Table 1.

Pre-clinical trials targeting CD47-based combination strategies in cancer.

Agents targeting CD47	Additional combinational regimen	Experiment model	Administration design	Key findings of combination regimen	Ref.
Chemotherapy
MIAP301	Cyclophosphamide or Paclitaxel	A20 B cell malignancy C57BL/6 mice	i.p. Paclitaxel (40 mg/kg) or Cyclophosphamide (60 mg/kg) was administered 1 day before i.t. anti-CD47 antibody	Enhanced the anti-tumor effect; Preserved the memory immune response to tumor re-challenge	33
MIAP410	Cisplatin	LLC lung cancer C57BL/6 mice	Cisplatin (2.5 mg/kg) and anti-CD47 antibody (2.5 mg/kg) for 3 times	Enhanced anti-tumor effect; Prolonged survival time	35
B6H12	Doxorubicin	MNNG/HOS osteosarcoma NSG mice	i.v. Doxorubicin (1 mg/kg) on Days 0, 2, 4 i.p. anti-CD47 antibody (10 mg/kg) on Days 1, 3, 5	Reduced the tumor bioluminescence flux; Inhibited pulmonary metastases; Improved survival rate	26
B6H12	Doxorubicin	Patient-derived xenograft liver cancer NOD/SCID mice	i.p. anti-CD47 antibody (400 μg/mouse) i.v Doxorubicin (2 mg/kg) simultaneously	Enhanced anti-tumor effect	40
CD47 morpholino	Doxorubicin	PLC/PRF/5, or patient-derived xenograft hepatocellular carcinoma Nude mice	i.p. Doxorubicin (2 mg/kg) i.p. CD47 morpholino	Triggered complete eradication of tumors in PLC/PRF/5 tumor models; Enhanced anti-tumor effect in patient-derived tumor xenograft models	39
MIAP410	Temozolomide	GL261 glioblastoma or CT-2A astrocytoma C57BL/6 mice	i.p. Temozolomide (20 mg/kg) on Days 7, 8, 9 i.p. Temozolomide (80 mg/kg) and MIAP410 (100 μg) on Days 11, 13, 15	Inhibited tumor growth; Prolonged survival	27
B6H12	Gemcitabine	Patient-derived xenograft pancreatic cancer NU-Foxn1nu nude mice	i.p. Gemcitabine (125 mg/kg) from Day 14 to 56, twice a week i.p. anti-CD47 (500 mg/mouse) from Day 14 to 35, every day	Resulted in sustained tumor regression; Prevented disease relapse	41
B6H12	Abraxane	Patient-derived xenograft pancreatic cancer NU-Foxn1nu nude mice	i.v. Abraxane (50 mg/kg) from Day 14 to 28, every 4 days i.p. anti-CD47 (500 mg/mouse) from Day 14 to 35, every day	Resulted in sustained tumor regression; Prevented disease relapse	41
B6H12	Cabazitaxel	MDA-MB-231 breast cancer RAG2−/−, γc−/− BALB/c mice	i.v. anti-CD47 antibody (4 mg/kg) once every week i.t. Cabazitaxel (40 μg/kg) once every week	Inhibited tumor development	30
B6H12	Paclitaxel	Daudi, or SUDHL-2 B cell malignancy RAG2−/−, γc−/− BALB/c mice; A20 B cell malignancy BALB/c mice	i.v. or i.t. Nab-paclitaxel in combination with anti-CD47 antibody	Triggered tumor burden reduction; Prolonged survival times	31
Radiotherapy
Hu5F9-G4	Irradiation	Patient-derived orthotopic xenograft glioblastoma NSG mice	Anti-CD47 antibody followed irradiation (10 Gy)	Inhibited tumor growth and increased median survival times (combo 137 days vs. anti-CD47 antibody 93.5 days vs. irradiation 116 days)	53
Pep-20-D12	Irradiation	CT26 colon cancer C57BL/6 mice	Locally irradiation (20 Gy) i.p. Pep-20-D12 (2 mg/kg) every day for 2 weeks	Triggered tumor regression	47
CD47 morpholino	Irradiation	15-12RM fibrosarcoma BALB/c mice	i.p. CD47 morpholino (750 μL of 10 mmol/L), 48 h later, locally irradiation (10 Gy)	Reduced tumor growth (96% reduction in combo vs. saline alone)	51
