinib, momelotinib (CYT0387), NS-018, pacritinib (SB1518), peficitinib (ASP015K), ruxolitinib, tofacitinib (formerly tasocitinib), INCB052793, and XL019.

[0177] Matrix metalloproteinase (MMP) inhibitors In various embodiments, the agents that inhibit the binding between CD47 and SIRPα (e.g., magrolimab) and VEGFA / VEGFR inhibitors (e.g., bevacizumab) described herein are also useful as inhibitors of matrix metallopeptidases (MMPs), such as MMP1 (NCBI Gene ID: 4312), MMP2 (NCBI Gene ID: 4313), MMP3 (NCBI Gene ID: 4314), MMP7 (NCBI Gene ID: 4316), MMP8 (NCBI Gene ID: 4317), MMP9 (NCBI Gene ID: 4318); MMP10 (NCBI Gene ID: 4319); MMP11 (NCBI Gene ID: 4320); MMP12 (NCBI Gene ID: 4321), MMP13 (NCBI Gene ID: 4322), MMP14 (NCBI Gene ID: 4323), MMP15 (NCBI Gene ID: 4324), MMP16 (NCBI Gene ID: 4325), MMP17 (NCBI Gene ID: 4326), MMP18 (NCBI Gene ID: 4327), MMP19 (NCBI Gene ID: 4330), MMP20 (NCBI Gene ID: 4331), MMP21 (NCBI Gene ID: 4332), MMP22 (NCBI Gene ID: 4333), MMP23 (NCBI Gene ID: 4334), MMP24 (NCBI Gene ID: 4335), MMP25 (NCBI Gene ID: 4336), MMP26 (NCBI Gene ID: 4337), MMP27 (NCBI Gene ID: 4338), MMP28 (NCBI Gene ID: 4339), MMP29 (NCBI Gene ID: 4340), MMP29 (NCBI Gene ID: 4341), MMP30 (NCBI Gene ID: and / or an inhibitor of MMP28 (NCBI Gene ID: 79148). Examples of MMP9 inhibitors include, but are not limited to, marimastat (BB-2516), cipemastat (Ro32-3555), GS-5745 (andecaliximab), and those described in WO 2012 / 027721 (Gilead Biologics).

[0178] RAS and RAS pathway inhibitors In various embodiments, agents that inhibit the binding between CD47 and SIRPα (e.g., magrolimab) and VEGFA / VEGFR inhibitors (e.g., bevacizumab) described herein inhibit the KRAS proto-oncogene, GTPase (KRAS; also known as NS; NS3; CFC2; RALD; K-Ras; KRAS1; KRAS2; RASK2; KI-RAS; CK-RAS; K-RAS2A; K-RAS2B; K-RAS4A; K-RAS4B; c-Ki-ras2; NCBI Gene ID: 3845); NRAS The therapeutic agent may further be combined with an inhibitor of proto-oncogene, GTPase (NRAS; aka NS6; CMNS; NCMS; ALPS4; N-ras; NRAS1; NCBI Gene ID: 4893); HRas proto-oncogene, GTPase (HRAS; aka CTLO; KRAS; HAMSV; HRAS1; KRAS2; RASH1; RASK2; Ki-Ras; p21ras; CH-RAS; cK-ras; H-RASIDX; c-Ki-ras; C-BAS / HAS; C-HA-RAS1; NCBI Gene ID: 3265). Ras inhibitors may inhibit Ras either at the polynucleotide level (e.g., transcription inhibitors) or at the polypeptide level (e.g., GTPase enzyme inhibitors). In some embodiments, the inhibitor targets one or more proteins in the Ras pathway, e.g., inhibiting one or more of EGFR, Ras, Raf (A-Raf, B-Raf, C-Raf), MEK (MEK1, MEK2), ERK, PI3K, AKT, and mTOR.

[0179] In various embodiments, an agent that inhibits the binding between CD47 and SIRPα (e.g., magrolimab) and a VEGFA / VEGFR inhibitor (e.g., bevacizumab) described herein is further combined with an inhibitor of KRAS. Examples of KRAS inhibitors include AMG-510, COTI-219, MRTX-1257, ARS-3248, ARS-853, WDB-178, BI-3406, BI-1701963, ARS-1620(G12C), SML-8-73-1(G12C), compound 3144(G12D), Kobe0065 / 2602(Ras GTP), RT11, MRTX-849(G12C), and K-RAS(G12D) selective inhibitory peptides, including KRpep-2(Ac-RRCPLYISYDPVCRR-NH2) (SEQ ID NO:256) and KRpep-2d(Ac-RRRRCPLYISYDPVCRRRR-NH2) (SEQ ID NO:257).

[0180] In various embodiments, the agents described herein that inhibit the binding between CD47 and SIRPα (e.g., magrolimab) and VEGFA / VEGFR inhibitors (e.g., bevacizumab) are further combined with inhibitors of KRAS mRNA. Exemplary KRAS mRNA inhibitors include anti-KRAS U1 adaptor-, AZD-4785, siG12D-LODER™, and siG12D exosomes.

[0181] In various embodiments, the agents described herein that inhibit the binding between CD47 and SIRPα (e.g., magrolimab) and VEGFA / VEGFR inhibitors (e.g., bevacizumab) are further combined with inhibitors of MEK. Exemplary MEK inhibitors that may be co-administered include binimetinib, cobimetinib, PD-0325901, pimasertib, RG-7304, selumetinib, trametinib, and selumetinib.

[0182] In various embodiments, the agents described herein that inhibit the binding between CD47 and SIRPα (e.g., magrolimab) and VEGFA / VEGFR inhibitors (e.g., bevacizumab) are further combined with inhibitors of AKT. Exemplary AKT inhibitors that may be co-administered include RG7440, MK-2206, ipatasertib, afuresertib, AZD5363, and ARQ-092, capivasertib, triciribine, ABTL-0812 (PI3K / Akt / mTOR).

[0183] In various embodiments, the agents described herein that inhibit the binding between CD47 and SIRPα (e.g., magrolimab) and VEGFA / VEGFR inhibitors (e.g., bevacizumab) are further combined with inhibitors of Raf. Exemplary Raf inhibitors that may be co-administered include BGB-283 (Raf / EGFR), HM-95573, LXH-254, LY-3009120, RG7304, TAK-580, dabrafenib, vemurafenib, encorafenib (LGX818), PLX8394. RAF-265 (Raf / VEGFR), ASN-003 (Raf / PI3K).

[0184] In various embodiments, the agents described herein that inhibit the binding between CD47 and SIRPα (e.g., magrolimab) and VEGFA / VEGFR inhibitors (e.g., bevacizumab) are further combined with inhibitors of ERK. Exemplary ERK inhibitors that may be co-administered include LTT-462, LY-3214996, MK-8353, ravoxertinib, GDC-0994, and ulixertinib.

[0185] In various embodiments, the agents described herein that inhibit the binding between CD47 and SIRPα (e.g., magrolimab) and VEGFA / VEGFR inhibitors (e.g., bevacizumab) are further combined with inhibitors of PI3K. Exemplary PI3K inhibitors that may be co-administered include idelalisib (Zydelig®), alpelisib, buparlisib, pitilisib, eganelisib (IPI-549). Exemplary PI3K / mTOR inhibitors that may be co-administered include dactolisib, omipalisib, voxtalisib, gedatolisib, GSK2141795, RG6114.

[0186] In various embodiments, the agents described herein that inhibit the binding between CD47 and SIRPα (e.g., magrolimab) and VEGFA / VEGFR inhibitors (e.g., bevacizumab) are further combined with inhibitors of mTOR. Exemplary mTOR inhibitors that may be co-administered include sapoanisertib, vistusertib (AZD2014), ME-344, sirolimus (oral nano-amorphous formulation, cancer), TYME-88 (mTOR / cytochrome P450 3A4).

[0187] In certain embodiments, Ras-driven cancers (e.g., NSCLC) with CDKN2A mutations can be suppressed by co-administration of the MEK inhibitor selumetinib and the CDK4 / 6 inhibitor palbociclib. See, e.g., Zhou, et al., Cancer Lett. 2017 Nov 1; 408: 130-137. Also, K-RAS and mutant N-RAS can be reduced by the irreversible inhibitor neratinib of ERBB1 / 2 / 4. See, e.g., Booth, et al., Cancer Biol Ther. 2018 Feb 1; 19(2): 132-137.

[0188] In various embodiments, the agents described herein that inhibit the binding between CD47 and SIRPα (e.g., magrolimab) and VEGFA / VEGFR inhibitors (e.g., bevacizumab) are further combined with inhibitors of the RAS. Examples of RAS inhibitors include NEO-100 and rigosertib.

[0189] In various embodiments, the agents described herein that inhibit the binding between CD47 and SIRPα (e.g., magrolimab) and VEGFA / VEGFR inhibitors (e.g., bevacizumab) are further combined with an EGFR antagonist, such as AMG-595, necitumumab, ABBV-221, depatuxizumab mafodotin (ABT-414), tomzotuximab, ABT-806, vectibix, modotuximab, RM-1929, etc.

[0190] In various embodiments, the agents that inhibit binding between CD47 and SIRPα (e.g., magrolimab) and VEGFA / VEGFR inhibitors (e.g., bevacizumab) described herein are further combined with inhibitors of protein tyrosine phosphatase non-receptor type 11 (PTPN11; BPTP3, CFC, JMML, METCDS, NS1, PTP-1D, PTP2C, SH-PTP2, SH-PTP3, SHP2; NCBI gene ID: 5781). Examples of SHP2 inhibitors include TNO155 (SHP-099), RMC-4550, JAB-3068, RMC-4630, SAR442720, and those described in WO2018172984 and WO2017211303.

[0191] In various embodiments, the agents described herein that inhibit the binding between CD47 and SIRPα (e.g., magrolimab) and VEGFA / VEGFR inhibitors (e.g., bevacizumab) are further combined with an inhibitor of mitogen-activated protein kinase 7 (MAP2K7, JNKK2, MAPKK7, MEK, MEK7, MKK7, PRKMK7, SAPKK-4, SAPKK4; NCBI Gene ID: 5609). Examples of MEK inhibitors include antroquinol, binimetinib, CK-127, cobimetinib (GDC-0973, XL-518), MT-144, selumetinib (AZD6244), sorafenib, trametinib (GSK1120212), uprosertib + trametinib, PD-0325901, pimasertib, LTT462, AS703988, CC-90003, refametinib, TAK-733, CI-1040, and RG7421.

[0192] In various embodiments, the agents that inhibit the binding between CD47 and SIRPα (e.g., magrolimab) and VEGFA / VEGFR inhibitors (e.g., bevacizumab) described herein inhibit the binding between CD47 and SIRPα and / or VEGFA / VEGFR inhibitors (e.g., bevacizumab) by inhibiting ... pha, p110-alpha; NCBI Gene ID: 5290); phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta (PIK3CB, P110BETA, PI3K, PI3KBETA, PIK3C1; NCBI Gene ID: 5291); phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit gamma (PIK3CG, PI3CG, PI3K, PI3Kgamma, PIK3, p110gamma, p120-PI3K; Gene ID: 5494);and / or further combined with an inhibitor of phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta (PIK3CD, APDS, IMD14, P110DELTA, PI3K, p110D, NCBI gene ID: 5293). In some embodiments, the PI3K inhibitor is a pan-PI3K inhibitor. Examples of PI3K inhibitors include ACP-319, AEZA-129, AMG-319, AS252424, AZD8186, BAY1082439, BEZ235, bimiralisib (PQR309), bupallisib (BKM120), BYL719 (alpelisib), carboxyamidotriazole orotate (CTO), CH5132799, CLR-457, CLR-1401, copanlisib (BAY80-6946), DS-7423, dactolisib, duvelisib (IPI-145), fimepinostat (CUDC-907), gedatolisib (PF-05212384), GDC-0032, GDC-0084 (RG7666), G DC-0077, pictilisib (GDC-0941), GDC-0980, GSK2636771, GSK2269577, GSK2141795, idelalisib (Zydelig®), INCB040093, INCB50465, IPI-443, IPI-549, KAR4141, LY294002, L Y3023414, NERLYNX® (neratinib), nemiralisib (GSK2269557), omipalisib (GSK2126458, GSK458), OXY111A, panulisib (P7170, AK151761), PA799, perifosine (KRX-0401), piralalisib (SAR245408);XL147), pukitinib mesylate (XC-302), SAR260301, seravelisib (UCB-5857), seravelisib (INK-1117, MLN-1117, TAK-117), SF1126, sonolisib (PX-866), RG6114, RG7604, rigosertib sodium (ON-01910 sodium), RP5090, tenalisib (RP6530), RV-17 29, SRX3177, taselisib, TG100115, umbralisib (TGR-1202), TGX221, voxtalisib (SAR245409), VS-5584, WX-037, X-339, X-414, XL499, XL756, wortmannin, ZSTK474, and the compounds disclosed in International Publication Nos. WO 2005 / 113556 (ICOS) and WO 2013 / 052699 (Gilead Sciences, Inc., 2013). Examples of compounds disclosed in Gilead Sciences include, but are not limited to, those disclosed in Gilead Sciences, 2013 / 116562 (Gilead Calistoga), 2014 / 100765 (Gilead Calistoga), 2014 / 100767 (Gilead Calistoga), and 2014 / 201409 (Gilead Sciences);

[0193] Spleen tyrosine kinase (SYK) inhibitors In various embodiments, the agents described herein that inhibit the binding between CD47 and SIRPα (e.g., magrolimab) and VEGFA / VEGFR inhibitors (e.g., bevacizumab) are further combined with an inhibitor of spleen-associated tyrosine kinase (SYK, p72-Syk, gene number: 6850). Examples of SYK inhibitors include, but are not limited to, 6-(1H-indazol-6-yl)-N-(4-morpholinophenyl)imidazo[1,2-a]pyrazin-8-amine, BAY-61-3606, celduratinib (PRT-062607), enstopretinib, fostamatinib (R788), HMPL-523, NVP-QAB 205 AA, R112, R343, tamatinib (R406), and those described in U.S. Pat. No. 8,450,321 (Gilead Connecticut), and those described in U.S. Patent Application Publication No. 2015 / 0175616.

[0194] Tyrosine kinase inhibitors (TKIs) In various embodiments, the agents described herein that inhibit the binding between CD47 and SIRPα (e.g., magrolimab) and VEGFA / VEGFR inhibitors (e.g., bevacizumab) are further combined with a tyrosine kinase inhibitor (TKI), which may target the epidermal growth factor receptor (EGFR) and receptors for fibroblast growth factor (FGF), platelet-derived growth factor (PDGF), and vascular endothelial growth factor (VEGF). Examples of TKIs include, but are not limited to, axitinib, afatinib, ARQ-087 (derazantinib), asp5878, AZD3759, AZD4547, bosutinib, brigatinib, cabozantinib, cediranib, crenolanib, crizotinib, dacomitinib, dasatinib, dovitinib, E-6201, erdafitinib, erlotinib, gefitinib, gilteritinib (ASP-2215), FP-1039, HM61713, icotinib, imatinib, and KX2. -391 (Src), lapatinib, restortinib, lenvatinib, midostaurin, nintedanib, ODM-203, olmutinib, osimertinib (AZD-9291), pazopanib, ponatinib, poziotinib, quizartinib, radotinib, rociletinib, surufatinib (HMPL-012), sunitinib, famitinib L-malate, (MAC-4), tiboanib, TH-4000, and MEDI-575 (anti-PDGFR antibody), and TAK-659.

[0195] Chemotherapy drugs (standard treatment) In various embodiments, the agents described herein that inhibit the binding between CD47 and SIRPα (e.g., magrolimab) and VEGFA / VEGFR inhibitors (e.g., bevacizumab) are further combined with a chemotherapeutic or anti-tumor agent.

[0196] As used herein, the term "chemotherapeutic agent" or "chemotherapeutic agent" (or "chemotherapy" in the case of treatment with a chemotherapy agent) is meant to encompass any non-proteinaceous (e.g., non-peptidic) compound useful in the treatment of cancer. Examples of chemotherapeutic agents include, but are not limited to, alkylating agents such as thiotepa and cyclophosphamide (CYTOXAN®); alkyl sulfonates such as busulfan, improsulfan, and piposulfan; aziridines such as benzodepa, carboquone, meturedepa, and uredepa; ethylenimines and methylamelanamines, including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimerylomelanamine; acetogenins such as bullatacin and bullatacinone; camptothecins, including the synthetic analog topotecan; bryostatin, kallistatin; CC-1065, including synthetic analogs of adozelesin, carzelesin, and bizeresin; cryptoxanthin, which are useful in the treatment of cancer. phycins, especially cryptophycin 1 and cryptophycin 8; dolastatins; duocarmycins, including synthetic analogs KW-2189 and CBI-TMI; eleutherobin; 5-azacytidine; pancratistatin; sarcodictyin; spongistatins; nitrogen mustards, such as chlorambucil, chlornaphazine, cyclophosphamide, glufosfamide, evofosfamide, bendamustine, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembitine, phenesterine, prednimustine, trofosfamide, and uracil mustard; nitrosoureas, such as carmustine, chlorozotocin, foremstine, lomustine, nimustine, and ranimustine;Antibiotics, such as enediyne antibiotics (e.g., calicheamicins, especially calicheamicin gamma II and calicheamicin phi I1), dynemicins, including dynemicin A, bisphosphonates such as clodronate, esperamicin, neocarzinostatin chromophore and related chromoprotein enediyne antibiotic chromophores, aclacinomycin, actinomycin, anthramycin, azaserine, bleomycin, cactinomycin, carabimycin, carminomycin, carzinophilin, chromoproteins ... doxorubicin, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin (including morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin, and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, marcelomycin, mitomycins such as mitomycin C, mycophenolic acid, nogalamycin, olivomycin, peplomycin, porfiromycin, puromycin, keramycin, and lomimycin. dorbicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, and zorubicin; antimetabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as demopterin, methotrexate, pteropterin, and trimetrexate; purine analogs such as cladribine, pentostatin, fludarabine, 6-mercaptopurine, thiamiprine, and thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, and floxuridine; androgens such as calsterone, dromostanolone propionate, epithiostanol, mepitiostane, and testolactone; antiadrenal drugs such as aminoglutethimide, mitotane, and trilostane; folic acid supplements such as floric acid; radiotherapeutic agents such as radium-223, 177-Lu-PSMA-617; trichothecenes, especially T-2 toxin, veracrine A, roridin A, and anguidine;Taxoids such as paclitaxel (TAXOL®), albumin-bound or nab-paclitaxel (ABRAXANE®), docetaxel (TAXOTERE®), cabazitaxel, BIND-014, tesetaxel; platinum analogues such as cisplatin and carboplatin, NC-6004 nanoplatin; aceglatone; aldophosphamide glycosides; aminolevulinic acid; eniluracil; amsacrine; hestravucil; bisantrene; edatrexate; defofamine ;Demecolcine;Diaziquone;Erformucine;Elliptinium acetate;Epothilone;Etoglucide;Gallium nitrate;Hydroxyurea;Lentinan;Leucovorin;Lonidamine;Maytansinoids, such as maytansine and ansamitocin;Mitoguazone;Mitoxantrone;Mopidamol;Nitracrine;Fenamet;Pirarubicin;Losoxantrone;Fluoropyrimidines;Folinic acid;Podophyllic acid, 2-ethylhydrazide;Procarbazine;Polysaccharide K (PSK);Razoxane;Rhizoxin;Schizophy oran;spirogermanium;tenuazonic acid;trabectedin, triaziquone;2,2',2''-trichlorotriemylamine;urethane;vindesine;dacarbazine;mannomustine;mitobronitol;mitolactol;pipobroman;gacitosine;arabinoside ("Ara-C");cyclophosphamide;thiotepa;chlorambucil;gemcitabine (GEMZAR®);6-thioguanine;mercaptopurine;methotrexate;vinblastine;platinum;etoposide (VP-16);ifosfamide;mitobronitol; Xantrone; Vancristine; Vinorelbine (NAVELBINE®); Novantrone; Teniposide; Edatrexate; Daunomycin, Aminopterin, Xeloda; Ibandronate; CPT-11; Topoisomerase inhibitors RFS2000; Difluoromethylornithine (DFMO); Retinoids, e.g., retinoic acid; Capecitabine; NUC-1031; FOLFOX (Folinic acid, 5-fluorouracil, oxaliplatin); FOLFIRI (Folinic acid, 5-fluorouracil, irinotecan);These include FOLFOXIRI (folinic acid, 5-fluorouracil, oxaliplatin, irinotecan), FOLFIRINOX (folinic acid, 5-fluorouracil, irinotecan, oxaliplatin), as well as pharma- ceutically acceptable salts, acids, or derivatives of any of the above. Such agents may be conjugated to an antibody or any of the targeting agents described herein to create an antibody drug conjugate (ADC) or targeted drug conjugate;

[0197] Also included within the definition of "chemotherapeutic agent" are antihormonal agents such as antiestrogens and selective estrogen receptor modulators (SERMs), inhibitors of the enzyme aromatase, antiandrogens, and pharma- ceutically acceptable salts, acids, or derivatives of any of the above that act to modulate or inhibit hormone action on tumors. Examples of antiestrogens and SERMs include, for example, tamoxifen (including NOLVADEX™), raloxifene, droloxifene, 4-hydroxytamoxifen, trioxyfene, keoxyfene, LY117018, onapristone, and toremifene (FARESTON®). Inhibitors of the enzyme aromatase regulate estrogen production in the adrenal gland. Examples include 4(5)-imidazole, aminoglutethimide, megestrol acetate (MEGACE®), exon 100, cyclosporine ... Examples of antiandrogens include semestane, formestane, fadrozole, vorozole (RIVISOR®), letrozole (FEMARA®), and anastrozole (ARIMIDEX®). Examples of antiandrogens include apalutamide, abiraterone, enzalutamide, flutamide, galeterone, nilutamide, bicalutamide, leuprolide, goserelin, ODM-201, APC-100, and ODM-204. Examples of progesterone receptor antagonists include onapristone.

[0198] Antiangiogenic Agents In various embodiments, the agents described herein that inhibit the binding between CD47 and SIRPα (e.g., magrolimab) and VEGFA / VEGFR inhibitors (e.g., bevacizumab) are further combined with an anti-angiogenic agent. Antiangiogenic agents that may be co-administered include, but are not limited to, retinoid acid and its derivatives, 2-methoxyestradiol, ANGIOSTATIN®, ENDOSTATIN®, regorafenib, necupranib, suramin, squalamine, tissue inhibitor of metalloproteinase-1, tissue inhibitor of metalloproteinase-2, plasminogen activator inhibitor-1, plasminogen activator inhibitor-2, cartilage-derived inhibitor, paclitaxel (nab-paclitaxel), platelet factor 4, protamine sulfate (clupeine), sulfated chitin derivatives (prepared from snow crab shells), sulfated polysaccharide peptidoglycan complex (sp-pg), staurosporine, proline analogs such as l-azetidine-2-carboxylic acid (LACA), modulators of matrix metabolism, cis-hydroxyproline, d,I-3,4-dehydro proline, thiaproline, α,α'-dipyridyl, beta-aminopropionitrile fumarate, 4-propyl-5-(4-pyridinyl)-2(3h)-oxazolone, methotrexate, mitoxantrone, heparin, interferon, 2 macroglobulin serum, chicken inhibitor of metalloproteinase-3 (ChIMP-3), chymostatin, beta-cyclodextrin tetradecasulfate, eponemycin, fumagillin, sodium gold thiomalate, d-penicillamine, beta-1-anticollagenase serum, alpha-2-antiplasmin, bisantrene, lobenzarit disodium, n-2-carboxyphenyl-4-chloroanthonylate disodium or "CCA", thalidomide, angiogenesis-suppressing steroids, carboxyaminoimidazole, metalloproteinase inhibitors such as BB-94, and S100A9 inhibitors such as tasquinimod. Other anti-angiogenic agents include antibodies, preferably monoclonal antibodies against the following angiogenic growth factors: beta-FGF, alpha-FGF, FGF-5, VEGF isoforms, VEGF-C, HGF / SF, and Ang-1 / Ang-2.

[0199] Antifibrotic Agents In various embodiments, the agents that inhibit the binding between CD47 and SIRPα (e.g., magrolimab) and VEGFA / VEGFR inhibitors (e.g., bevacizumab) described herein are further combined with anti-fibrotic agents. Anti-fibrotic agents that may be co-administered include, but are not limited to, compounds such as beta-aminoproprionitrile (BAPN) and compounds disclosed in U.S. Pat. No. 4,965,288 for inhibitors of lysyl oxidase and their use in treating diseases and conditions associated with abnormal deposition of collagen, and U.S. Pat. No. 4,997,854 for compounds that inhibit LOX for the treatment of various pathological fibrotic conditions, which are incorporated herein by reference. Further exemplary inhibitors are described in U.S. Pat. No. 4,943,593, U.S. Pat. No. 5,021,456, U.S. Pat. No. 5,059,714, U.S. Pat. No. 5,120,764, U.S. Pat. No. 5,182,297, U.S. Pat. No. 5,252,608, U.S. Pat. No. 2-(1-naphthyloxymemyl)-3-fluoroallylamine, and U.S. Patent Application Publication No. 2004 / 0248871, which are incorporated herein by reference.

[0200] Exemplary antifibrotic agents include primary amines that react with the carbonyl group of the active site of lysyl oxidase, more specifically, those that produce products stabilized by resonance after binding to the carbonyl, such as the following primary amines: emilenmamine, hydrazine, phenylhydrazine, and their derivatives; semicarbazide and urea derivatives; aminonitriles, such as BAPN or 2-nitroethylamine; unsaturated or saturated haloamines, such as 2-bromo-ethylamine, 2-chloroethylamine, 2-trifluoroethylamine, 3-bromopropylamine, and p-halobenzylamines; and also selenohomocysteine ​​lactones.

[0201] Other antifibrotic agents are copper chelators that may or may not permeate cells. Exemplary compounds include indirect inhibitors that inhibit the aldehyde derivatives derived from the oxidative deamination of lysyl and hydroxylysyl residues by lysyl oxidase. Examples include thiolamines, particularly D-penicillamine and its analogs, such as 2-amino-5-mercapto-5-methylhexanoic acid, D-2-amino-3-methyl-3-((2-acetamidoethyl)dithio)butanoic acid, p-2-amino-3-methyl-3-((2-aminoethyl)dithio)butanoic acid, sodium-4-(((p-1-dimethyl-2-amino-2-carboxyethyl)dithio)butane sulphurate, 2-acetamidoethyl-2-acetamidoethanethiolsulfanate, and sodium-4-mercaptobutanesulfinate trihydrate.

[0202] Anti-inflammatory agents In various embodiments, the agents described herein that inhibit the binding between CD47 and SIRPα (e.g., magrolimab) and VEGFA / VEGFR inhibitors (e.g., bevacizumab) are further combined with an anti-inflammatory agent. Exemplary anti-inflammatory agents include arginase (ARG1 (NCBI Gene ID: 383), ARG2 (NCBI Gene ID: 384)), carbonic anhydrase (CA1 (NCBI Gene ID: 759), CA2 (NCBI Gene ID: 760), CA3 (NCBI Gene ID: 761), CA4 (NCBI Gene ID: 762), CA5A (NCBI Gene ID: 763), CA5B (NCBI Gene ID: 11238), CA6 (NCBI Gene ID: 765), CA7 (NCBI Gene ID: 766), CA8 (NCBI Gene ID: 767), CA9 (NCBI Gene ID: 768), CA10 (NCBI Gene ID: 56934), CA11 (NCBI Gene ID: 770), CA12 (NCBI Gene ID: 771), CA13 (NCBI Gene ID: 377677), CA14 ( NCBI Gene ID: 23632), prostaglandin endoperoxide synthase 1 (PTGS1, COX-1; NCBI Gene ID: 5742), prostaglandin endoperoxide synthase 2 (PTGS2, COX-2; NCBI Gene ID: 5743), secretory phospholipase A2, prostaglandin E synthase (PTGES, PGES; Gene ID: 9536), arachidonate 5-lipoxygenase (ALOX5, 5-LOX; NCBI Gene ID: 240), soluble epoxide hydrolase 2 (EPHX2, SEH; NCBI Gene ID: 2053), and / or mitogen-activated protein kinase kinase kinase 8 (MAP3K8, TPL2; NCBI Gene ID: 1326). In some embodiments, the inhibitor is a dual inhibitor, for example, a COX-2 / COX-1, COX-2 / SEH, COX-2 / CA, COX-2 / 5-LOX dual inhibitor.

[0203] Examples of inhibitors of prostaglandin endoperoxide synthase 1 (PTGS1, COX-1; NCBI gene ID: 5742) that may be co-administered include, but are not limited to, mofezolac, GLY-230, and TRK-700.

[0204] Examples of inhibitors of prostaglandin endoperoxide synthase 2 (PTGS2, COX-2; NCBI Gene ID: 5743) that may be co-administered include, but are not limited to, diclofenac, meloxicam, parecoxib, etoricoxib, AP-101, celecoxib, AXS-06, diclofenac potassium, DRGT-46, AAT-076, maceoshuri, lumiracoxib, meloxicam, valdecoxib, zaltoprofen, nimesulide, anitrazafen, apricoxib, cimicoxib, deracoxib, flumisole, firocoxib, macoxib, NS-398, pamicogrel, parecoxib, robenacoxib, rofecoxib, rutaecarpine, tilmacoxib, and zaltoprofen. Examples of dual COX1 / COX2 inhibitors that may be co-administered include, but are not limited to, HP-5000, lornoxicam, ketorolac tromethamine, bromfenac sodium, ATB-346, HP-5000. Examples of dual COX-2 / carbonic anhydrase (CA) inhibitors that may be co-administered include, but are not limited to, pormacoxib and imrecoxib.

[0205] Examples of inhibitors of secretory phospholipase A2, prostaglandin E synthase (PTGES, PGES; Gene ID: 9536) that may be co-administered include, but are not limited to, LY3023703, GRC27864, and the compounds described in International Publication Nos. 2015158204, 2013024898, 2006063466, and 200705961. No. 0, No. 2007124589, No. 2010100249, No. 2010034796, No. 2010034797, No. 2012022793, No. 20120 No. 76673, No. 2012076672, No. 2010034798, No. 2010034799, No. 2012022792, No. 2009103778, No. 20 11048004, 2012087771, 2012161965, 2013118071, 2013072825, 2014167444, Same No. 2009138376, No. 2011023812, No. 2012110860, No. 2013153535, No. 2009130242, No. 20091466 96, 2013186692, 2015059618, 2016069376, 2016069374, 2009117985, 2009064250, 2009064251, 2009082347, 2009117987, and 2008071173. Additionally, metformin has been found to inhibit the COX2 / PGE2 / STAT3 axis and can be co-administered. See, e.g., Tong, et al., Cancer Lett. (2017) 389: 23-32, and Liu, et al., Oncotarget. (2016) 7(19): 28235-46.

[0206] Carbonic anhydrases that may be co-administered (e.g., CA1 (NCBI Gene ID: 759), CA2 (NCBI Gene ID: 760), CA3 (NCBI Gene ID: 761), CA4 (NCBI Gene ID: 762), CA5A (NCBI Gene ID: 763), CA5B (NCBI Gene ID: 11238), CA6 (NCBI Gene ID: 765), CA7 (NCBI Gene ID: 766), CA8 (NCBI Gene ID: 767), CA9 (NCBI Gene ID: 768), Examples of inhibitors of one or more of CA10 (NCBI Gene ID: 768), CA10 (NCBI Gene ID: 56934), CA11 (NCBI Gene ID: 770), CA12 (NCBI Gene ID: 771), CA13 (NCBI Gene ID: 377677), CA14 (NCBI Gene ID: 23632) include, but are not limited to, acetazolamide, methazolamide, dorzolamide, zonisamide, brinzolamide, and diclophenamide. Dual COX-2 / CA1 / CA2 inhibitors that may be co-administered include CG100649.

[0207] Examples of inhibitors of arachidonate 5-lipoxygenase (ALOX5, 5-LOX; NCBI gene ID: 240) that may be co-administered include, but are not limited to, meclofenamate sodium, zileuton.

[0208] Examples of soluble epoxide hydrolase 2 (EPHX2, SEH; NCBI Gene ID: 2053) inhibitors that may be co-administered include, but are not limited to, compounds described in WO2015148954. Dual COX-2 / SEH inhibitors that may be co-administered include compounds described in WO2012082647. Dual SEH and fatty acid amide hydrolase (FAAH; NCBI Gene ID: 2166) inhibitors that may be co-administered include compounds described in WO2017160861.

[0209] Examples of inhibitors of mitogen-activated protein kinase kinase kinase 8 (MAP3K8, tumor progression locus 2, TPL2; NCBI Gene ID: 1326) that may be co-administered include, but are not limited to, GS-4875, GS-5290, BHM-078, as well as those described in, for example, WO 2006124944, WO 2006124692, WO 2014064215, WO 2018005435, Teli, et al., J Enzyme Inhib Med Chem. (2012) 27(4): 558-70, Gangwall, et al., Curr Top Med Chem. (2013) 13(9): 1015-35, Wu, et al., Bioorg Med Chem Lett. (2009) 19(13): 3485-8, Kaila, et al. al., Bioorg Med Chem. (2007) 15(19):6425-42, and Hu, et al., Bioorg Med Chem Lett. (2011) 21(16):4758-61.

[0210] Tumor oxygenators In various embodiments, the agents described herein that inhibit the binding between CD47 and SIRPα (e.g., magrolimab) and VEGFA / VEGFR inhibitors (e.g., bevacizumab) are further combined with agents that promote or increase tumor oxygenation or reoxygenation or prevent or reduce tumor hypoxia. Exemplary agents that may be co-administered include, for example, hypoxia inducible factor-1 alpha (HIF-1α) inhibitors, e.g., PT-2977, PT-2385; VEGF inhibitors, e.g., bevacizumab, IMC-3C5, GNR-011, tanibirumab, LYN-00101, ABT-165; and / or oxygen carrier proteins such as OMX-302 and HNOX proteins (e.g., heme-nitric oxide and / or oxygen binding protein (HNOX)), e.g., as described in WO 2007 / 137767, WO 2007 / 139791, WO 2014 / 107171, and WO 2016 / 149562.

[0211] ImmunotherapyIn various embodiments, the agents that inhibit binding between CD47 and SIRPα (e.g., magrolimab) and VEGFA / VEGFR inhibitors (e.g., bevacizumab) described herein are further combined with an immunotherapeutic agent. Examples of immunotherapeutic agents that may be co-administered include abagovomab, ABP-980, adecatumumab, afutuzumab, alemtuzumab, altumomab, amatuximab, anatumomab, arcitumomab, bavituximab, bectumomab, biosimilar of bevacizumab, bivatuzumab. , blinatumomab, brentuximab, cantuzumab, catumaxomab, CC49, cetuximab, sitatuzumab, cixutumumab, clivatuzumab, conatumumab, dacetuzumab, darotuzumab, daratumumab, detumomab, dinutuximab, drozitumab, durigotumab duligotumab, dusigitumab, ecromeximab, emibetuzumab, ensituximab, ertumaxomab, etaracizumab, farletuzumab, figitumumab, flanvotumab, futuximab imab), gemtuzumab, girentuximab, glembatumumab, ibritumomab, igovomab, imgatuzumab, indatuximab, inotuzumab, intetumumab, ipilimumab (YERVOY®, MDX-010, BMS-734016, and MDX-101), iratumumab,Labetuzumab, lexatumumab, lintuzumab, lorvotuzumab, lucatumumab, matuzumab, milatuzumab, minretumomab, mitumomab, moxetumomab, moxetumomab pasudotox, naptumomab, narnatumumab tumab, necitumumab, nimotuzumab, nofetumomab, OBI-833, obinutuzumab, ocaratuzumab, ofatumumab, olaratuzumab, onartuzumab, oportuzumab, oregovomab, panitumumab, parsatuzumab, pasudotox, patritumab, pemtumomab, pertuzumab, pintumomab, pretum pritumumab, racotumomab, radretumab, ramucirumab (Cyramza®), rilotumumab, rituximab, lobatumumab, samaryzumab, satumomab, sibrotuzumab, siltuximab, solitomab, simtuzumab, tacatuzumab, These include, but are not limited to, taplitumomab, tenatumomab, teprotumumab, tigatuzumab, tositumomab, trastuzumab, biosimilars of trastuzumab, tucotuzumab, ubilituximab, veltuzumab, vorsetuzumab, votumumab, zalutumumab, and 3F8. Rituximab is used in the treatment of marginal zone lymphoma, WM, CLL, and small lymphocytic lymphoma, among others.It can be used to treat indolent B-cell cancers. The combination of rituximab and chemotherapy agents is particularly effective.

[0212] The exemplified therapeutic antibodies may further be labeled with or combined with radioisotope particles, such as indium-111, yttrium-90 (90Y clivatuzumab), or iodine-131.

[0213] In some embodiments, the immunotherapeutic agent is an antibody drug conjugate (ADC). Exemplary ADCs that may be co-administered include, but are not limited to, drug-conjugated antibodies, fragments thereof, or antibody mimetics that target the proteins or antigens listed above and herein (e.g., Table B). Exemplary ADCs that may be co-administered include, but are not limited to, gemtuzumab, brentuximab, trastuzumab, inotuzumab, glenbatumumab, anetuzumab, mirvetuximab, depatuximab, novalpituzumab, vadastuximab, labetuzumab, sacituzumab, rifastuzumab, indusatuzumab, polatuzumab, pinatuzumab, sucraliz ... Mab, coltuximab, indatuximab, milatuzumab, rovalpituzumab, ABBV-011, ABBV-2029, ABBV-321, ABBV-647, MLN0264 (anti-GCC, guanylyl cyclase C), T-DM1 (trastuzumab emtansine, Kadcycla); SYD985 (anti-HER2, duocarmycin), milatuzumab- Doxorubicin (hCD74-DOX), DCDT2980S, belantamab mafodotin (GSK2857916), polatuzumab vedotin (RG-7596), SGN-CD70A, SGN-CD19A, inotuzumab ozogamicin (CMC-544), lorvotuzumab mertansine, SAR3419, sacituzumab govitecan (TRODELVY ( Trademark), isactuzumab govitecan, enfortumab vedotin (ASG-22ME), ASG-15ME, DS-8201 (trastuzumab deruxtecan), 225Ac-lintuzumab, U3-1402, 177Lu-tetraxetane-tetuloma, tisotumab vedotin, anetumab ravtansineravtansine), CX-2009, SAR-566658, W-0101, ABBV-085, gemtuzumab ozogamicin, ABT-414, glembatuzumab vedotin (CDX-011), labetuzumab govitecan (IMMU-130), rifasuzumab vedotin, (RG-7599), milatuzumab doxorubicin (IMMU-110), indatuximab ravtansine (BT-062), pinatuzumab vedotin (RG-7593), SG N-LIV1A, SGN-CD33A, SAR566658, MLN2704, SAR408701, robalbuspizumab tesirin, ABBV-399, AGS-16C3F, ASG-22ME, AGS67E, AMG172, AMG595, AGS-15E, BAY1129980, BAY1187982, BAY94-934 (anetumab vedotin), GSK2857916, Humax-TF-ADC (tisotumab vedotin vedotin), IMGN289, IMGN529, IMGN853 (mirvetuximab soravtansine), LOP628, PCA062, MDX-1203, MEDI-547, PF-06263507, PF-06647020, PF-06647263, PF-06664178, PF-06688992, PF-06804103, RG7450, RG7458, RG7598, SAR566658, SGN-CD33A, DS-1602, and DS-7300, DS-6157, DS-6000, TAK-164, MEDI2228, MEDI7247, AMG575. ADCs that can be co-administered are described, for example, in Lambert, et al., Adv Ther (2017) 34:1015-1035 and de Goeij, Current Opinion in Immunology (2016) 40:14-23.