Targeted therapy
Anti-CD47 F (ab′) fragments	Trastuzumab + Irradiation	4T1 breast cancer BALB/c mice	i.t. anti-CD47 F (ab′) fragments (100 μg/mouse) i.t. Trastuzumab (5 mg/kg) Locally irradiation (5 Gy per day for 2 days)	Enhanced tumor inhibition; Increased necrotic area	52
MIAP410	Trastuzumab	MM3MG, breast cancer BALB/c mice; KPL-4 breast cancer SCID-beige BALB/c mice	i.p Trastuzumab (200 μg/mouse) i.p anti-CD47 antibody (300 μg/mouse)	Prolonged survival rate; Delayed tumor growth	67
Hu5F9-G4	Trastuzumab	BT474 breast cancer NSG mice	i.p. Trastuzumab (100 μg/week) i.p. Hu5F9-G4 (250 μg) every other day	Enhanced anti-tumor effect Prolonged survival rate in ADCC-tolerant cancer cells-xenograft model	70
B6H12	Blinatumomab	Raji B cell malignancy NOD/SCID mice	i.v. anti-CD47 antibody (10 mg/kg) every 3 days, 6 times in total i.v. Blinatumomab (3 mg/kg) daily, 16 times in total	Enhanced anti-tumor effect	96
Immunotherapy
A4	Anti-PD-L1 antibody	B16F10 melanoma C57BL/6J mice	i.p. A4 (200 μg) for 14 days i.p. anti-PD-L1 (250 μg/dose) every other day for 14 days	Delayed tumor growth; Prolonged the survival	112
A4	Anti-PD-L1 antibody + anti-TRP-1 antibody	B16F10 melanoma C57BL/6J mice	i.p. A4 (200 μg/dose) for 14 days i.p. anti-PD-L1 antibody (250 μg/dose) every other day for 14 days i.p. anti-TRP-1 antibody every other day for 14 days	Delayed tumor growth; Improved the disease-free survival; Presented a durable immune memory response	112
CD47 morpholino	Ipilimumab + Irradiation	B16F10 melanoma C57BL/6J mice	i.p. CD47 morpholino (10 μmol/L) 10 Gy local irradiation i.p. anti-CTLA4 antibody (100 μg)	Increased tumor necrosis; Increased survival	48
A4	GVAX + anti-CTLA-4 antibody	B16F10 melanoma C57BL/6J mice	s.c. irradiated GVAX cells (5 × 105) in 250 μL of HBSS i.p. A4 (200 μg/dose) for 14 days i.p. anti-CTLA-4 (200 μg/dose) every other day for 14 days	Prolonged the survival; Enhanced the immune response after local delivery of A4; Caused considerable toxicity	120
MIAP301	Poly(I:C)	MC38 colon cancer C57BL/6J mice	i.p. anti-CD47 antibody (200 mg/mouse) every 3 days, began on Day 8 and stopped on Day 23 i.p. Poly(I:C) (50 μg) on Days 8, 11, 14, 17, 20, 23	Suppressed tumor growth; Prolonged survival	127
MIAP301	cGAMP	E0771 breast cancer C57BL/6J mice	i.t. anti-CD47 antibody (5 μg/mouse) i.t. cGAMP (0.5 μg/mouse)	Suppressed tumor growth (5/9 mice were completely cured); Prolonged survival time; Induced immune memory response	140
αCD47-IgG1	Oncolytic virus (OV-αCD47-G1)	A2780 ovarian cancer Athymic nude mice	i.v. 2 × 105 PFU OV-αCD47-G1 in 10 μL of saline	Slowed tumor progression	142
αmCD47-IgG2b	Oncolytic virus (OV-αmCD47-G2b)	ID8 ovarian cancer C57BL/6 mice	i.p 1 × 106 PFU OV-αmCD47-G2b in 100 μL of saline	Showed the strongest anti-tumor effect	142
αCD47-IgG1	Oncolytic virus (OV-αCD47-G1)	GBM43 glioblastoma Athymic nude mice; CT2A-hCD47 glioblastoma C57BL/6 mice	i.c. 2 × 105 PFU OV-αCD47-G1 in 3 μL of saline	Prolonged survival time in immunodeficient mice; Improved anti-tumor outcome in immunocompetent mice	143
A4-IgG2b	Oncolytic virus (OV-A4-IgG2b)	CT2A glioblastoma C57BL/6 mice	i.c. 2 × 105 PFU OV-A4-IgG2b in 3 μL of saline	Improved anti-tumor outcome	143