[0214] Exemplary therapeutic agents (e.g., anti-cancer or anti-tumor agents) that can be conjugated to a drug-conjugated antibody, fragment thereof, or antibody mimetic include, but are not limited to, monomethyl auristatin E (MMAE), monomethyl auristatin F (MMAF), calicheamicins, ansamitocins, maytansine or analogs thereof (e.g., mertansine / emtansine (DM1), ravtansine / soravtansine (DM4)), anthracyclines (e.g., doxorubicin, daunorubicin, epirubicin, idarubicin), pyrrolobenzodiazepine (PBD) DNA crosslinker SC-DR002 (D6.5), duocarmycins, microtubule inhibitors (MTXs), and the like. inhibitors, MTIs) (e.g., taxanes, vinca alkaloids, epothilones), pyrrolobenzodiazepines (PBDs) or dimers thereof, duocarmycins (A, B1, B2, C1, C2, D, SA, CC-1065) and other anti-cancer or anti-neoplastic agents described herein.

[0215] Cancer Gene Therapy and Cell Therapy In various embodiments, the agents described herein that inhibit the binding between CD47 and SIRPα (e.g., magrolimab) and VEGFA / VEGFR inhibitors (e.g., bevacizumab) are further combined with cancer gene therapy and cell therapy. Cancer gene therapy and cell therapy include insertion of normal genes into cancer cells to replace mutated or altered genes; gene modification to silence mutated genes; genetic approaches to directly kill cancer cells; infusion of immune cells designed to enhance immune response against cancer cells or to activate the patient's own immune system (T cells or natural killer cells) to kill cancer cells or to replace most of the patient's own immune system to find and kill cancer cells; genetic approaches to modify cell activity to further change the endogenous immune responsiveness against cancer.

[0216] cell therapy In various embodiments, the agents that inhibit binding between CD47 and SIRPα (e.g., magrolimab) and VEGFA / VEGFR inhibitors (e.g., bevacizumab) described herein are further combined with one or more cell therapy agents. Exemplary cell therapies include, but are not limited to, the co-administration of one or more of a population of immune cells. In some embodiments, the immune cells are natural killer (NK) cells, NK-T cells, T cells, gamma delta T cells, B cells, cytokine-induced killer (CIK) cells, macrophages (MAC) cells, tumor infiltrating lymphocytes (TIL), granulocytes, innate lymphocytes, megakaryocytes, monocytes, macrophages, platelets, thymocytes, myeloid cells, and / or dendritic cells (DC). In some embodiments, the cell therapy involves co-administration of T cell therapy, e.g., a population of alpha / beta TCR T cells, gamma / delta TCR T cells, regulatory T (Treg) cells, and / or TRuC™ T cells. In some embodiments, the cell therapy involves co-administration of NK cell therapy, e.g., NK-92 cells or JK500 cells. Optionally, the cell therapy can involve co-administration of cells that are autologous, syngeneic, or allogeneic to the subject.

[0217] In some embodiments, the cell therapy involves the co-administration of immune cells engineered to express a chimeric antigen receptor (CAR) or a T cell receptor (TCR). In certain embodiments, the population of immune cells is engineered to express a CAR, where the CAR comprises a cancer antigen binding domain. In other embodiments, the population of immune cells is engineered to express a T cell receptor (TCR) that is engineered to target a tumor-derived peptide displayed on the surface of a tumor cell. In one embodiment, the immune cells engineered to express a chimeric antigen receptor (CAR) or a T cell receptor (TCR) are T cells. In another embodiment, the immune cells engineered to express a chimeric antigen receptor (CAR) or a T cell receptor (TCR) are NK cells.

[0218] With regard to the structure of the CAR, in some embodiments, the CAR comprises an antigen binding domain, a transmembrane domain, and an intracellular signaling domain. In some embodiments, the intracellular domain comprises a primary signaling domain, a costimulatory domain, or both a primary signaling domain and a costimulatory domain. In some embodiments, the primary signaling domain is CD3 zeta, CD3 gamma, CD3 delta, CD3 epsilon, common FcR gamma (FCERIG), FcR beta (Fc epsilon, Rlb), CD79a, CD79b, Fc gamma RIIa, DAP10, and DAP12, 4-1BB / CD137, activating NK cell receptor, immunoglobulin protein, B7-H3, BAFFR, BLAME (SLAMF8), BTLA, CD100 (SEMA4D ), CD103, CD160 (BY55), CD18, CD19, CD19a, CD2, CD247, CD27, CD276 (B7-H3), CD28, CD29, CD3 delta, CD3 epsilon, CD3 gamma, CD30, CD4, CD40, CD49a, CD49D, CD49f, CD69, CD7, CD84, CD8 alpha, CD8 beta, CD96 (Tactile), CD11a, CD11b, CD11c, CD11d, CDS, CEACAM1, CRT AM, cytokine receptor, DAP-10, DNAM1 (CD226), Fc gamma receptor, GADS, GITR, HVEM (LIGHTR), IA4, ICAM-1, ICAM-1, Ig alpha (CD79a), IL-2R beta, IL-2R gamma, IL-7R alpha, inducible T cell costimulator (ICOS), integrin, ITGA4, ITGA4, ITGA6, ITGAD, ITGAE, ITGAL, ITGAM, ITGAX, ITGB2, ITGB7, ITGB1, KIRDS2, LAT, LFA-1, ligand binding to CD83, LIGHT, LIGHT, LTBR, ​​Ly9 (CD229), Ly108), lymphocyte function-associated antigen-1 (LFA-1;and / or a functional signaling domain of one or more proteins selected from CD1-1a / CD18), MHC class 1 molecule, NKG2C, NKG2D, NKp30, NKp44, NKp46, NKp80 (KLRF1), OX-40, PAG / Cbp, programmed death-1 (PD-1), PSGL1, SELPLG (CD162), signaling lymphocyte activation molecule (SLAM protein), SLAM (SLAMF1, CD150; IPO-3), SLAMF4 (CD244, 2B4), SLAMF6 (NTB-A, SLAMF7, SLP-76, TNF receptor protein, TNFR2, TNFSF14, Toll ligand receptor, TRANCE / RANKL, VLA1, or VLA-6, or fragments, truncations, or combinations thereof;

[0219] In some embodiments, the costimulatory domain is selected from the group consisting of CD27, CD28, 4-1BB (CD137), OX40, CD30, CD40, PD-1, ICOS, CD2, CD7, LIGHT, NKG2C, lymphocyte function-associated antigen-1 (LFA-1), MYD88, B7-H3, a ligand that specifically binds CD83, CDS, ICAM-1, GITR, BAFFR, HVEM (LIGHTR), SLAMF7, NKp80 ( KLRFI), CD19, CD4, CD8 alpha, CD8 beta, IL2R beta, IL2R gamma, IL7R alpha, ITGA4, VLA1, CD49a, ITGA4, IA4, CD49D, ITGA6, VLA-6, CD49f, ITGAD, ITGAE, CD103, ITGAL, CD1A (NCBI gene ID: 909), CD1B (NCBI gene ID: 910), CD1C (NCBI gene ID: 91 1), CD1D (NCBI gene ID: 912), CD1E (NCBI gene ID: 913), ITGAM, ITGAX, ITGB1, CD29, ITGB2 (CD18, LFA-1), ITGB7, TNFR2, TRANCE / RANKL, DNAM1 (CD226), SLAMF4 (CD244, 2B4), CD84, CD96 (Tactile), CEACAM1, CRTAM, Ly9 (CD229), CD16 The present invention includes a functional domain of one or more proteins selected from the group consisting of 0 (BY55), PSGL1, CD100 (SEMA4D), CD69, SLAMF6 (NTB-A, Ly108), SLAM (SLAMF1, CD150, IPO-3), BLAME (SLAMF8), SELPLG (CD162), LTBR, ​​LAT, GADS, SLP-76, PAG / Cbp, NKp44, NKp30, NKp46, and NKG2D.

[0220] In some embodiments, the transmembrane domain is selected from the group consisting of the alpha, beta, or zeta chain of the T cell receptor, CD28, CD3 epsilon, CD3 delta, CD3 gamma, CD45, CD4, CD5, CD7, CD8 alpha, CD8 beta, CD9, CD11a, CD11b, CD11c, CD11d, CD16, CD18, CD22, CD33, CD37, CD64, CD80, CD86, CD134, CD137, CD154, KIRDS2, OX40, CD2, CD27, ICOS (CD278), 4-1BB (CD137), G ITR, CD40, BAFFR, HVEM (LIGHTR), SLAMF7, NKp80 (KLRF1), CD19, CD19a, IL2R beta, IL2R gamma, IL7R alpha, ITGA1, VLA1, CD49a, ITGA4, IA4, CD49D, ITGA6, VLA-6, CD49f, ITGAD, CD1A, CD1B, CD1C, CD1D, CD1E, ITGAE, CD103, ITGAL, ITGAM, ITGAX, ITGB1, ITGB2, ITGB7, CD29, ITGB2 (LFA-1, CD18), ITGB7, TNFR2, DNAM1(CD226), SLAMF4(CD244, 2B4), CD84, CD96(TACTILE), CEACAM1, CRTAM, Ly9(CD229), CD160(BY55), PSGL1, CD100(SEMA4D) , SLAMF6 (NTB-A, Ly108), SLAM (SLAMF1, CD150, IPO-3), BLAME (SLAMF8), SELPLG (CD162), LTBR, ​​PAG / Cbp, NKp44, NKp30, NKp46, NKG2D, and NKG2C activity The antibody comprises a transmembrane domain derived from a protein selected from an activated NK cell receptor, an immunoglobulin protein, BTLA, CD247, CD276 (B7-H3), CD30, CD84, CDS, a cytokine receptor, an Fc gamma receptor, GADS, ICAM-1, Ig alpha (CD79a), an integrin, LAT, a ligand that binds CD83, LIGHT, an MHC class 1 molecule, PAG / Cbp, TNFSF14, a Toll ligand receptor, TRANCE / RANKL, or a fragment, truncation, or combination thereof.

[0221] In some embodiments, the CAR comprises a hinge domain. The hinge domain is selected from the group consisting of CD2, CD3 delta, CD3 epsilon, CD3 gamma, CD4, CD7, CD8 alpha, CD8 beta, CD11a (ITGAL), CD11b (ITGAM), CD11c (ITGAX), CD11d (ITGAD), CD18 (ITGB2), CD19 (B4), CD27 (TNFRSF7), CD28, CD28T, CD29 (ITGB1), CD30 (TNFRSF8), CD40 (TNFRSF5), CD48 (SLAMF2), CD49a (ITGA1), CD49d (ITGA4), CD4 9f (ITGA6), CD66a (CEACAM1), CD66b (CEACAM8), CD66c (CEACAM6), CD66d (CEACAM3), CD66e (CEACAM5), CD69 (CLEC2), CD79A (B cell antigen receptor complex-associated alpha chain), CD79B (B cell antigen receptor complex-associated beta chain), CD84 (SLAMF5), CD96 (Tactile), CD100 (SEMA4D), CD103 (ITGAE), CD134 (OX40), CD137 (4-1BB), CD150 (SLAMF1), CD 158A(KIR2DL1), CD158B1(KIR2DL2), CD158B2(KIR2DL3), CD158C(KIR3DP1), CD158D(KIRDL4), CD158F1(KIR2DL5A), CD158F2(KIR2DL5B), CD158K (KIR3DL2), CD160(BY55), CD162(SELPLG), CD226(DNAM1), CD229(SLAMF3), CD244(SLAMF4), CD247(CD3-Zeta), CD258(LIGHT), CD268(BAFFR), CD27 0(TNFSF14), CD272(BTLA), CD276(B7-H3), CD279(PD-1), CD314(NKG2D), CD319(SLAMF7), CD335(NK-p46), CD336(NK-p44), CD337(NK-p30), CD35 2 (SLAMF6), CD353 (SLAMF8), CD355 (CRTAM), CD357 (TNFRSF18), inducible T cell costimulatory factor (ICOS), LFA-1 (CD11a / CD18), NKG2C, DAP-10, ICAM-1, NKp80 (KLRF1),The antibody may be derived from a protein selected from IL-2R beta, IL-2R gamma, IL-7R alpha, LFA-1, SLAMF9, LAT, GADS (GrpL), SLP-76 (LCP2), PAG1 / CBP, CD83 ligand, Fc gamma receptor, MHC class 1 molecule, MHC class 2 molecule, TNF receptor protein, immunoglobulin protein, cytokine receptor, integrin, activating NK cell receptor, or Toll ligand receptor, IgG1, IgG2, IgG3, IgG4, IgA, IgD, IgE, IgM, or a fragment or combination thereof.

[0222] In some embodiments, the TCR or CAR antigen binding domain or immunotherapeutic agent (e.g., a monospecific or multispecific antibody or antigen-binding fragment thereof or an antibody mimetic) described herein binds to a tumor-associated antigen (TAA). In some embodiments, the tumor associated antigen is CD19; CD123; CD22; CD30; CD171; CS-1 (CD2 subset 1, also referred to as CRACC, SLAMF7, CD319, and 19A24); C-type lectin-like molecule-1 (CLL-1 or CLECLI); CD33; epidermal growth factor receptor variant III (EGFRvlll); ganglioside G2 (GD2); ganglioside GD3 (αNeuSAc(2-8)αNeuSAc(2-3)βDGaip(1-4)bDGIcp(1-1)Cer); ganglioside GM3 (αNeuSAc(2-3)βDGalp(1-4)βDGlcp(1-1)Cer); GM-CSF receptor; TNF receptor superfamily member 17 (TNFRSF17, BCMA); B-lymphocyte cell adhesion molecule; Tn antigen ((Tn Ag) or (GaINAcu-Ser / Thr)); prostate-specific membrane antigen (PSMA); receptor tyrosine kinase-like orphan receptor 1 (RORI); tumor-associated glycoprotein 72 (TAG72); CD38; CD44v6; carcinoembryonic antigen (CEA); epithelial cell adhesion molecule (EPCAM); B7H3 (CD276); KIT (CD117); interleukin-13 receptor subunit alpha-2 (IL-13Ra2 or CD213A2); mesothelin; interleukin-11 receptor alpha (IL-11Ra); prostate stem cell antigen antigen, PSCA); protease serine 21 (testisin or PRSS21); vascular endothelial growth factor receptor 2 (VEGFR2); HLA class I antigen A-2 alpha; HLA antigen; Lewis (Y) antigen; CD24; platelet-derived growth factor receptor beta (PDGFR-beta); stage-specific embryonic antigen-4 (SSEA-4); CD20;delta like 3 (DLL3); folate receptor alpha; folate receptor beta; GDNF alpha 4 receptor; receptor tyrosine protein kinase; ERBB2 (Her2 / neu); mucin 1, cell surface associated (MUC1); APRIL receptor; ADP-ribosyl cyclase-1; Ephb4 tyrosine kinase receptor; DCAMKL1 serine threonine kinase; aspartate beta-hydroxylase; epidermal growth factor receptor (EGFR); neural cell adhesion molecule (NCAM); prostase; prostatic acid phosphatase (PAP); elongation factor 2 mutated (ELF2M); ephrin B2; fibroblast activation protein alpha (FAP); insulin-like growth factor 1 receptor (IGF-I receptor); carbonic anhydrase IX IX, CAIX; proteasome (macropain) subunit, beta type, 9 (LMP2); glycoprotein 100 (gp100); oncogene fusion protein consisting of breakpoint cluster region (BCR) and Abelson murine leukemia viral oncogene homolog 1 (abl) (bcr-abl); tyrosinase; ephrin type-A receptor 2 (EphA2); ephrin type-A receptor 3 (EphA3), fucosyl-GM1; sialyl Lewis adhesion molecule (sLe); transglutaminase 5 (TGS5); high molecular weight-melanoma associated antigen (HMWMAA); o-acetyl-GD2 ganglioside (o-acetyl-GD2 ganglioside, OAcGD2); folate receptor beta; tumor endothelial marker 1 (TEM1 / CD248); tumor endothelial marker 7-related (TEM7R);Six transmembrane epithelial antigen I of the prostate (STEAP1); claudin 6 (CLDN6); thyroid stimulating hormone receptor (TSHR); G protein-coupled receptor class C group 5, member D (GPRCSD); IL-15 receptor (IL-15); chromosome X open reading frame 61 (CXORF61); CD97; CD179a; anaplastic lymphoma kinase (ALK); polysialic acid; placenta-specific 1 (PLAC1); hexasaccharide moiety of globoH glycoceramide (GloboH); mammary differentiation antigen (NY-BR-1); uroplakin 2 (UPK2); Hepatitis A virus cellular receptor 1 (HAVCR1); adrenoceptor beta 3 (adrenoceptor beta 3, ADRB3); pannexin 3 (PANX3); G protein-coupled receptor 20 (GPR20); lymphocyte antigen 6 complex, locus K9 (LY6K); olfactory receptor 51E2 (ORS IE2); TCR gamma alternate reading frame protein (TARP); Wilms tumor protein (WT1); cancer / testis antigen 1 (NY-ESO-1); cancer / testis antigen 2 (LAGE-la); melanoma associated antigen 1 (MAGE-A1); melanoma associated antigen 3 (MAGE-A3); melanoma associated antigen 4 (MAGE-A4); T cell receptor beta 2 chain C; ETS translocation variant gene 6 located on chromosome 12p (ETV6-AML); sperm protein 17 17, SPA17); X antigen family, member 1A (XAGE1); angiopoietin-binding cell surface receptor 2 (Tie2); melanoma cancer testis antigen-1 (MADCT-1);melanoma cancer testis antigen-2 (MAD-CT-2); Fos-related antigen 1; tumor protein p53 (p53); p53 mutant; prostein; survivin; telomerase; prostate cancer tumor antigen-1 (PCTA-1 or galectin 8); melanoma antigen 1 recognized by T cells (MelanA or MARTI); rat sarcoma (Ras) mutant; human telomerase reverse transcriptase (hTERT); sarcoma translocation breakpoints; melanoma inhibitor of apoptosis apoptosis, ML-IAP; ERG (transmembrane protease, serine 2 (TMPRSS2) ETS fusion gene); N-acetylglucosaminyltransferase V (NA17); paired box protein Pax-3 (PAX3); androgen receptor; cyclin-A1; cyclin B1; v-myc avian myeloma viral oncogene neuroblastoma-derived homolog (MYCN); Ras Homolog Family Member C (RhoC); tyrosinase-related protein 2 (TRP-2); cytochrome P450 1B1 (CYP IBI); CCCTC-binding agent (zinc finger protein)-like (BORIS or Brother of the Regulator of Imprinted Sites), squamous cell carcinoma antigen recognized by T cells 3 (SART3); paired box protein Pax-5 (PAX5); proacrosin-binding protein sp32 (OY-TES I); lymphocyte-specific protein tyrosine kinase (LCK); A kinase anchor protein 4 (AKAP-4); peptidoglycan recognition protein, synovial sarcoma, X breakpoint 2 (SSX2); receptor for advanced glycation end products (RAGE-I); renal ubiquitous 1 (RUI); renal ubiquitous 2 (RU2); legumain; human papilloma virus E6 (HPV E6);human papilloma virus E7 (HPV E7); intestinal carboxylesterase; heat shock protein 70-2 mutant (mut hsp70-2); CD79a; CD79b; CD72; leukocyte-associated immunoglobulin-like receptor 1 (LAIRI); Fc fragment of IgA receptor (FCAR or CD89); leukocyte immunoglobulin-like receptor subfamily A member 2 (LILRA2); CD300 molecule-like family member f f, CD300LF); C-type lectin domain family 12 member A (CLEC12A); bone marrow stromal cell antigen 2 (BST2); EGF-like module-containing mucin-like hormone receptor-like 2 (EMR2); lymphocyte antigen 75 (LY75); glypican-2 (GPC2); glypican-3 (GPC3); Fc receptor-like 5 (Fc receptor-like 5, FCRL5); and immunoglobulin lambda-like polypeptide 1 (IGLL1). In some embodiments, the target is an epitope of a tumor-associated antigen that is presented on MHC.;

[0223] In some embodiments, the tumor antigen is CD150, 5T4, ActRIIA, B7, TNF receptor superfamily member 17 (TNFRSF17, BCMA), CA-125, CCNA1, CD123, CD126, CD138, CD14, CD148, CD15, CD19, CD20, CD200, CD21, CD22, CD23, CD24, CD25, CD26, CD261, CD262, CD30, CD33, CD362, CD37, CD38, CD4, CD40, CD40L, CD44, CD46, CD5, C D52, CD53, CD54, CD56, CD66a-d, CD74, CD8, CD80, CD92, CE7, CS-1, CSPG4, ED-B Fibronectin, EGFR, EGFRvIII, EGP-2, EGP-4, EPHa2, ErbB2, ErbB3, ErbB4, FBP, HER1-HER2 combination, HER2-HER3 combination, HERV-K, HIV-1 envelope glycoprotein gp120, HIV-1 envelope glycoprotein gp41, HLA-DR, HLA class I antigen alpha G, HM1.24, K-Ras GTPase, HMW-MAA, HER2, HER2 / neu, IGF-1R, IL-11Ralpha, IL-13R-alpha2, IL-2, IL-22R-alpha, IL-6, IL-6R, Ia, Ii, L1-CAM, L1-cell adhesion molecule, Lewis Y, Ll-CAM, MAGE A3, MAGE-A1, MART-1, MUC1, NKG2C ligand, NKG2D ligand, NYESO-1, OEPHa2, PIGF, PSCA, PSMA, ROR1, T101, TAC, TAG72, TIM-3, TRAIL R1, TRAIL R1 (DR4), TRAIL-R2 (DR5), VEGF, VEGFR2, WTI, G protein-coupled receptor, alpha-fetoprotein (AFP), angiogenic agent, exogenous cognate binding molecule (ExoCBM), oncogene product, antifolate receptor, c-Met, carcinoembryonic antigen (CEA), cyclin (D1), ephrin B2, epithelial tumor antigen, estrogen receptor, fetal acetylcholine e receptor, folate binding protein, gp100, hepatitis B surface antigen, Epstein-Barr nuclear antigen 1 , latent membrane protein 1, secreted protein BARF1, P2X7 purinergic receptor, syndecan-1, kappa chain, kappa light chain, kdr, lambda chain, livin, melanoma-associated antigen, mesothelin, mouse double minute 2 homolog (MDM2), mucin 16 (MUC16), mutant p53, mutant ras, necrosis antigen, carcinoembryonic antigen, ROR2, progesterone receptor, prostate-specific antigen, tEGFR, tenascin, P2-microglobulin, Fc receptor-like 5 (FcRL5).

[0224] Examples of cell therapies include AMG-119, Algenpantucel-L, ALOFISEL®, Sipuleucel-T, (BPX-501) rivogenlecleucel US Patent Publication No. 9089520, WO 2016100236, AU-105, ACTR-087, activated allogeneic natural killer cells CNDO-109-AANK, MG-4101, AU-101, BPX-601, FATE-NK100, LFU-835 hematopoietic stem cells, Imilecleucel-T, baltaleucel-T, PNK-007, UCARTCS1, ET-1504, ET-1501, ET-1502, ET-190, CD19-ARTEMIS, ProHema, bone marrow stem cell therapy with FT-1050 treatment, CD4CARNK-92 cells, SNK-01, NEXI-001, CryoStim, AlloStim, lentiviral transduced huCART-meso cells, CART-22 cells, EGFRt / 19-28z / 4-1BBL CAR T cells, autologous 4H11-28z / fIL-12 / EFGRt T cells, CCR5-SBC-728-HSPC, CAR4-1BBZ, CH-296, dnTGFbRII-NY-ESOc259T, Ad-RTS-IL-12, IMA-101, I MA-201, CARMA-0508, TT-18, CMD-501, CMD-503, CMD-504, CMD-502, CMD-601, CMD-602, CSG-005, LAAP T cell therapy, PD-1 knockout T cell therapy (esophageal cancer / NSCLC), anti-MUC1 CAR T cell therapy (esophageal cancer / NSCLC), anti-MUC1 CAR T cell therapy + PD-1 knockout T cell therapy (esophageal cancer / NSCLC), anti-KRAS G12D mTCR PBL, anti-CD123 CAR T cell therapy, anti-mutation neoantigen TCR T cell therapy, tumor lysate / MUC1 / survivin PepTivator-loaded dendritic cell vaccine, autologous dendritic cell vaccine (metastatic melanoma, intradermal / intravenous), anti-LeY-scFv-CD28-zeta CAR T cells, PRGN-3005, iC9-GD2-CAR-IL-15T-cells, HSC-100, ATL-DC-101, MIDRIX4-LUNG, MIDRIXNEO, FCR-001, PLX Stem Cell Therapy, MDR-101, GeniusVac-Mel4, ilixadencel, allogeneic mesenchymal stem cell therapy, romyelocel L, CYNK-001, ProTrans, ECT-100, MSCTRAIL, dilanubicel, FT-516, ASTVAC-2, E-CEL These include, but are not limited to, UVEC, CK-0801, allogeneic alpha / beta CD3+ T cell and CD19+ B cell depleted stem cells (hematological disorders, TBX-1400, HLCN-061, umbilical cord-derived Hu-PHEC cells (hematological malignancies / aplastic anemia), AP-011, apceth-201, apceth-301, SENTI-101, stem cell therapy (pancreatic cancer), ICOVIR15-cBiTE, CD33HSC / CD33 CAR-T, PLX-Immune, SUBCUVAX, CRISPR allogeneic gamma-delta T cell based gene therapy (cancer), ex vivo CRISPR allogeneic healthy donor NK cell based gene therapy (cancer), ex vivo allogeneic induced pluripotent stem cell-derived NK cell based gene therapy (solid tumors), and anti-CD20 CAR T cell therapy (non-Hodgkin's lymphoma).

[0225] Additional agents for targeting tumors Additional agents for targeting tumors include alpha-fetoprotein modulators such as ET-1402, and AFP-TCR; anthrax toxin receptor 1 modulators, e.g., anti-TEM8 CAR T cell therapy; TNF receptor superfamily member 17 (TNFRSF17, BCMA), such as bb-2121 (ide-cel), bb-21217, JCARH125, UCART-BCMA, ET-140, MCM-998, LCAR-B38M, CART-BCMA, SEA-BCMA, BB212, ET-140, P-BCMA-101, AUTO-2 (APRIL-CAR), JNJ-68284528; anti-CLL-1 antibodies (see, e.g., International Application No. PCT / US / 2017 / 025573); anti-PD-L1-CAR tank cell therapy, such as KD-045; anti-PD-L1 t-haNK, e.g., PD-L1 t-haNK; anti-CD45 antibodies, e.g., 131I-BC8 (lomab-B); anti-HER3 antibodies, e.g., LJM716, GSK2849330; APRIL receptor modulators, e.g., anti-BCMA CAR T cell therapy, Descartes-011; ADP-ribosyl cyclase-1 / APRIL receptor modulators, e.g., anti-BCMA / anti-CD38 dual CAR T cell therapy; CART-ddBCMA; B7 homolog 6, e.g., CAR-NKp30 and CAR-B7H6;B lymphocyte antigen CD19, e.g., TBI-1501, CTL-119 huCART-19 T cells, liso-cel, JCAR-015 U.S. Pat. No. 7,446,190, JCAR-014, JCAR-017 (WO 2016196388, WO 2016033570, WO 2015157386), axicabtagene siloleucel ciloleucel) (KTE-C19, Yescarta®), KTE-X19, U.S. Pat. No. 7,741,465, U.S. Pat. No. 6,319,494, UCART-19, EBV-CTL, Ttisagenleucel-T (CTL019), WO 2012079000, WO 2017049166, CD19CAR-CD28-CD3zeta-EGFRt-expressing T cells, CD19 / 4-1BBL armed CAR T cell therapy, C-CAR-011, CIK-CAR.CD19, CD19CAR-28-zeta T cells, PCAR-019, MatchCART, DSCAR-01, IM19 CAR-T, TC-110; anti-CD19 CAR T cell therapy (B-cell acute lymphoblastic leukemia, University of the National University of Malaysia); anti-CD19 CAR T cell therapy (acute lymphoblastic leukemia / non-Hodgkin's lymphoma, Heidelberg University Hospital), anti-CD19 CAR T cell therapy (IL-6 expression suppression, cancer, Shanghai Unicar-Therapy Bio-medicine) Technology), MB-CART2019.1 (CD19 / CD20), GC-197 (CD19 / CD7), CLIC-1901, ET-019003, anti-CD19-STAR-T cells, AVA-001, BCMA-CD19 cCAR(CD19 / APRIL), ICG-134, ICG-132(CD19 / CD20), CTA-101, WZTL-002, anti-CD19 / anti-CD20 double CAR T cells (chronic lymphocytic leukemia / B cell lymphoma), HY-001, ET-019002, YTB-323, GC-012 (CD19 / APRIL), GC-022 (CD19 / CD22), CD19CAR-CD28-CD3 zeta-EGFRt expressing Tn / mem; allogeneic anti-CD19 CART cells such as UCAR-011, ICTCAR-014, GC-007F, PTG-01, CC-97540; GC-007G; APRIL receptor modulators;SLAM family member 7 modulators, BCMA-CS1 cCAR; autologous dendritic cell tumor antigens (ADCTA), such as ADCTA-SSI-G; B-lymphocyte antigen CD20, e.g., ACTR707 ATTCK-20, PBCAR-20A; allogeneic T cells expressing CD20 CARs, such as LB-1905; B-lymphocyte antigen CD19 / B-lymphocyte antigen 22, e.g., TC-310; B-lymphocyte antigen 22 cell adhesion, e.g., UCART-22, JCAR-018 International Publication No. WO2016090190; NY-ESO-1 modulators, e.g., GSK-3377794, TBI-1301, GSK3537142; carbonic anhydrase, e.g., DC-Ad-GMCAIX; caspase 9 suicide gene, e.g., CaspaCIDe DLI, BPX-501; CCR5, e.g., SB-728; CCR5 gene inhibitor / TAT gene / TRIM5 gene stimulator, e.g., CCR5 shRNA / TRIM5 alpha / TAR decoy lentiviral vector transduced autologous CD34 positive hematopoietic progenitor cells; CDw123, e.g., MB-102, IM-23, JEZ-567, UCART-123; CD4, e.g., ICG-122; CD5 modulator, e.g., CD5.28z CART cells; anti-CD22, e.g., anti-CD22 CART; anti-CD30, e.g., TT-11; dual anti-CD33 / anti-CLL, such as LB-1910 1;CD40 ligand, e.g., BPX-201, MEDI5083;CD56, e.g., allogeneic CD56 positive CD3 negative natural killer cells (myeloid malignancies);CD19 / CD7 modulators, e.g., GC-197;T cell antigen CD7 modulators, e.g., anti-CD7 CAR T cell therapy (CD7 positive hematologic malignancies);CD123 modulators, e.g., UniCAR02-T-CD123;anti-CD276, e.g., anti-CD276 CART;CEACAM protein 5 modulators, e.g., MG7-CART;claudin 6, e.g., CSG-002;claudin 18.2, e.g., LB-1904;chlorotoxin, e.g., CLTX-CART;EBV targeting, e.g., CMD-003;MUC16EGFR, e.g., autologous 4H11-28z / fIL-12 / EFGRt T cells; endonucleases, e.g., PGN-514, PGN-201;Epstein-Barr virus specific T lymphocytes, e.g., TT-10; Epstein-Barr nuclear antigen 1 / latent membrane protein 1 / secreted protein BARF1 modulators, e.g., TT-10X; Erbb2, e.g., CST-102, CIDeCAR; Ganglioside (GD2), e.g., 4SCAR-GD2; Gamma delta T cells, e.g., ICS-200; Folate hydrolase 1 (FOLH1, glutamic acid carboxypeptidase II, PSMA; NCBI Gene ID: 2346), e.g., CIK-CAR.PSMA, CART-PSMA-TGFβRDN, P-PSMA-101; Glypican-3 (GPC3), e.g., TT-16, GLYCAR; Hemoglobin, e.g., PGN-236; Hepatocyte growth factor receptor, e.g., anti-cMet RNA CAR T; HLA class I antigen A-2 alpha modulators, e.g., FH-MCVA2TCR; HLA class I antigen A-2 alpha / melanoma associated antigen 4 modulators, e.g., ADP-A2M4CD8; HLA antigen modulators, e.g., FIT-001, NeoTCR-P1; human papillomavirus E7 proteins such as KITE-439 (see, e.g., International Application PCT / US2015 / 033129); ICAM-1 modulators, e.g., AIC-100; immunoglobulin gamma Fc receptor III, e.g., ACTR087; IL-12, e.g., DC-RTS-IL- 12;IL-12 agonist / mucin 16, e.g., JCAR-020;IL-13 alpha 2, e.g., MB-101;IL-15 receptor agonists such as PRGN-3006, ALT-803;Interleukin-15 / Fc fusion proteins (e.g., XmAb24306), recombinant interleukin-15 (e.g., AM0015, NIZ-985), pegylated IL-15 (e.g., NKTR-255);IL-2, e.g., CST-101;Interferon alpha ligands, e.g., autologous tumor cell vaccine + systemic CpG-B + IFN-alpha (cancer);K-Ras GTPases, e.g., anti-KRAS G12V mTCR cell therapy; neural cell adhesion molecule L1 L1CAM (CD171), e.g., JCAR-023; latent membrane protein 1 / latent membrane protein 2, e.g., Ad5f35-LMPd1-2 transduced autologous dendritic cells;MART-1 melanoma antigen modulators, e.g., MART-1 F5 TCR engineered PBMC; melanoma associated antigen 10, e.g., MAGE-A10C796T MAGE-A10 TCR; melanoma associated antigen 3 / melanoma associated antigen 6 (MAGE A3 / A6) such as KITE-718 (see, e.g., International Application PCT / US2013 / 059608); mesothelin, e.g., CSG-MESO, TC-210; mucin 1 modulators, e.g., ICTCAR-052, Tn MUC-1 CAR-T, ICTCAR-053; anti-MICA / MICB, e.g., CYAD-02; NKG2D, e.g., NKR-2; Ntrkr1 tyrosine kinase receptor, e.g., JCAR-024; PRAMET cell receptor, e.g., BPX-701; prostate stem cell antigen modulators, e.g., MB-105; roundabout homolog 1 modulators, e.g., ATCG-427; peptidoglycan recognition protein modulators, e.g., Tag-7 gene-modified autologous tumor cell vaccine; PSMA-CAR T cell therapy (PSMA, e.g., lentiviral vectors, castration-resistant prostate cancer); SLAM family member 7 modulators, e.g., IC9-Luc90-CD828Z; TGF beta receptor modulators, e.g., DNR.NPC These include, but are not limited to, T cells; T lymphocytes, e.g., TT-12; T lymphocyte stimulators, e.g., ATL-001; TSH receptor modulators, e.g., ICTCAR-051; tumor infiltrating lymphocytes, such as LN-144, LN-145; and / or Wilms tumor proteins, such as JTCR-016, WT1-CTL, ASP-7517;

[0226] MCL1 Apoptosis Regulator, BCL2 Family Member (MCL1) Inhibitor In various embodiments, the anti-CD47 or anti-SIRPα agents described herein are combined with an inhibitor of MCL1 apoptosis regulator, BCL2 family member (MCL1, TM; EAT; MCL1L; MCL1S; Mcl-1; BCL2L3; MCL1-ES; bcl2-L-3; mcl1 / EAT; NCBI gene ID: 4170). Examples of MCL1 inhibitors include AMG-176, AMG-397, S-64315, and AZD-5991, 483-LM, A-1210477, UMI-77, JKY-5-037, and those described in WO 2018183418, WO 2016033486, WO 2019222112, and WO 2017147410.

[0227] Cytokine-induced SH2-containing protein (CISH) inhibitors In various embodiments, the agents described herein that inhibit binding between CD47 and SIRPα (e.g., magrolimab) and VEGFA / VEGFR inhibitors (e.g., bevacizumab) are further combined with inhibitors of cytokine-inducible SH2-containing proteins (CISH; CIS; G18; SOCS; CIS-1; BACTS2; NCBI Gene ID: 1154). Examples of CISH inhibitors include those described in WO2017100861, WO2018075664, and WO2019213610.

[0228] Gene Editor In various embodiments, the agents that inhibit the binding between CD47 and SIRPα (e.g., magrolimab) and VEGFA / VEGFR inhibitors (e.g., bevacizumab) described herein are further combined with gene editing agents. Exemplary gene editing systems that can be co-administered include, but are not limited to, CRISPR / Cas9 systems, zinc finger nuclease systems, TALEN systems, homing endonuclease systems (e.g., ARCUS), and homing meganuclease systems.

[0229] Other drugs with unspecified targets In various embodiments, the agents that inhibit the binding between CD47 and SIRPα (e.g., magrolimab) and VEGFA / VEGFR inhibitors (e.g., bevacizumab) described herein are available from Human Immunoglobulin (10% liquid formulation), Cuvitru (Human Immunoglobulin (20% solution), Levofolinate Disodium, IMSA-101, BMS-986288, IMUNO BGC Moreau Further combined with RJ, R-OKY-034F, GP-2250, AR-23, calcium levofolinate, porfimer sodium, RG6160, ABBV-155, CC-99282, polifeprozan 20 with carmustine, Veregen, gadoxetate disodium, gadobutrol, gadoterate meglumine, gadoteridol, 99mTc-sestamibi, pomalidomide, pacibanil, and / or valrubicin.

[0230] Exemplary Combination Therapies In various embodiments, the agents described herein that inhibit the binding between CD47 and SIRPα (e.g., magrolimab) and VEGFA / VEGFR inhibitors (e.g., bevacizumab) are further combined with a standard of care regimen for treating colorectal cancer.

[0231] Therapeutic agents used to treat CRC include bevacizumab, capecitabine, cetuximab, fluorouracil, irinotecan, leucovorin, oxaliplatin, panitumumab, ziv-aflibercept, and any combination thereof. In some embodiments, therapeutic agents used to treat CRC include bevacizumab (AVASTIN®), leucovorin, 5-FU, oxaliplatin (FOLFOX), pembrolizumab (KEYTRUDA®), FOLFIRI, regorafenib (STIVARGA®), aflibercept (ZALTRAP®), cetuximab (ERBITUX®), Lonsurf (ORCANTAS®), XELOX, FOLFOXIRI, or combinations thereof. In some embodiments, therapeutic agents used to treat CRC include bevacizumab + leucovorin + 5-FU + oxaliplatin (FOLFOX), bevacizumab + FOLFIRI, bevacizumab + FOLFOX, aflibercept + FOLFIRI, cetuximab + FOLFIRI, bevacizumab + XELOX, and bevacizumab + FOLFOXIRI. In some embodiments, therapeutic agents used to treat CRC include binimetinib + encorafenib + cetuximab, trametinib + dabrafenib + panitumumab, trastuzumab + pertuzumab, napabucasin + FOLFIRI + bevacizumab, nivolumab + ipilimumab.

[0232] Additional exemplified combination therapies In some embodiments, the agents that inhibit the binding between CD47 and SIRPα (e.g., magrolimab) and VEGFA / VEGFR inhibitors (e.g., bevacizumab) described herein are co-administered with one or more therapeutic agents selected from a PI3K inhibitor, a FLT3R agonist, a PD-1 antagonist, a PD-L1 antagonist, an MCL1 inhibitor, a CCR8 binding agent, an HPK1 antagonist, a DGKα inhibitor, a CISH inhibitor, a PARP-7 inhibitor, a Cbl-b inhibitor, a KRAS inhibitor (e.g., a KRAS G12C or G12D inhibitor), a KRAS degrader, a beta-catenin degrader, a Helios degrader, a CD73 inhibitor, an adenosine receptor antagonist, a TIGIT antagonist, a TREM1 binding agent, a TREM2 binding agent, a CD137 agonist, a GITR binding agent, an OX40 binding agent, and a CAR-T cell therapy.