Bispecific antibody or fusion protein
CD47/CD20		Raji B cell malignancy NSG mice	i.p. (300, 500, or 1000 μg)	Prolonged survival significantly	87
CD47/CD19		Raji Non-Hodgkin lymphoma NOD/SCID mice	i.p. (400 μg) 3 times per week for 3 weeks	Induced tumor regression; Reduced “off-target” toxicity	92
NI-1701		Raji B cell malignancy NOD/SCID mice	i.v. (4 or 5 doses, 10 or 20 mg/kg) once a week for 4 or 5 weeks.	Controlled tumor growth	91
NI-1701		Patient-derived xenograft B cell malignancies Humanized NSG mice	i.v. (20 mg/kg) on Days 7, 14, 21, 28, and 35	Eradicated tumor burden	91
CD47/Glypican3		Hep3B hepatocellular carcinoma NOD/SCID mice	i.p. (10 mg/kg) twice a week for 3 weeks	Exerted superior antitumor effects by macrophages and neutrophils	101
Bi-SP		A431 squamous cell carcinoma NOD/SCID mice	i.p. (10 or 40 mg/kg) on Days 0, 5, 10, 15	Delayed tumor growth	63
VEGFR1D2–SIRPαD1 fusion protein		U87 glioblastoma nude mice	i.p. SIRPα–VEGFR1 (10 mg/kg) twice a week	Reduced tumor volume	77
PF-07257876		B16F10 melanoma C57BL/6J mice	i.p. (20 mg/kg) three times a week for a total for 9 doses	Inhibited tumor growth	111
PF-07257876		MC38 colon cancer C57BL/6 mice	i.p. (10, 20, and 40 mg/kg) for a total of 6 doses	Inhibited tumor growth	111
PF-07257876		CT26 colon cancer BALB/c mice	i.p. (5 mg/kg) every 3–4 days for a total for 3 doses	Inhibited tumor growth; Prolonged the survival times (75% combo vs. 12.5% monotherapy)	111
Bispecific anti-PD-L1–SIRPα		MC38 colon cancer C57BL/6 mice	i.t. (50 μg/mouse) on Days 11 and 14 after tumor inoculation	Inhibited tumor growth; Extended mouse survival	107
Bispecific anti-PD-L1–SIRPα		CT26 colon cancer BALB/c mice	i.t. (100 μg/mouse) on Days 10 and 14 after tumor inoculation	Extended mouse survival	107
IBI322		Raji B cell malignancy NOD-SCID mice	i.p. (0.17 mg/kg) dosage once every 2 days for 6 continuous doses	Presented rapid and nearly completed tumor regression	110
IBI322		A375 melanoma NOG mice	i.p. (1.1 mg/kg) dosage once every 2 days for 6 continuous doses	Inhibited tumor growth	110
Anti-CTLA4–SIRPα fusion protein		Patient-derived xenograft lung cancer Humanized NSG mice	i.p. (30 μg) Day 12 i.p. after (200 μg) twice a week for a total of four times	Inhibited tumor growth via tumor Treg depletion	122
Anti-CTLA4–SIRPα fusion protein		MC38 colon cancer C57BL/6 mice	i.p. (20 μg) once on Day 13	Inhibited tumor growth via tumor Treg depletion	122
Anti-CTLA4–SIRPα fusion protein		CT26 colon cancer BALB/c mice	i.p. (50 μg) once on Day 6	Inhibited tumor growth via tumor Treg depletion	122
DSP107		Diffuse large B cell lymphoma Humanized NSG mice	i.p. 250 μg or 150 μL DSP107 every other day for 6 consecutive treatments	Inhibited tumor growth (2 out of 6 mice being tumor-free at the end of the experiment)	139
SIRPα–Fc–CD40L fusion protein		CT26 colon cancer; A20 B cell malignancy; WEHI-3 acute myelomonocytic leukemia BALB/c mice	i.p. mSIRPα–Fc–CD40L fusion protein	Enhanced the anti-tumor effect; Enhanced a type I interferon response	141

i.c., intracranial injection; i.p., intraperitoneally injection; i.t., intratumoral injection; i.v., intravenously injection; s.c., subcutaneous injection.