[0233] In some embodiments, the agents that inhibit the binding between CD47 and SIRPα (e.g., magrolimab) and VEGFA / VEGFR inhibitors (e.g., bevacizumab) described herein are selected from the group consisting of PI3Kδ inhibitors (e.g., idealisib), FLT3L-Fc fusion proteins (e.g., GS-3583), anti-PD-1 antibodies (pembrolizumab, nivolumab, zimblerimab), small molecule PD-L1 inhibitors (e.g., GS-4224), anti-PD-L1 antibodies (e.g., atezolizumab, avelumab), small molecule MCL1 inhibitors (e.g., GS-9716), small molecule HPK1 inhibitors (e.g., GS-6451), HPK1 degraders (PROTACs; e.g., ARV-766), small molecule DGKα inhibitors, small molecule CD73 inhibitors (e.g., quemab, quemliclustat (AB680), anti-CD73 antibodies (e.g., oleculab), dual A2a / A2b adenosine receptor antagonists (e.g., etrumadenant (AB928)), anti-TIGIT antibodies (e.g., tiragolumab, vibostolimab, domvanalimab, AB308), anti-TREM1 antibodies (e.g., PY159), anti-TREM2 antibodies (e.g., PY314), CD137 agonists (e.g., AGEN-2373), GITR / OX40 binders (e.g., AGEN-1223), and CAR-T cell therapy (e.g., axicabtagene siloleucel, brexucabtagene autoleucel, autoleucel, tisagenleucel, and tisagenleucel.

[0234] In some embodiments, the agents that inhibit binding between CD47 and SIRPα (e.g., magrolimab) and VEGFA / VEGFR inhibitors (e.g., bevacizumab) described herein are co-administered with one or more therapeutic agents selected from idealisib, GS-3583, zimblerimab, GS-4224, GS-9716, GS-6451, quemlicustat (AB680), etrumadenant (AB928), domvanalimab, AB308, PY159, PY314, AGEN-1223, AGEN-2373, axicabtadine ciloreucel, and brexcabtadine autoleucel.

[0235] 5. Medication and Scheduling The methods described herein include administration of a therapeutically effective dose of a composition, eg, a therapeutically effective dose of an agent that inhibits binding between CD47 and SIRPα, and a therapeutically effective dose of a VEGFA / VEGFR inhibitor.

[0236] The composition is administered to the patient in an amount sufficient to substantially eliminate the target cells, as described above. An amount sufficient to achieve this is defined as a "therapeutically effective dose" that can provide an improvement in overall survival. The term "therapeutically effective amount" is an amount effective to ameliorate the symptoms of a disease (e.g., cancer as described herein). A therapeutically effective amount can be a "prophylactically effective amount" when prevention is considered a therapy. Single or multiple administrations of the composition can be administered depending on the dosage and frequency required and tolerated by the patient. The particular dose used for treatment can depend on the mammal's condition and medical history, as well as other factors such as age, weight, sex, route of administration, and efficiency.

[0237] In some embodiments, a combination therapeutic amount of an agent that inhibits binding between CD47 and SIRPα as described herein and a VEGFA / VEGFR inhibitor, optionally including one or more additional therapeutic agents as described herein, can (i) reduce the number of diseased cells; (ii) reduce tumor size; (iii) inhibit, suppress, slow to some extent, and preferably stop diseased cell infiltration into peripheral organs; (iv) inhibit (e.g., slow to some extent, and preferably stop) tumor metastasis; (v) inhibit tumor growth; (vi) prevent or delay the appearance and / or recurrence of tumors; and / or (vii) alleviate to some extent one or more of the symptoms associated with cancer or a myeloproliferative disorder. In some embodiments, a combined therapeutic amount of an agent that inhibits binding between CD47 and SIRPα as described herein and a VEGFA / VEGFR inhibitor, optionally with one or more additional therapeutic agents as described herein, can (i) reduce the number of cancer cells; (ii) reduce tumor size; (iii) inhibit, suppress, slow to some extent, and preferably stop cancer cell invasion into peripheral organs; (iv) inhibit (e.g., slow to some extent, and preferably stop) tumor metastasis; (v) inhibit tumor growth; (vi) prevent or delay the appearance and / or recurrence of tumors, and / or (vii) alleviate to some extent one or more symptoms associated with cancer. In various embodiments, the amount is sufficient to ameliorate, alleviate, reduce, and / or delay one or more symptoms of cancer.

[0238] An "increased" or "enhanced" amount (e.g., with respect to cancer cell proliferation or proliferation, anti-tumor response, cancer cell metastasis) refers to an increase that is 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 fold or more (e.g., 100, 500, 1000 fold) (including all integers and decimal points between and above 1, e.g., 2.1, 2.2, 2.3, 2.4, etc.) of the amounts or levels described herein. This can 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.

[0239] A "decreased" or "reduced" or "lesser" amount (e.g., with respect to tumor size, cancer cell proliferation or growth) refers to a decrease that is 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 and above 1 and above, e.g., 1.5, 1.6, 1.7, 1.8, etc.) of the amounts or levels described herein. This can also include a decrease of at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90%, at least 100%, at least 150%, at least 200%, at least 500%, or at least 1000% of the amounts or levels described herein. In various embodiments, tumor burden is determined using a linear dimensional method (e.g., Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 (Eisenhauer, et al., Eur J Cancer. (2009) 45(2):228-47). In various embodiments, tumor burden is determined using a volumetric analysis (e.g., positron emission tomography (PET) / computed tomography (CT) scan). See, e.g., Paydary, et al., Mol Imaging Biol. (2019) 21(1):1-10; Li, et al., AJR Am J Roentgenol. (2021) 217(6):1433-1443; and Kerner, et al., EJNMMI Res. (2016) Dec;6(1):33.

[0240] As used herein, "anti-tumor effect" refers to a biological effect that may be presented 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 increase in overall survival or progression-free survival, an increase in life expectancy, or an improvement in various physiological symptoms associated with a tumor. Anti-tumor effect may also refer to the prevention of tumor onset or recurrence, for example, recurrence after remission.

[0241] The effective dose of the combination agent for the treatment of cancer varies depending on many different factors, including the means of administration, the target site, the physiological condition of the patient, whether the patient is human or animal, other drugs administered, and whether the treatment is prophylactic or therapeutic. Usually, the patient is a human, but non-human mammals, such as companion animals such as dogs, cats, horses, non-human primates, and experimental animals such as rabbits, mice, and rats, can also be treated. The therapeutic dose can be set to optimize safety and efficacy.

[0242] A therapeutically effective dose of an anti-CD47 antibody can depend on the particular agent used, but is typically about 10 mg / kg body weight or more (e.g., about 10 mg / kg or more, about 15 mg / kg or more, about 20 mg / kg or more, about 25 mg / kg or more, about 30 mg / kg or more, about 35 mg / kg or more, about 40 mg / kg or more, about 45 mg / kg or more, about 50 mg / kg or more, or about 55 mg or more, or about 60 mg / kg or more, or about 65 mg or more, or about 70 mg / kg or more), or from about 10 mg / kg, from about 15 mg / kg to about 70 mg / kg (e.g., from about 10 mg / kg to about 67.5 mg / kg, or from about 10 mg / kg, from about 15 mg / kg to about 60 mg / kg).

[0243] In some embodiments, the therapeutically effective dose of the anti-CD47 antibody is 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, or 67.5 mg / kg. In some embodiments, the therapeutically effective dose of the anti-CD47 antibody is 10-60 mg / kg. In some embodiments, the therapeutically effective dose of the anti-CD47 antibody is 10-67.5 mg / kg. In some embodiments, the anti-CD47 antibody is administered at a dose of at least 10-30, 20-30, 15-60, 30-60, 10, 15, 20, 30, 40, 45, 50, or 60 mg of antibody per kg of body weight.

[0244] The therapeutic dose of the anti-CD47 antibody can be a fixed dose. For example, a fixed dose can be administered regardless of the weight of a particular subject. Alternatively, the fixed dose can be given based on the weight of a particular subject within a particular weight range, for example, a first range of 100 kg or less, or a second range of more than 100 kg. The fixed dose can be, for example, 1000-5000, 2000-4000, 2000-3500, 2400-3500, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000, 2100, 2200, 2300, 2400, 2500, 2600, 2700, 2800, 2900, 3000, 3100, 3200, 3300, 3400, 3500, 3600, 3700, 3800, 3900, 4000, 4100, 4200, 4300, 4400, 4500, 4600, 4700, 4800, 4900, 5000, 5100, 5200, 5300, 5400, 5500, 5600, 5700, 5800, 5900, 6000, 6100, 6200, 6300, 6400, 6500, 6600, 6700, 6800, 6900, 7000, 7100, 00, 2800, 2900, 3000, 3100, 3200, 3300, 3400, 3500, 3600, 3700, 3800, 3900, 4000, 4100, 4200, 4300, 4400, 4500, 4600, 4700, 4800, 4900, 5000 mg, or any intermediate number thereof.

[0245] The method may include administering a primer agent to the subject, followed by administering a therapeutically effective dose of anti-CD47 to the subject. In some embodiments, administering the therapeutically effective dose occurs at least about 3 days (e.g., at least about 4 days, at least about 5 days, at least about 6 days, at least about 7 days, at least about 8 days, at least about 9 days, or at least about 10 days) after initiating administration of the primer agent. This period of time is sufficient, for example, to provide enhanced reticulocyte production by the individual. In some embodiments, the anti-CD47 agent is an isolated anti-CD47 antibody.

[0246] Administration of a therapeutically effective dose of anti-CD47 can be achieved in many different ways. In some cases, a primer agent is administered followed by administration of two or more therapeutically effective doses. Suitable administration of a therapeutically effective dose can involve administration of a single dose, or can involve administration of doses daily, twice weekly, weekly, biweekly, monthly, annually, etc. In some cases, a therapeutically effective dose is administered as two or more doses of increasing concentration (i.e., increasing doses), where (i) all of the doses are therapeutic doses, or (ii) a sub-therapeutic dose (or two or more sub-therapeutic doses) are given initially, and a therapeutic dose is achieved by the escalation. As one non-limiting example to illustrate escalating concentrations (i.e., increasing doses), a therapeutically effective dose can be administered weekly, beginning with a sub-therapeutic dose (e.g., a dose less than 10 mg / kg, e.g., 5 mg / kg, 4 mg / kg, 3 mg / kg, 2 mg / kg, or 1 mg / kg), and each subsequent dose can be increased by a particular increment (e.g., 5 mg / kg, 10 mg / kg, 15 mg / kg) or by various increments until a therapeutic dose (e.g., 15 mg / kg, 30 mg / kg, 45 mg / kg, 60 mg / kg) is reached, at which point administration can be stopped or continued with one or more additional therapeutic doses (e.g., a continued therapeutic dose, or an escalating therapeutic dose, e.g., a dose of 15 mg / kg, 30 mg / kg, 45 mg / kg, 60 mg / kg). As another non-limiting example to illustrate escalating concentrations (i.e., increasing doses), a therapeutically effective dose can be administered weekly, beginning with one or more relatively low therapeutic doses (e.g., doses of 10 mg / kg, 15 mg / kg, or 30 mg / kg), with each subsequent dose increasing by a particular increment (e.g., 10 mg / kg or 15 mg / kg) or by various increments until a relatively high therapeutic dose (e.g., 30 mg / kg, 45 mg / kg, 60 mg / kg, 100 mg / kg, etc.) is reached, at which point administration can be stopped or continued (e.g., one or more continued or escalating therapeutic doses, e.g., doses of 30 mg / kg, 45 mg / kg, 60 mg / kg, 100 mg / kg).In various embodiments, a relatively low therapeutic dose is administered more frequently (e.g., two or more doses of 15 mg / kg administered weekly (Q1W) or two or more doses of 30 mg / kg administered every two weeks (Q2W)) and a relatively high therapeutic dose is administered less frequently (e.g., two or more doses of 45 mg / kg administered every three weeks (Q3W) or two or more doses of 60 mg / kg administered monthly or every four weeks (Q4W)). In some embodiments, administration of the therapeutically effective dose may be a continuous infusion, and the dose may be varied (e.g., escalated) over time.

[0247] The dose required to achieve and / or maintain a particular serum level of the administered composition is proportional to the time between doses and inversely proportional to the dose administered. Thus, as the frequency of administration increases, the required dose decreases. Optimization of the administration strategy will be readily understood and performed by those skilled in the art. Exemplary treatment regimens involve administration once every two weeks, or once a month, or once every three to six months. The therapeutics described herein are typically administered multiple times. The interval between single doses can be weeks, months, or years. The intervals can also be irregular as indicated by measuring the blood levels of the therapeutic in the patient. Alternatively, the therapeutics described herein can be administered as sustained release formulations, in which case less frequent administrations are used. The dosage and frequency vary depending on the half-life of the polypeptide in the patient. In some embodiments, the interval between each single dose is one week. In some embodiments, the interval between each single dose is two weeks. In some embodiments, the interval between each single dose is three weeks. In some embodiments, the interval between each single dose is four weeks. In some embodiments, the interval between each single dose of anti-CD47 antibody is 1 week. In some embodiments, the interval between each single dose of anti-CD47 antibody is 2 weeks. In some embodiments, the interval between each single dose of anti-CD47 antibody is 3 weeks. In some embodiments, the interval between each single dose of anti-CD47 antibody is 4 weeks. In some embodiments, the interval between each single dose of magrolimab is 1 week. In some embodiments, the interval between each single dose of magrolimab is 2 weeks. In some embodiments, the interval between each single dose of magrolimab is 3 weeks. In some embodiments, the interval between each single dose of magrolimab is 4 weeks.

[0248] "Maintenance dose" is a dose intended to be a therapeutically effective dose.For example, in an experiment to determine a therapeutically effective dose, multiple different maintenance doses can be administered to different subjects.Therefore, some of the maintenance doses can be therapeutically effective doses, and others can be sub-therapeutic doses.

[0249] In prophylactic applications, relatively low dosages may be administered at relatively infrequent intervals over an extended period of time. Some patients continue to receive treatment for the rest of their lives. In other therapeutic applications, relatively high dosages at relatively short intervals may be used until the progression of the disease is reduced or terminated, preferably until the patient shows partial or complete improvement in the symptoms of the disease. The patient can then be administered a prophylactic regimen.

[0250] The term "priming dose" or "priming dose" as used herein refers to a dose of an anti-CD47 antibody that primes a subject to receive a therapeutically effective dose of the anti-CD47 antibody such that the therapeutically effective dose does not result in severe loss of RBCs (reduction in hematocrit or reduction in hemoglobin). The particular appropriate priming dose of an anti-CD47 antibody may vary depending on the nature of the agent used and a number of subject-specific factors (e.g., age, weight, etc.). Examples of suitable priming doses of an anti-CD47 antibody include about 0.5 mg / kg to about 5 mg / kg, about 0.5 mg / kg to about 4 mg / kg, about 0.5 mg / kg to about 3 mg / kg, about 1 mg / kg to about 5 mg / kg, about 1 mg / kg to about 4 mg / kg, about 1 mg / kg to about 3 mg / kg, about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, and about 5 mg / kg. In some embodiments, the priming dose is preferably 1 mg / kg.

[0251] In some embodiments of the methods described herein, the anti-CD47 antibody is administered to the subject as a priming dose in the range of about 0.5 mg to about 10 mg, e.g., about 0.5 to about 5 mg / kg antibody, optionally 4 mg / kg, 3 mg / kg, 2 mg / kg, or 1 mg / kg antibody. In some embodiments, the anti-CD47 antibody is administered to the subject as a therapeutic dose in the range of about 20 to about 67.5 mg / kg antibody, optionally 15 to 60 mg / kg antibody, optionally 30 to 60 mg / kg antibody, optionally 15 mg / kg antibody, 20 mg / kg antibody, 30 mg / kg antibody, 45 mg / kg antibody, 60 mg / kg antibody, or 67.5 mg / kg antibody.

[0252] The priming dose of the anti-CD47 antibody can be a constant priming dose. For example, the constant priming dose can be administered regardless of the weight of the particular subject. Alternatively, the constant priming dose can be given based on the weight of the particular subject within a particular weight range, for example, a first range of 100 kg or less, or a second range of 100 kg or more. The constant priming dose can be, for example, 10-200, 50-100, 80-800, 80-400, 80-200, 70-90, 75-85, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 240, 300, 320, 400, 500, 600, 700, or 800 mg, or any intermediate number of mg therebetween.

[0253] In some embodiments, an effective priming dose of magrolimab is provided, where an effective priming dose in a human is approximately about 1 mg / kg, e.g., at least about 0.5 mg / kg to a maximum of about 5 mg / kg or less, at least about 0.75 mg / kg to a maximum of about 1.25 mg / kg or less, at least about 0.95 mg / kg to a maximum of about 1.05 mg / kg or less, and can be approximately 1 mg / kg.

[0254] In some embodiments, the initial dose of CD47 or SIRPα binding agent is infused over a period of at least about 2 hours, at least about 2.5 hours, at least about 3 hours, at least about 3.5 hours, at least about 4 hours, at least about 4.5 hours, at least about 5 hours, at least about 6 hours, or more. In some embodiments, the initial dose is infused over a period of about 2.5 hours to about 6 hours, e.g., about 3 hours to about 4 hours. In some such embodiments, the dose of agent in the infusion is about 0.05 mg / ml to about 0.5 mg / ml, e.g., about 0.1 mg / ml to about 0.25 mg / ml.

[0255] In other embodiments, the initial dose, e.g., a priming dose, of the CD47 or SIRPα binding agent is administered by continuous infusion, e.g., an osmotic pump, delivery patch, etc., and the dose is administered over a period of at least about 6 hours, at least about 12 hours, at least about 24 hours, at least about 2 days, at least about 3 days. Many such systems are known in the art. For example, the DUROS technology provides a two-compartment system separated by a piston. One of the compartments consists of an osmotic engine specifically formulated with excess solid NaCl, which is present throughout the delivery period, resulting in a constant osmotic gradient. It also consists of a semipermeable membrane at one end through which water is drawn into the osmotic engine, establishing a large, constant osmotic gradient between the tissue fluid and the osmotic engine. The other compartment consists of a drug solution and has an opening through which the drug is released by the osmotic gradient. This helps provide site-specific and systemic drug delivery when implanted in a human. The preferred site of implantation is subcutaneous placement on the inside of the upper arm.

[0256] Following administration of the priming agent, a therapeutic dose of an anti-CD47 or anti-SIRPα agent is administered, allowing for a period of time effective for increased reticulocyte production. The therapeutic dose can be administered in many different ways. In some embodiments, the priming agent is administered, followed by two or more therapeutically effective doses, for example, on a weekly dosing schedule. In some embodiments, the therapeutically effective dose of the anti-CD47 agent is administered as two or more doses of increasing concentration, while in other embodiments, the doses are the same. Red hemagglutination is reduced after the priming dose.

[0257] The therapeutically effective dose of an anti-SIRPα antibody can depend on the particular agent used, but is typically about 10 mg or more, e.g., about 30 mg, 50 mg, 100 mg, 200 mg, 400 mg, or 800 mg or more. For example, multiple administrations of an anti-SIRPα antibody that does not have Fc effector function can be administered at regular intervals, e.g., every 2 weeks (Q2W), every 3 weeks (Q3W), every 4 weeks (Q4W), over an extended period of time, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 months.

[0258] With regard to dosing of the VEGFA / VEGFR inhibitor (e.g., bevacizumab), in some embodiments, bevacizumab is administered at one or more doses ranging from 5 mg / kg to 15 mg / kg, e.g., 5 mg / kg to 7.5 mg / kg, or 7.5 mg / kg to 15 mg / kg. In some embodiments, the VEGFA / VEGFR inhibitor (e.g., bevacizumab) is administered at one or more doses of 5 mg / kg.

[0259] In some embodiments, magrolimab is administered initially at a priming dose of 1 mg / kg, then at one or more therapeutic doses of 30 mg / kg, followed by one or more therapeutic doses of 60 mg / kg. In some embodiments, magrolimab is administered initially at a priming dose of 1 mg / kg, then at one or more therapeutic doses of 20 mg / kg, followed by one or more therapeutic doses of 45 mg / kg. In some embodiments, magrolimab is administered initially at a priming dose of 1 mg / kg, then at one or more therapeutic doses of 15 mg / kg, followed by one or more therapeutic doses of 30 mg / kg.

[0260] In some embodiments, magrolimab and bevacizumab are administered for a first, second, and third 28 day cycle; a) in a first 28 day cycle, magrolimab is administered at a dose of 1 mg / kg on day 1 and 30 mg / kg weekly (QW) beginning on day 8, and bevacizumab is administered at a dose of 5 mg / kg on days 1 and 15; b) in a second 28 day cycle, magrolimab is administered at a dose of 30 mg / kg every week (QW) and bevacizumab is administered at a dose of 5 mg / kg on days 1 and 15; c) In the third 28-day cycle, magrolimab is administered at a dose of 30 mg / kg Q2W and bevacizumab is administered at a dose of 5 mg / kg on days 1 and 15.

[0261] In some embodiments, magrolimab and bevacizumab are administered for a first, second, and third 28 day cycle; a) in a first 28 day cycle, magrolimab is administered at a dose of 1 mg / kg on day 1 and 20 mg / kg weekly (QW) beginning on day 8; bevacizumab is administered at a dose of 5 mg / kg on days 1 and 15; b) in a second 28 day cycle, magrolimab is administered at a dose of 20 mg / kg every week (QW) and bevacizumab is administered at a dose of 5 mg / kg on days 1 and 15; c) In the third 28-day cycle, magrolimab is administered at a dose of 20 mg / kg Q2W and bevacizumab is administered at a dose of 5 mg / kg on days 1 and 15.

[0262] In some embodiments, magrolimab and bevacizumab are administered for a first, second, and third 28 day cycle; a) in a first 28 day cycle, magrolimab is administered at a dose of 1 mg / kg on day 1 and 15 mg / kg weekly (QW) beginning on day 8, and bevacizumab is administered at a dose of 5 mg / kg on days 1 and 15; b) in a second 28 day cycle, magrolimab is administered at a dose of 15 mg / kg every week (QW) and bevacizumab is administered at a dose of 5 mg / kg on days 1 and 15; c) In the third 28-day cycle, magrolimab is administered at a dose of 15 mg / kg Q2W and bevacizumab is administered at a dose of 5 mg / kg on days 1 and 15.

[0263] In some embodiments, the agent that inhibits binding between CD47 and SIRPα and the VEGFA / VEGFR inhibitor are administered in a combined synergistic amount. As used herein, a "combined synergistic amount" refers to the sum of a first amount (e.g., the amount of the agent that inhibits binding between CD47 and SIRPα) and a second amount (e.g., the amount of the VEGFA / VEGFR inhibitor) that results in a synergistic effect (i.e., an effect that is greater than additive). Thus, the terms "synergy," "synergistic," "synergistic," "combined synergistic amount," and "synergistic therapeutic effect," which are used interchangeably herein, refer to a measured effect of the compounds administered in combination that is greater than the sum of the individual effects of each compound administered alone as a single agent.

[0264] Co-administration of an agent that inhibits binding between CD47 and SIRPα and a VEGFA / VEGFR inhibitor can allow for lower dosages of one or both therapeutic agents. In embodiments, a synergistic amount can be about 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% of the amount of the agent that inhibits binding between CD47 and SIRPα when used separately from the VEGFA / VEGFR inhibitor. In embodiments, a synergistic amount can be about 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% of the amount of a VEGFA / VEGFR inhibitor when used separately from the agent that inhibits binding between CD47 and SIRPα.

[0265] Dosage and frequency may vary depending on the half-life of the therapeutic agent in the patient. One of skill in the art will appreciate that such guidelines are adjusted for the molecular weight of the active agent, for example, in the use of antibody fragments, in the use of antibody conjugates, in the use of SIRPα reagents, in the use of soluble CD47 peptides, and the like. Dosage may also vary as needed for local administration, e.g., intranasal, inhalation, and the like, or systemic administration, e.g., intramuscular (im), intraperitoneal (ip), intravenous (iv), subcutaneous (sc), intratumoral, intracranial, and the like. In some embodiments, the agent that inhibits binding between CD47 and SIRPα and the VEGFA / VEGFR inhibitor are administered simultaneously. In some embodiments, the agent that inhibits binding between CD47 and SIRPα and the VEGFA / VEGFR inhibitor are administered sequentially. For example, the agent that inhibits binding between CD47 and SIRPα described herein may be administered within seconds, minutes, hours, or days of administration of a VEGFA / VEGFR inhibitor. In some embodiments, a unit dose of an agent that inhibits binding between CD47 and SIRPα is administered first, followed within seconds, minutes, hours, or days by a unit dose of a VEGFA / VEGFR inhibitor. Alternatively, a unit dose of a VEGFA / VEGFR inhibitor is administered first, followed within seconds, minutes, hours, or days by a unit dose of an agent that inhibits binding between CD47 and SIRPα. In other embodiments, a unit dose of an agent that inhibits binding between CD47 and SIRPα is administered first, followed within hours (e.g., 1-12 hours, 1-24 hours, 1-36 hours, 1-48 hours, 1-60 hours, 1-72 hours) by administration of a unit dose of a VEGFA / VEGFR inhibitor. In yet other embodiments, a unit dose of a VEGFA / VEGFR inhibitor is administered first, followed several hours (e.g., 1-12 hours, 1-24 hours, 1-36 hours, 1-48 hours, 1-60 hours, 1-72 hours) later by administration of an agent that inhibits binding between CD47 and SIRPα.

[0266] 6. Condition receiving treatment Methods of treating, ameliorating, alleviating, or preventing or delaying recurrence or metastasis of colorectal cancer (CRC) in a subject are provided, comprising administering to the subject (a) an agent that inhibits binding between CD47 and SIRPα, and (b) a VEGFA / VEGFR inhibitor. In various embodiments, the CRC is an adenocarcinoma, gastrointestinal carcinoid tumor, primary colorectal lymphoma, squamous cell carcinoma, gastrointestinal stromal tumor (GIST), leiomyosarcoma, or melanoma. In some embodiments, the CRC is a familial or hereditary colorectal cancer, such as hereditary nonpolyposis colorectal cancer (HNPCC) or familial adenomatous polyposis (FAP). Other types of colorectal cancer that can be treated by the methods described herein include, for example, Turcot's syndrome, Peutz-Jeghers syndrome (PJS), Familial Colorectal Cancer (FCC), and Juvenile Polyposis Coli. In some embodiments, the subject is a human.

[0267] As used herein, "treatment" or "treating" is an approach to obtain beneficial or desired results, including clinical results. For example, beneficial or desired clinical results may include one or more of the following: (i) reducing another symptom caused by the disease, (ii) reducing the extent of the disease and stabilizing the disease (e.g., preventing or delaying the worsening of the disease), (iii) preventing or delaying the spread of the disease (e.g., metastasis), (iv) preventing or delaying the onset or recurrence of the disease, delaying or slowing the progression of the disease, (v) improving the disease state, providing remission (partial or total) of the disease, reducing the dose of one or more other drugs required to treat the disease, (vi) delaying the progression of the disease and improving the quality of life, and / or (vii) prolonging survival. Beneficial or desired clinical results may be observed in more patients or subjects who have undergone the methods or treatments described herein.

[0268] In various embodiments, the methods described herein are directed to treating, ameliorating, alleviating, reducing, preventing, or delaying recurrence or metastasis of colorectal cancer (CRC), e.g., metastatic CRC, e.g., inoperable CRC, e.g., CRC that has progressed after at least one prior treatment. In some embodiments, the cancer has progressed after at least one prior anti-cancer therapy. In some embodiments, the cancer has progressed after at least one prior anti-cancer therapy selected from anti-VEGFA therapy (e.g., bevacizumab, aflibercept), a chemotherapy regimen comprising a platinum coordination complex (e.g., FOLFOX (folinic acid, 5-fluorouracil, oxaliplatin); FOLFIRI (folinic acid, 5-fluorouracil, irinotecan); FOLFOXIRI (folinic acid, 5-fluorouracil, oxaliplatin, irinotecan), FOLFIRINOX (folinic acid, 5-fluorouracil, irinotecan, oxaliplatin), XELIRI (capecitabine, irinotecan), XELOXIRI (capecitabine, oxaliplatin, irinotecan)), a platinum coordination complex therapy (e.g., cisplatin, oxiloplatin, and carboplatin), an immune checkpoint inhibitor therapy (e.g., anti-PD1 antibody therapy or anti-PD-L1 antibody therapy). In some embodiments, the CRC has progressed following therapy with one or more of the following therapies in the absence of magrolimab: bevacizumab, capecitabine, cetuximab, fluorouracil, irinotecan, leucovorin, oxaliplatin, panitumumab, ziv-aflibercept, and any combination thereof. In some embodiments, the therapeutic agents used to treat CRC include bevacizumab (AVASTIN®), leucovorin, 5-FU, oxaliplatin (FOLFOX), pembrolizumab (KEYTRUDA®), FOLFIRI, regorafenib (STIVARGA®), aflibercept (ZALTRAP®), cetuximab (ERBITUX®), Lonsurf (ORCANTAS®), XELOX, FOLFOXIRI, or combinations thereof.In some embodiments, therapeutic agents used to treat CRC include bevacizumab + leucovorin + 5-FU + oxaliplatin (FOLFOX), bevacizumab + FOLFIRI, bevacizumab + FOLFOX, aflibercept + FOLFIRI, cetuximab + FOLFIRI, bevacizumab + XELOX, and bevacizumab + FOLFOXIRI. In some embodiments, therapeutic agents used to treat CRC include binimetinib + encorafenib + cetuximab, trametinib + dabrafenib + panitumumab, trastuzumab + pertuzumab, napabucasin + FOLFIRI + bevacizumab, nivolumab + ipilimumab.

[0269] In various embodiments, the CRC is classified as stage I, i.e., according to the TNM classification system. In various embodiments, the CRC is classified as stage II (e.g., IIA, IIB, or IIC), i.e., according to the TNM classification system. In various embodiments, the CRC is classified as stage III (e.g., IIIA, IIIB, or IIIC), i.e., according to the TNM classification system. In various embodiments, the CRC is classified as stage IV (e.g., IVA, IVB, or IVC), i.e., according to the TNM classification system. See Delattre, et al., Cancer Treat Rev. (2022) Feb; 103: 102325.

[0270] In some embodiments, the subject is treatment-naive, i.e., administration of a combination of an agent that inhibits binding between CD47 and SIRPα (e.g., magrolimab) and a VEGFA / VEGFR inhibitor (e.g., bevacizumab) is a first-line cancer therapy.

[0271] "Prevention" or "preventing" refers to any treatment (i.e., medication, drug, treatment) of a disease or condition (i.e.,) that does not cause the clinical symptoms of the disease or condition to develop. In some embodiments, the compounds may be administered to subjects (including humans) who are at risk or have a family history of the disease or condition.

[0272] "Delaying" the onset of cancer means to postpone, hinder, delay, prevent, stabilize, and / or postpone the onset of the disease. The delay can be of various lengths of time, depending on the disease being treated and / or the subject's medical history. As will be appreciated by those skilled in the art, a sufficient or significant delay can, in effect, encompass prevention, in that the individual does not develop the disease. A method of "delaying" the onset of cancer is one that reduces the probability of disease onset in a given time frame and / or reduces the extent of disease in a given time frame, compared to the absence of the method. Such comparisons are typically based on clinical studies using a statistically significant number of subjects. Onset of disease may be detectable using standard methods, such as routine physical examination, blood sampling, mammography, imaging, or biopsy. Onset may also be initially undetectable and may refer to disease progression, including emergence, recurrence, and onset.

[0273] The term "amelioration" refers to any therapeutically beneficial outcome in the treatment, including prevention, reduction in the severity or progression, remission, or cure of a disease state, e.g., a cancer disease state.

[0274] 7. Kit Also described herein are kits that include one or more unit doses of an active agent described herein, such as an agent that inhibits binding between CD47 and SIRPα (e.g., magrolimab) and a VEGFA / VEGFR inhibitor (e.g., bevacizumab), as well as formulations thereof, and instructions for use. In various embodiments, the agent that inhibits binding between CD47 and SIRPα and the VEGFA / VEGFR inhibitor may be in the same or different containers. The kit can further contain at least one additional reagent, e.g., an agent for a chemotherapy regimen (e.g., FOLFOX (folinic acid, 5-fluorouracil, oxaliplatin); FOLFIRI (folinic acid, 5-fluorouracil, irinotecan); FOLFOXIRI (folinic acid, 5-fluorouracil, oxaliplatin, irinotecan), FOLFIRINOX (folinic acid, 5-fluorouracil, irinotecan, oxaliplatin), XELIRI (pecitabine, irinotecan), XELOXIRI (pecitabine, oxaliplatin, irinotecan), an immune checkpoint inhibitor. The kit typically includes a label indicating the intended use of the contents of the kit. The term label includes any written or recorded material affixed to or supplied with the kit, or which otherwise accompanies the kit.

[0275] In some embodiments, one or both of the agent that inhibits binding between CD47 and SIRPα (e.g., magrolimab) and the VEGFA / VEGFR inhibitor (e.g., bevacizumab) are provided in a dosage form (e.g., a therapeutically effective dosage form). In some embodiments, one or both of the agent that inhibits binding between CD47 and SIRPα (e.g., magrolimab) and the VEGFA / VEGFR inhibitor (e.g., bevacizumab) are provided in two or more different dosage forms (e.g., two or more different therapeutically effective dosage forms). In the context of a kit, one or both of the agent that inhibits binding between CD47 and SIRPα (e.g., magrolimab) and the VEGFA / VEGFR inhibitor (e.g., bevacizumab) can be provided in liquid or solid form in any convenient packaging (e.g., stick pack, dose pack, etc.).

[0276] The agent that inhibits the binding between CD47 and SIRPα (e.g., magrolimab) and the VEGFA / VEGFR inhibitor (e.g., bevacizumab) may be provided in the same or separate containers, as appropriate. In various embodiments, the agent that inhibits the binding between CD47 and SIRPα (e.g., magrolimab) and the VEGFA / VEGFR inhibitor (e.g., bevacizumab) are provided in separate containers. One or both of the agent that inhibits the binding between CD47 and SIRPα (e.g., magrolimab) and the VEGFA / VEGFR inhibitor (e.g., bevacizumab) are provided in one or more containers, and the containers have labels. Suitable containers include, for example, bottles, vials, ampoules, syringes (including pre-filled syringes), and test tubes. The containers can be formed from a variety of materials, such as glass or plastic. The container holds a composition effective for treating a condition and may have a sterile access port (e.g., the container may be an intravenous solution bag or a vial having a stopper pierceable by a hypodermic needle). The active agent in one composition is an agent that inhibits binding between CD47 and SIRPα (e.g., an anti-CD47 antibody, e.g., magrolimab). The active agent in the second composition is a VEGFA / VEGFR inhibitor (e.g., bevacizumab). A label on or associated with the container indicates that the composition is used for treating a selected condition. The article of manufacture may further comprise one or more containers containing, e.g., a pharmaceutically acceptable buffer for use as a diluent. Exemplary buffers include, but are not limited to, phosphate buffered saline, Ringer's solution, and / or dextrose solution. The kit may further include other materials desirable from a commercial and user standpoint, including other buffers, diluents, filters, needles, syringes, and package inserts containing instructions for use.

[0277] In various embodiments, the kits of the invention comprise a primer agent (e.g., an erythropoiesis-stimulating agent (ESA)) and an anti-CD47 agent. In some embodiments, the kits comprise two or more primer agents. In some embodiments, the kits comprise two or more anti-CD47 agents. In some embodiments, the primer agent is provided in a dosage form (e.g., a priming dosage form). In some embodiments, the primer agent is provided in two or more different dosage forms (e.g., two or more different priming dosage forms).

[0278] In addition to the above components, the subject kits may further include (in certain embodiments) instructions for carrying out the subject methods. These instructions may be present in the subject kits in a variety of forms, one or more of which may be present in the kit. One form in which these instructions may be present is as information printed on a suitable medium or substrate, e.g., paper on which the information is printed, such as in the kit packaging, in a package insert, etc. Yet another form in which these instructions may be present is a computer readable medium, such as a diskette, compact disk (CD), flash drive, etc., on which the information is recorded. Yet another form in which these instructions may be present is a website address that may be used via the Internet to access the information at the removed site. EXAMPLES

[0279] The following examples are offered to illustrate, but not to limit, the claimed invention. Example 1 A Phase 2, Randomized, Open-Label Study to Evaluate the Safety and Efficacy of Magrolimab in Combination with Bevacizumab and FOLFIRI Versus Bevacizumab and FOLFIRI in Previously Treated Advanced Inoperable Metastatic Colorectal Cancer (mCRC)

[0280] Objectives and Evaluation Items Table 1 shows the study objectives and evaluation items. [Table 1]

[0281] research design A schematic diagram of the study is provided in Figure 1.

[0282] This is a phase 2, randomized, open-label, multicenter study to evaluate magrolimab in combination with bevacizumab and FOLFIRI in previously treated patients with progressive inoperable mCRC who have progressed after one prior systemic therapy and do not harbor BRAF V600E mutation or high microsatellite instability (MSI-H).

[0283] The study will involve two cohorts:

[0284] Safety validation cohort: Magrolimab in combination with bevacizumab and FOLFIRI in previously treated patients with progressive inoperable mCRC.

[0285] Following completion of the safety cohort, the randomization cohort will be open for enrollment.

[0286] Randomized cohort: Maglolimab in combination with bevacizumab and FOLFIRI (experimental arm A) versus bevacizumab and FOLFIRI (control arm B) in previously treated patients with progressive inoperable mCRC.

[0287] Safety cohort: Initially, six patients will be enrolled in a safety cohort at the starting dose level. There will be a 28-day DLT evaluation period.

[0288] No dose-dependent toxicity was observed with magrolimab, but to maintain the effective dose of the combination partner drug, dose tapering for magrolimab will be performed as follows: If 2 or less of 6 DLT-evaluable patients experience a DLT in the first 28 days, enrollment into the randomized cohort will begin at this dose level as the RP2D. If more than two patients experience at least one DLT during the first 28 days, enrollment at the current dose level will be immediately stopped and dose tapers will occur. Up to six other patients will then be enrolled and evaluated in the same manner at the lower dose level. Once the RP2D is determined, the sponsor will open the randomization cohorts.

[0289] Approximately 6 patients will be enrolled in the safety cohort. Additional patients may be added to the safety cohort or enrolled in the dose taper cohort.

[0290] Dose-Limiting Toxicity (DLT) Evaluation Period for the Safety Cohort: The DLT evaluation period is the first 28 days and applies to the safety cohort. Patients are considered evaluable for evaluation of DLT if any of the following criteria are met during the DLT evaluation period: Patients experienced a DLT at any time after the start of the first infusion of magrolimab. Patients will not experience DLTs and will complete at least three infusions of magrolimab and at least two doses of bevacizumab and FOLFIRI in the safety cohort.

[0291] If a patient experiences a DLT during the DLT evaluation period, the patient will discontinue treatment. Patients who are not evaluable for DLT evaluation in the safety cohort will be replaced.

[0292] Randomized cohort: Once the safety confirmation cohort is completed and the RP2D of magrolimab in combination with bevacizumab and FOLFIRI is determined, the sponsor will open the randomized cohort. In this open-label, randomized, two-arm study, patients with mCRC will be randomized in a 2:1 ratio to receive either magrolimab in combination with bevacizumab and FOLFIRI (experimental arm A) or bevacizumab and FOLFIRI (control arm B). The primary efficacy assessment is investigator-assessed PFS, with the primary analysis occurring after 85 PFS events. Randomization stratification factors include: (1) Kirsten rat sarcoma (KRAS) mutation vs. wild-type status, (2) geographic region (United States [US] vs. European Union [EU] / Rest of the World [ROW]), and (3) presence vs. absence of liver metastases.

[0293] Duration of treatment All patients will continue on study treatment unless they meet study treatment discontinuation criteria. Survival follow-up will be conducted via telephone every 2 months until death or end of study. The duration of survival follow-up will be limited to 3 years.

[0294] Target population Previously treated patients with progressive inoperable mCRC who have progressed after one prior systemic therapy and do not harbor BRAF V600E mutation or MSI-H. Patients with mismatch repair deficiency will be excluded. However, patients may be included regardless of KRAS mutation status. Magrolimab's mechanism of action is believed to favor development in both KRAS wild-type and mutant settings. Data from the 5F9004 study (i.e., NCT02953782) did not identify any subpopulations that would specifically benefit from magrolimab. KRAS-mutated CRC is present in 45% of patients, portends poor prognosis, and is difficult to target.

[0295] Diagnosis and main eligibility criteria: Inclusion criteria All patients must meet all of the following inclusion criteria to be eligible to participate in this study. 1) The patient provides informed consent. 2) Patients were willing and able to comply with the visits and procedures outlined in the study protocol. 3) Male or female, at least 18 years of age. 4) Previously treated patients with inoperable mCRC who have progressed on or after one prior systemic therapy and are ineligible for checkpoint inhibitor therapy (checkpoint inhibitor-eligible patients defined as MSI-H or mismatch repair deficient (dMMR) are excluded). Note: Maintenance therapy does not count as a separate treatment option. 5) At least 3 weeks of chemotherapy- and bevacizumab-free (if applicable). 6) Histologically or cytologically confirmed adenocarcinoma of the colon or rectum origin (excluding appendix and anal canal cancer), in the setting where curative resection is not indicated, that has progressed on or after one prior systemic therapy. This therapy must have included 5-fluorouracil (5-FU)-based chemotherapy with oxaliplatin and either bevacizumab, or bevacizumab or cetuximab or panitumumab for patients with RAS wild-type and left-sided tumors. 7) Measurable disease (at least one measurable metastatic lesion by RECIST V1.1 criteria and the lesion is not located in a previous radiation field). Previously irradiated lesions can only be considered measurable disease if disease progression has been clearly documented at that site since irradiation. 8) Patients must have an ECOG performance status of 0 or 1. 9) Life expectancy of at least 12 weeks. 10) Laboratory test values, blood cell counts: Hemoglobin (Hb) must be ≥ 9 g / dL prior to first dose of study treatment. Note: Transfusions are allowed to meet Hb eligibility. b. At least 1.5 × 10 9 Absolute neutrophil count in / L c. At least 100 × 10 9 / L of platelets 11) Adequate liver function as demonstrated by: a. AST ≤2.5 × ULN, or ≤5 × ULN in patients with liver metastases b. ALT ≤2.5×ULN, or ≤5×ULN in patients with liver metastases c. Bilirubin ≤ 1.5 x ULN, or 3.0 x ULN and predominantly unconjugated if patient has documented history of Gilbert syndrome or genetic equivalent. 12) Patients must have adequate renal function demonstrated by a creatinine clearance of at least 30 mL / min (calculated by the Cockcroft Gault formula). 13) Pretreatment blood crossmatch has been completed. 14) Male and female patients of childbearing potential who engage in heterosexual intercourse must agree to use the contraceptive method specified in the protocol.

[0296] Exclusion criteria Patients who meet any of the following exclusion criteria should not be enrolled in the study. 1) Prior anticancer therapy, including chemotherapy, hormonal therapy, or investigational agent, within 3 weeks or at least 4 half-lives (up to 4 weeks, whichever is shorter) prior to magrolimab dosing. 2) Known BRAF V600E or MSI-H mutation or dMMR. 3) Persistent grade 2 or greater gastrointestinal bleeding. 4) Patients who received a dose escalation scheme (eg, LV / 5-FU and bevacizumab followed by FOLFOX or FOLFIRI and bevacizumab) and / or patients who were intolerant to bevacizumab. 5) Patients who had previously received irinotecan therapy. 6) Patients with no prior bevacizumab treatment for colorectal cancer. 7) Patients with known allergy or hypersensitivity to monoclonal antibodies (bevacizumab, magrolimab), or Chinese hamster ovary cell products, or any other humanized or recombinant antibodies, or any other investigational chemotherapy, and their excipients. 8) Clinically significant coronary artery disease or myocardial infarction within 6 months prior to enrollment. 9) Peripheral neuropathy greater than grade 1 (CTCAE version 5.0). 10) Known dihydropyrimidine dehydrogenase deficiency. 11) History of acute bowel obstruction or subobstruction, inflammatory bowel disease, or extensive small bowel resection. Presence of a colonic prosthesis. 12) Non-healing wounds, active gastric or duodenal ulcers, or fractures. 13) History of abdominal fistula, tracheo-esophageal fistula, any other grade 4 gastrointestinal perforation, non-digestive fistula, or intraperitoneal abscess within 6 months prior to screening. 14) Poorly controlled arterial hypertension (systolic pressure >150mmHg and / or diastolic pressure >100mmHg) with or without antihypertensive medication. 15) History of hypertensive crisis or hypertensive encephalopathy. 16) Thromboembolic events (e.g., transient ischemic stroke, stroke, subarachnoid hemorrhage) in the 6 months prior to enrollment, excluding peripheral deep vein thrombosis treated with anticoagulants. 17) Positive serum pregnancy test. 18) Breastfeeding women. 19) Active central nervous system (CNS) disease. Patients with asymptomatic, stable treated CNS disease (radiation and / or surgery and / or other CNS-directed therapy who have not received corticosteroids for at least 4 weeks) are permitted. 20) RBC transfusion dependent, defined as needing more than 2 packed RBC transfusions in the 4 weeks prior to screening. RBC transfusions are permitted during the screening period and prior to enrollment to meet Hb inclusion criteria. 21) History of hemolytic anemia, autoimmune thrombocytopenia, or Evans syndrome within the past 3 months. 22) Known hypersensitivity to the study drug, metabolites, or any of the formulation excipients. 23) Prior treatment with a CD47 or signal regulatory protein alpha targeting agent. 24) Current participation in another interventional clinical study. 25) Known inherited or acquired bleeding disorder. 26) Any significant disease or medical condition, as assessed by the investigator and sponsor, that would substantially increase the risk-benefit ratio of participation in the study, including, but not limited to, acute myocardial infarction within the past 6 months, unstable angina pectoris, poorly controlled diabetes mellitus, significant active infection, and congestive heart failure New York Heart Association class III or IV. 27) Secondary malignancies, excluding treated basal cell or localized squamous cell skin cancer, localized prostate cancer, or other malignancies in which the patient is not receiving active anticancer therapy and has been in complete remission for more than 2 years. 28) Known active or chronic hepatitis B or C infection or HIV infection in medical history. 29) Uncontrolled pleural effusion. 30) Uncontrolled hypercalcemia (ionized calcium >1.5 mmol / L) or symptomatic hypercalcemia requiring continued use of bisphosphonate therapy. 31) Poorly controlled tumor-related pain. 32) Severe / critical systemic infection within 4 weeks of randomization.

[0297] Note: Focal non-CNS radiation therapy, prior hormonal therapy with luteinizing hormone-releasing hormone agonists for breast cancer, and treatment with bisphosphonates and receptor activator of nuclear factor kappa B ligand (RANKL) inhibitors are not exclusion criteria. There is no minimum washout period required for these therapies. Patients should recover from the effects of radiation.

[0298] FOLFIRI as a chemotherapy backbone The decision to incorporate FOLFIRI was based on biology / MOA, treatment landscape, as well as standard of care (SOC) in advanced colorectal cancer. FOLFIRI is the preferred chemotherapy backbone in second-line mCRC in the United States and is used interchangeably with FOLFOX in the European Union (EU). Fluorouracil, a fluoropyrimidine, has been reported to alleviate immunosuppression by reducing myeloid-derived immunosuppressive cells such as myeloid-derived suppressor cells. Irinotecan has also been shown to upregulate the expression of immunogenic cell death markers and promote phagocytosis of tumor cells by phagocytes (Pozzi, et al., Nat Med (2016) 22(6):624-31).

[0299] The data presented herein are consistent with the conclusion that irinotecan was more effective than oxaliplatin in increasing cell surface expression of prophagocytic receptors and promoting phagocytosis of colorectal cancer cells, regardless of their mutational profile (Figure 2). CRC cells treated with irinotecan were also more likely to undergo growth inhibition (Figure 3). In immunocompromised mice bearing subcutaneous HT-29 tumors, the combination of magrolimab and irinotecan provided superior tumor growth control compared to magrolimab and oxaliplatin (Figure 4). These findings support the use of FOLFIRI as a chemotherapy backbone for magrolimab.

[0300] Medication and Administration The magrolimab dosing regimens for the safety and randomized cohorts are shown in Tables 2 and 3. [Table 2] FOLFIRI = 5-fluorouracil, irinotecan, and leucovorin; IV = intravenous, QW = weekly, Q2W = every 2 weeks a) Bevacizumab should be administered according to standard of care and / or institutional guidelines. Recommendations include administering the first dose within 60-90 minutes. If well tolerated, subsequent infusions may be administered within 10-30 minutes. b) FOLFIRI should be administered according to standard of care and / or institutional guidelines, as detailed in the table. [Table 3] FOLFIRI = 5-fluorouracil, irinotecan, and leucovorin; IV = intravenous, QW = weekly, Q2W = every 2 weeks, RP2D = recommended phase 2 dose. a) Bevacizumab should be administered according to standard of care and / or institutional guidelines. Recommendations include administering the first dose within 60-90 minutes. If well tolerated, subsequent infusions may be administered within 10-30 minutes. b) FOLFIRI should be administered according to standard of care and / or institutional guidelines, as detailed in the table.

[0301] It is understood that the examples and embodiments described herein are for illustrative purposes only, and that various modifications or changes in light thereof will be suggested to those skilled in the art and are to be included within the spirit and scope of this application and the scope of the appended claims. All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety for all purposes.

Claims

1. 1. A method of treating previously treated progressive inoperable metastatic colorectal cancer in a subject, comprising administering to the subject an effective amount of a) an agent that inhibits the binding between CD47 and SIRPα, and b) co-administering an agent that inhibits binding between vascular endothelial growth factor A (VEGFA) and one or more VEGFA cognate receptors.

2. 2. The method of claim 1, wherein the one or more VEGFA cognate receptors are selected from fms-related receptor tyrosine kinase 1 (FLT1, also known as VEGFR1) and kinase insert domain receptor (KDR, also known as VEGFR2).

3. 3. The method of claim 1 or 2, further comprising concurrently administering a chemotherapy regimen.

4. 4. The method of claim 3, comprising concurrently administering a FOLFOX regimen, a FOLFIRI regimen, a XELIRI (also known as CAPIRI) regimen, a FOLFOXIRI regimen, a XELOXIRI regimen, or a FOLFIRINOX regimen.

5. 5. The method of claim 3 or 4, comprising concurrently administering a FOLFIRI regimen or a XELIRI regimen.

6. The method of any one of claims 1 to 5, wherein the cancer has cell surface expression of CD47.

7. The method of any one of claims 1 to 6, wherein the cancer does not contain a BRAF V600E mutation.

8. The method of any one of claims 1 to 7, wherein the cancer does not contain high microsatellite instability.

9. The method of any one of claims 1 to 8, wherein the cancer has one or more KRAS mutations and the subject has not responded to anti-EGFR antibody therapy.

10. The method of any one of claims 1 to 9, wherein the cancer is an adenocarcinoma of colon or rectal origin.

11. The method of any one of claims 1 to 10, wherein the cancer has progressed after one or more prior systemic therapies.

12. 12. The method of claim 11, wherein the one or more prior therapies comprise administration of one or more agents selected from the group consisting of 5-fluorouracil (5-FU), oxaliplatin, bevacizumab, cetuximab, and panitumumab.

13. 13. The method of any one of claims 1-12, wherein the treatment results in a reduction in total tumor burden of at least 15%, at least 20%, at least 30%, or at least 40% as determined using a linear dimensional method (e.g., RECIST v1.1).

14. The method of any one of claims 1 to 13, comprising reducing the size or eliminating metastases.

15. The method of any one of claims 1 to 14, wherein the agent that inhibits the binding between CD47 and SIRPα comprises an antibody that binds to CD47.

16. 16. The method of claim 15, wherein the antibody that binds to CD47 is selected from magrolimab, lemzoparlimab, retaplimab, ligufalimab, AO-176, simlidarlimab (IBI-322), gentulizumab, ZL-1201, IMC-002, SRF-231, CC-90002 (also known as INBRX-103), NI-1701 (also known as TG-1801), and STI-6643.

17. The method of any one of claims 1 to 14, wherein the agent that inhibits the binding between CD47 and SIRPα comprises an antibody that binds to SIRPα.

18. The method of claim 15, wherein the antibody that binds to SIRPα is selected from GS-0189 (also known as FSI-189), CC-95251, BI-765063, and APX-700.

19. The method of any one of claims 1 to 14, wherein the agent that inhibits the binding between CD47 and SIRPα comprises a SIRPα-Fc fusion protein.

20. 20. The method of claim 19, wherein the SIRPα-Fc fusion protein is selected from evolupercept (ALX-148), timdalpacept, TTI-621, TTI-622, JMT601 (CPO107), and SL-172154.

21. The method of any one of claims 1 to 20, wherein the agent that inhibits binding between VEGFA and one or more VEGFA cognate receptors comprises an antibody that binds to VEGFA.

22. 22. The method of claim 21, wherein the antibody that binds to VEGFA is selected from bevacizumab, ranibizumab, brolucizumab, ibonesimab, sevacizumab, and faricimab.

23. The method of any one of claims 1 to 20, wherein the agent that inhibits binding between VEGFA and one or more VEGFA cognate receptors comprises an antibody that binds to VEGFR2.

24. 24. The method of claim 23, wherein the antibody that binds to VEGFR2 is ramucirumab.

25. The method of any one of claims 1 to 20, wherein the agent that inhibits binding between VEGFA and one or more VEGFA cognate receptors comprises a VEGFA-Fc fusion protein.

26. 26. The method of claim 25, wherein the VEGFA-Fc fusion protein is selected from conbercept and aflibercept.

27. The method of any one of claims 1 to 20, wherein the agent that inhibits binding between VEGFA and one or more VEGFA cognate receptors comprises a small molecule inhibitor.

28. 28. The method of claim 27, wherein the small molecule is selected from surufatinib, catequintinib hydrochloride, fruquintinib, tivozanib, regorafenib, axitinib, vandetanib, chiauranib, pazopanib hydrochloride, sunitinib malate, and pegaptanib octasodium.

29. The method of any one of claims 1 to 28, further comprising administering one or more therapeutic antibodies.

30. 30. The method of any one of claims 1 to 29, further comprising co-administering an antibody that binds to epidermal growth factor receptor (EGFR).

31. 31. The method of claim 30, wherein the antibody that binds to EGFR is selected from cetuximab and panitumumab.

32. 32. The method of any one of claims 1 to 31, further comprising co-administering one or more blockers or inhibitors of one or more T cell stimulatory immune checkpoint proteins or receptors.

33. 33. The method of claim 32, wherein the one or more immune checkpoint inhibitors comprise a proteinaceous (e.g., antibody) inhibitor of PD-L1 (CD274), PD-1 (PDCD1), or CTLA4.

34. 34. The method of claim 32 or 33, wherein the one or more immune checkpoint proteins or receptors are selected from CD274 (CD274, PDL1, PD-L1) and programmed cell death 1 (PDCD1, PD1, PD-1).

35. The protein (e.g., antibody) inhibitor of CTLA4 is selected from the group consisting of ipilimumab, tremelimumab, BMS-986218, AGEN1181, AGEN1884 (zalifrelimab), BMS-986249, MK-1308, REGN-4659, ADU-1604, CS-1002, BCD-145, APL-509, JS-007, BA-3071, ONC-392, AGEN-2041, JHL-1155, KN-044, CG-01 61, ATOR-1144, PBI-5D3H5, FPT-155 (CTLA4 / PD-L1 / CD28), PF-06936308 (PD-1 / CTLA4), MGD-019 (PD-1 / CTLA4), KN-046 (PD-1 / CTLA4), MEDI-5752 (CTLA4 / PD-1), XmAb-20717 (PD-1 / CTLA4), and AK-104 (CTLA4 / PD-1).

36. The proteinaceous (e.g., antibody) inhibitors of programmed cell death 1 (PDCD1; NCBI Gene ID: 5133; CD279, PD-1, PD1) include, but are not limited to, zimberelimab (AB122, GLS-010, WBP-3055), pembrolizumab (KEYTRUDA®, MK-3475, SCH900475), nivolumab (OPDIVO®, BMS-936558, MDX-1106), cemiplimab (LIBTAYO®; cemiplimab-rwlc, REGN-2810), pidilizumab (CT -011), AMG-404, MEDI0680 (AMP-514), spartalizumab (PDR001), tislelizumab (BGB-A317), toripalimab (JS-001), genolimzumab (CBT-501, APL-501, GB226), SHR-1201, camrelizumab (SHR-1210), sintilimab (TYVYT®, IBI-308), dostallimab (TSR-042, WBP-285), lambrolizumab (MK-3475); sasunlimab (PF-06 801591), cetrelimab (JNJ-63723283), serplulimab (HLX-10), retifanlimab (MGA-012), balstilimab (AGEN2034), prorugolimab (BCD100), budigalimab (ABBV-181), bopratelimab (JTX-4014), AK-103 (HX-008), AK-105, CS-1003, BI-754091, LZM-009, Sym-021, BAT-1306, PD1-PIK, tebotelimab (MGD013; PD-1 / LAG-3), RO-724 7669 (PD-1 / LAG-3), FS-118 (LAG-3 / PD-L1), RO-7121661 (PD-1 / TIM-3), RG7769 (PD-1 / TIM-3), PF-06936308 (PD-1 / CTLA4), MGD-019 (PD-1 / CTLA4), KN-046 (PD-1 / CTLA4), XmAb-20717 (PD-1 / CTLA4), AK-104 (CTLA4 / PD-1), and MEDI-5752 (CTLA4 / PD-1).

37. Proteinaceous (e.g., antibody) inhibitors of the CD274 molecule (NCBI gene ID: Gene ID:29126; B7-H, B7H1, PD-L1) include atezolizumab (TECENTRIQ®), avelumab (BAVENCIO®; MSB0010718C), embafolimab (ASC22), durvalumab (IMFINZI®; MEDI-4736), BMS-936559 (MDX1105), cosibelimab (CK-301), lodapolimab (LY3300054), galibrimab (BGB A333), embafolimab (KN035), opucolimab (HLX20), manelimab (BCD135), CX-072, CBT-502 (TQB2450), MSB-2311, SHR-1316, sugemalimab (CS-1001; WBP3155), A167 (KL-A167, HBM9167), STI-A1015 (IMC-001), FAZ-053, BMS-936559 (MDX1105), INCB086550, GEN-104 6 (PD-L1 / 4-1BB), FPT-155 (CTLA4 / PD-L1 / CD28), M7824 (PD-L1 / TGFβ-EC domain), CA-170 (PD-L1 / VISTA), CDX-527 (CD27 / PD-L1), LY-3415244 (TIM-3 / PDL1), INBRX-105 (4-1BB / PDL1), and GNS-1480 (PD-L1 / EGFR).

38. 38. The method of any one of claims 1 to 37, further comprising co-administering an agonist of fms-related receptor tyrosine kinase 3 (FLT3).

39. 39. The method of claim 38, wherein the FLT3 agonist is selected from GS-3583 and CDX-301.

40. 40. The method of any one of claims 1 to 39, wherein the agent that inhibits binding between CD47 and SIRPα and the agent that inhibits binding between VEGFA and one or more VEGFA cognate receptors are administered in a combined synergistic amount.

41. 41. The method of any one of claims 1 to 40, wherein administration of an agent that inhibits binding between CD47 and SIRPα and an agent that inhibits binding between VEGFA and one or more VEGFA cognate receptors provides a synergistic effect.

42. 42. The method of claim 41, wherein the synergistic effect is an increase in cancer cell death and / or a decrease in cancer cell growth when comparing the effect of the combination to either an agent that inhibits binding between CD47 and SIRPα or an agent that inhibits binding between VEGFA and one or more VEGFA cognate receptors alone.

43. 42. The method of claim 41, wherein the synergistic effect is increased phagocytosis of cancer cells by macrophages when comparing the effect of the combination to either an agent that inhibits binding between CD47 and SIRPα or an agent that inhibits binding between VEGFA and one or more VEGFA cognate receptors alone.

44. 42. The method of claim 41 , wherein the synergistic effect is an increase or enhancement in tumor burden reduction when comparing the effect of the combination to either an agent that inhibits binding between CD47 and SIRPα or an agent that inhibits binding between VEGFA and one or more VEGFA cognate receptors alone.

45. The method of any one of claims 1 to 44, wherein the subject is a human.

46. 1. A method of treating, alleviating, reducing, preventing recurrence or metastasis of colorectal cancer in a subject, comprising co-administering to the subject effective amounts of magrolimab and bevancizumab.

47. 47. The method of claim 46, wherein the cancer is (i) unresectable, locally advanced, or (ii) metastatic.

48. 48. The method of claim 46 or 47, wherein the cancer is unresectable, locally advanced, and the subject is treatment naive.

49. 1. A method of treating previously treated progressive inoperable metastatic colorectal cancer in a subject, comprising administering to the subject an effective amount of a) magrolimab, and b) co-administering bevancizumab.

50. 50. The method of any one of claims 46 to 49, further comprising the concomitant administration of a chemotherapy regimen.

51. 51. The method of any one of claims 46 to 50, comprising concurrent administration of a FOLFOX regimen, a FOLFIRI regimen, a XELIRI (also known as CAPIRI) regimen, a FOLFOXIRI regimen, a XELOXIRI regimen, or a FOLFIRINOX regimen.

52. 52. The method of any one of claims 46 to 51, comprising concurrently administering a FOLFIRI regimen or a XELIRI regimen.

53. The method of any one of claims 46 to 52, wherein the cancer has cell surface expression of CD47.

54. 54. The method of any one of claims 46-53, wherein the cancer does not contain a BRAF V600E mutation.

55. 55. The method of any one of claims 46-54, wherein the cancer does not comprise high microsatellite instability.

56. 56. The method of any one of claims 46-55, wherein the cancer has one or more KRAS mutations and the subject has not responded to anti-EGFR antibody therapy.

57. 57. The method of any one of claims 46 to 56, wherein the cancer is an adenocarcinoma of colon or rectal origin.

58. 58. The method of any one of claims 46-57, wherein the cancer has progressed after one or more prior systemic therapies.

59. 59. The method of claim 58, wherein the one or more prior therapies comprise administration of one or more agents selected from the group consisting of 5-fluorouracil (5-FU), oxaliplatin, bevacizumab, cetuximab, and panitumumab.

60. 60. The method of any one of claims 46-59, wherein the treatment results in a reduction in total tumor burden of at least 15%, at least 20%, at least 30%, or at least 40% as determined using a linear dimensional method (e.g., RECIST v1.1).

61. 61. The method of any one of claims 47 to 60, comprising reducing the size or eliminating metastases.

62. 62. The method of any one of claims 46 to 61, further comprising administering one or more therapeutic antibodies.

63. 63. The method of any one of claims 46 to 62, further comprising co-administering an antibody that binds to epidermal growth factor receptor (EGFR).

64. 64. The method of claim 63, wherein the antibody that binds to EGFR is selected from cetuximab and panitumumab.

65. 65. The method of any one of claims 46-64, further comprising co-administering one or more blockers or inhibitors of one or more T cell stimulatory immune checkpoint proteins or receptors.

66. 66. The method of claim 65, wherein the one or more immune checkpoint inhibitors comprise a proteinaceous (e.g., antibody) inhibitor of PD-L1 (CD274), PD-1 (PDCD1), or CTLA4.

67. 67. The method of claim 65 or 66, wherein the one or more immune checkpoint proteins or receptors are selected from CD274 (CD274, PDL1, PD-L1) and programmed cell death 1 (PDCD1, PD1, PD-1).

68. The protein (e.g., antibody) inhibitor of CTLA4 is selected from the group consisting of ipilimumab, tremelimumab, BMS-986218, AGEN1181, AGEN1884 (zalifrelimab), BMS-986249, MK-1308, REGN-4659, ADU-1604, CS-1002, BCD-145, APL-509, JS-007, BA-3071, ONC-392, AGEN-2041, JHL-1155, KN-044, CG-01 61, ATOR-1144, PBI-5D3H5, FPT-155 (CTLA4 / PD-L1 / CD28), PF-06936308 (PD-1 / CTLA4), MGD-019 (PD-1 / CTLA4), KN-046 (PD-1 / CTLA4), MEDI-5752 (CTLA4 / PD-1), XmAb-20717 (PD-1 / CTLA4), and AK-104 (CTLA4 / PD-1).

69. The proteinaceous (e.g., antibody) inhibitor of programmed cell death 1 (PDCD1; NCBI Gene ID: 5133; CD279, PD-1, PD1) is selected from the group consisting of zimberelimab (AB122, GLS-010, WBP-3055), pembrolizumab (KEYTRUDA®, MK-3475, SCH900475), nivolumab (OPDIVO®, BMS-936558, MDX-1106), cemiplimab (LIBTAYO®; cemiplimab-rwlc, REGN-2810), pidilisumab (PI-1010), and rivaroxaban (RI-1010). (CT-011), AMG-404, MEDI0680 (AMP-514), spartalizumab (PDR001), tislelizumab (BGB-A317), toripalimab (JS-001), genolimuzumab (CBT-501, APL-501, GB226), SHR-1201, camrelizumab (SHR-1210), sintilimab (TYVYT®, IBI-308), dostallimab (TSR-042, WBP-285), lambrolizumab (MK-3475); sasunlimab (PF-06801591) , cetrelimab (JNJ-63723283), serplulimab (HLX-10), retifanlimab (MGA-012), balstilimab (AGEN2034), prorugolimab (BCD100), budigalimab (ABBV-181), bopratelimab (JTX-4014), AK-103 (HX-008), AK-105, CS-1003, BI-754091, LZM-009, Sym-021, BAT-1306, PD1-PIK, tebotelimab (MGD013; PD-1 / LAG-3), RO-724766 9 (PD-1 / LAG-3), FS-118 (LAG-3 / PD-L1), RO-7121661 (PD-1 / TIM-3), RG7769 (PD-1 / TIM-3), PF-06936308 (PD-1 / CTLA4), MGD-019 (PD-1 / CTLA4), KN-046 (PD-1 / CTLA4), XmAb-20717 (PD-1 / CTLA4), AK-104 (CTLA4 / PD-1), and MEDI-5752 (CTLA4 / PD-1).

70. Proteinaceous (e.g., antibody) inhibitors of the CD274 molecule (NCBI gene ID: Gene ID:29126; B7-H, B7H1, PD-L1) include atezolizumab (TECENTRIQ®), avelumab (BAVENCIO®; MSB0010718C), embafolimab (ASC22), durvalumab (IMFINZI®; MEDI-4736), BMS-936559 (MDX1105), cosibelimab (CK-301), lodapolimab (LY3300054), galibrimab (BGB A333), embafolimab (KN035), opucolimab (HLX20), manelimab (BCD135), CX-072, CBT-502 (TQB2450), MSB-2311, SHR-1316, sugemalimab (CS-1001; WBP3155), A167 (KL-A167, HBM9167), STI-A1015 (IMC-001), FAZ-053, BMS-936559 (MDX1105), INCB086550, GEN-104 68. The method of any one of claims 65 to 67, wherein the PD-L1 / TGFβ-EC domain is selected from the group consisting of 6 (PD-L1 / 4-1BB), FPT-155 (CTLA4 / PD-L1 / CD28), M7824 (PD-L1 / TGFβ-EC domain), CA-170 (PD-L1 / VISTA), CDX-527 (CD27 / PD-L1), LY-3415244 (TIM-3 / PDL1), INBRX-105 (4-1BB / PDL1), and GNS-1480 (PD-L1 / EGFR).

71. 71. The method of any one of claims 46-70, further comprising co-administering an agonist of fms-related receptor tyrosine kinase 3 (FLT3).

72. 72. The method of claim 71, wherein the FLT3 agonist is selected from GS-3583 and CDX-301.

73. 73. The method of any one of claims 46-72, wherein said magrolimab and said bevacizumab are administered in a combined synergistic amount.

74. 74. The method of any one of claims 46-73, wherein administration of said magrolimab and said bevacizumab provides a synergistic effect.

75. 75. The method of claim 74, wherein the synergistic effect is an increase in cancer cell death and / or a decrease in cancer cell growth when comparing the effect of the combination to either the magrolimab or the bevacizumab alone.

76. 75. The method of claim 74, wherein the synergistic effect is increased phagocytosis of cancer cells by macrophages when comparing the effect of the combination to either the magrolimab or the bevacizumab alone.

77. 75. The method of claim 74, wherein the synergistic effect is an increase or enhancement in tumor burden reduction when comparing the effect of the combination to either the magrolimab or the bevacizumab alone.

78. 78. The method of any one of claims 46-77, wherein the magrolimab is administered initially at a priming dose of less than 10 mg / kg, followed by one or more therapeutic doses of at least 15 mg / kg, such as at least 30 mg / kg, 45 mg / kg, 60 mg / kg.

79. 79. The method of any one of claims 46-78, wherein the magrolimab is administered initially at a priming dose of less than 5 mg / kg, followed by one or more therapeutic doses of at least 30 mg / kg, such as at least 45 mg / kg, 60 mg / kg.

80. 80. The method of any one of claims 46-79, wherein the magrolimab is administered initially at a priming dose of 1 mg / kg, then at one or more therapeutic doses of 30 mg / kg, followed by one or more therapeutic doses of 60 mg / kg.

81. 80. The method of any one of claims 46-79, wherein the magrolimab is administered initially at a priming dose of 1 mg / kg, then at one or more therapeutic doses of 20 mg / kg, followed by one or more therapeutic doses of 45 mg / kg.

82. 80. The method of any one of claims 46-79, wherein the magrolimab is administered initially at a priming dose of 1 mg / kg, then at one or more therapeutic doses of 15 mg / kg, followed by one or more therapeutic doses of 30 mg / kg.

83. 83. The method of any one of claims 46-82, wherein the magrolimab is administered intravenously, subcutaneously, or intratumorally.

84. 84. The method of any one of claims 46-83, wherein the bevacizumab is administered at one or more doses ranging from 5 mg / kg to 15 mg / kg, such as from 5 mg / kg to 7.5 mg / kg, or from 7.5 mg / kg to 15 mg / kg.

85. 85. The method of any one of claims 46-84, wherein the bevacizumab is administered in one or more doses of 5 mg / kg.

86. 86. The method of any one of claims 46-85, wherein the bevacizumab is administered intravenously, subcutaneously, or intratumorally.

87. the magrolimab and the bevacizumab are administered for first, second, and third 28 day cycles; a) in said first 28 day cycle, magrolimab is administered at a dose of 1 mg / kg on day 1 and at a dose of 30 mg / kg weekly (QW) beginning on day 8; and bevacizumab is administered at a dose of 5 mg / kg on days 1 and 15; b) in said second 28 day cycle, magrolimab is administered at a dose of 30 mg / kg every week (QW) and bevacizumab is administered at a dose of 5 mg / kg on days 1 and 15; c) in said third 28 day cycle, magrolimab is administered at a dose of 30 mg / kg Q2W and bevacizumab is administered at a dose of 5 mg / kg on days 1 and 15. The method of any one of claims 46-86,

88. the magrolimab and the bevacizumab are administered for first, second, and third 28 day cycles; a) in said first 28 day cycle, magrolimab is administered at a dose of 1 mg / kg on day 1 and at a dose of 20 mg / kg weekly (QW) beginning on day 8, and bevacizumab is administered at a dose of 5 mg / kg on days 1 and 15; b) in said second 28 day cycle, magrolimab is administered at a dose of 20 mg / kg every week (QW) and bevacizumab is administered at a dose of 5 mg / kg on days 1 and 15; c) In the third 28 day cycle, magrolimab is administered at a dose of 20 mg / kg Q2W and bevacizumab is administered at a dose of 5 mg / kg on days 1 and 15. The method of any one of claims 46-86,

89. the magrolimab and the bevacizumab are administered for first, second, and third 28 day cycles; a) in said first 28 day cycle, magrolimab is administered at a dose of 1 mg / kg on day 1 and 15 mg / kg weekly (QW) beginning on day 8; and bevacizumab is administered at a dose of 5 mg / kg on days 1 and 15; b) in said second 28 day cycle, magrolimab is administered at a dose of 15 mg / kg every week (QW) and bevacizumab is administered at a dose of 5 mg / kg on days 1 and 15; c) in said third 28 day cycle, magrolimab is administered at a dose of 15 mg / kg Q2W and bevacizumab is administered at a dose of 5 mg / kg on days 1 and 15. The method of any one of claims 46-86,

90. The method of any one of claims 46 to 77, wherein the subject is a human.

91. A kit comprising one or more unit doses of (a) an agent that inhibits binding between CD47 and SIRPα, and (b) an agent that inhibits binding between vascular endothelial growth factor A (VEGFA) and one or more VEGFA cognate receptors.

92. 92. The kit of claim 91, wherein the one or more VEGFA cognate receptors are selected from fms-related receptor tyrosine kinase 1 (FLT1, also known as VEGFR1) and kinase insert domain receptor (KDR, also known as VEGFR2).

93. 93. The kit of claim 91 or 92, further comprising one or more unit doses of a chemotherapy regimen.

94. 94. The kit of any one of claims 91-93, further comprising components of a FOLFOX regimen, a FOLFIRI regimen, a XELIRI (also known as CAPIRI) regimen, a FOLFOXIRI regimen, a XELOXIRI regimen, or a FOLFIRINOX regimen.

95. 95. The kit of any one of claims 91 to 94, comprising components of the FOLFIRI or XELIRI regimen.

96. 96. The kit of any one of claims 91 to 95, comprising components of a FOLFOX regimen, a FOLFIRI regimen, a XELIRI (also known as CAPIRI) regimen, a FOLFOXIRI regimen, a XELOXIRI regimen, or a FOLFIRINOX regimen.

97. 97. The kit of any one of claims 91 to 96, comprising components of the FOLFIRI or XELIRI regimen.

98. The kit of any one of claims 91 to 95, wherein the agent that inhibits binding between CD47 and SIRPα and the agent that inhibits binding between vascular endothelial growth factor A (VEGFA) and one or more VEGFA cognate receptors are contained in separate containers.

99. 99. The kit of claim 98, wherein the separate containers are selected from vials, ampoules, and pre-filled syringes.

100. The kit of any one of claims 91 to 99, wherein the agent that inhibits binding between CD47 and SIRPα comprises an antibody that binds to CD47.

101. The kit of claim 100, wherein the antibody that binds to CD47 is selected from magrolimab, lemzoparlimab, retaplimab, ligufalimab, AO-176, simridarlimab (IBI-322), gentulizumab, ZL-1201, IMC-002, SRF-231, CC-90002 (also known as INBRX-103), NI-1701 (also known as TG-1801), and STI-6643.

102. The kit of any one of claims 91 to 99, wherein the agent that inhibits binding between CD47 and SIRPα comprises an antibody that binds to SIRPα.

103. The kit of claim 102, wherein the antibody that binds to SIRPα is selected from GS-0189 (also known as FSI-189), CC-95251, BI-765063, and APX-700.

104. The kit of any one of claims 91 to 99, wherein the agent that inhibits binding between CD47 and SIRPα comprises a SIRPα-Fc fusion protein.

105. The kit of claim 104, wherein the SIRPα-Fc fusion protein is selected from ALX-148, TTI-621, TTI-622, JMT601 (CPO107), and SL-172154.

106. The kit of any one of claims 91 to 105, further comprising one or more therapeutic antibodies.

107. 107. The kit of any one of claims 91 to 106, further comprising one or more blockers or inhibitors of one or more T-cell inhibitory immune checkpoint proteins or receptors.

108. 108. The kit of any one of claims 91 to 107, comprising a proteinaceous (e.g., antibody) inhibitor of PD-L1 (CD274), PD-1 (PDCD1), or CTLA4.

109. The kit of claim 107 or 108, comprising a proteinaceous (e.g., antibody) inhibitor of PD-L1 (CD274) or PD-1 (PDCD1).

110. The protein (e.g., antibody) inhibitor of CTLA4 is selected from the group consisting of ipilimumab, tremelimumab, BMS-986218, AGEN1181, AGEN1884 (zalifrelimab), BMS-986249, MK-1308, REGN-4659, ADU-1604, CS-1002, BCD-145, APL-509, JS-007, BA-3071, ONC-392, AGEN2041, JHL-1155, KN-044, CG-0161 , ATOR-1144, PBI-5D3H5, FPT-155 (CTLA4 / PD-L1 / CD28), PF-06936308 (PD-1 / CTLA4), MGD-019 (PD-1 / CTLA4), KN-046 (PD-1 / CTLA4), MEDI-5752 (CTLA4 / PD-1), XmAb-20717 (PD-1 / CTLA4), and AK-104 (CTLA4 / PD-1).

111. Proteinaceous (e.g., antibody) inhibitors of programmed cell death 1 (PDCD1; NCBI Gene ID: 5133; CD279, PD-1, PD1) include zimberelimab (AB122, GLS-010, WBP-3055), pembrolizumab (KEYTRUDA®, MK-3475, SCH900475), nivolumab (OPDIVO®, BMS-936558, MDX-1106), cemiplimab (LIBTAYO®; cemiplimab-rwlc, REGN-2810), pidilisumab (PI-1000, PI-1000, PI-1000), and rituximab (Tregs, RT-PCR). (CT-011), AMG-404, MEDI0680 (AMP-514), spartalizumab (PDR001), tislelizumab (BGB-A317), toripalimab (JS-001), genolimuzumab (CBT-501, APL-501, GB226), SHR-1201, camrelizumab (SHR-1210), sintilimab (TYVYT®, IBI-308), dostallimab (TSR-042, WBP-285), lambrolizumab (MK-3475); sasunlimab (PF-068015 91), cetrelimab (JNJ-63723283), serplulimab (HLX-10), retifanlimab (MGA-012), balstilimab (AGEN2034), prorugolimab (BCD100), budigalimab (ABBV-181), bopratelimab (JTX-4014), AK-103 (HX-008), AK-105, CS-1003, BI-754091, LZM-009, Sym-021, BAT-1306, PD1-PIK, tebotelimab (MGD013; PD-1 / LAG-3), RO-7 247669 (PD-1 / LAG-3), FS-118 (LAG-3 / PD-L1), RO-7121661 (PD-1 / TIM-3), RG7769 (PD-1 / TIM-3), PF-06936308 (PD-1 / CTLA4), MGD-019 (PD-1 / CTLA4), KN-046 (PD-1 / CTLA4), XmAb-20717 (PD-1 / CTLA4), AK-104 (CTLA4 / PD-1), and MEDI-5752 (CTLA4 / PD-1).

112. Proteinaceous (e.g., antibody) inhibitors of the CD274 molecule (NCBI gene ID: Gene ID:29126; B7-H, B7H1, PD-L1) include atezolizumab (TECENTRIQ®), avelumab (BAVENCIO®; MSB0010718C), embafolimab (ASC22), durvalumab (IMFINZI®; MEDI-4736), BMS-936559 (MDX1105), cosibelimab (CK-301), lodapolimab (LY3300054), galibrimab (BGB A333), embafolimab (KN035), opucolimab (HLX20), manelimab (BCD135), CX-072, CBT-502 (TQB2450), MSB-2311, SHR-1316, sugemalimab (CS-1001; WBP3155), A167 (KL-A167, HBM9167), STI-A1015 (IMC-001), FAZ-053, BMS-936559 (MDX1105), INCB086550, GEN 109. The kit of claim 108, wherein the antibody is selected from the group consisting of PD-L1 / 4-1BB, FPT-155 (CTLA4 / PD-L1 / CD28), M7824 (PD-L1 / TGFβ-EC domain), CA-170 (PD-L1 / VISTA), CDX-527 (CD27 / PD-L1), LY-3415244 (TIM-3 / PDL1), INBRX-105 (4-1BB / PDL1), and GNS-1480 (PD-L1 / EGFR).

113. 113. The kit of any one of claims 91 to 112, further comprising co-administering an agonist of fms-related receptor tyrosine kinase 3 (FLT3).

114. The kit of claim 113, wherein the FLT3 agonist is selected from GS-3583 and CDX-301.

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