First-in-Human, First-in-Class Phase I Trial of the Anti-CD47 Antibody Hu5F9-G4 in Patients With Advanced Cancers

Abstract

PURPOSE To evaluate the safety, pharmacokinetics, and pharmacodynamics of Hu5F9-G4 (5F9), a humanized IgG4 antibody that targets CD47 to enable phagocytosis. PATIENTS AND METHODS Adult patients with solid tumors were treated in four cohorts: part A, to determine a priming dose; part B, to determine a weekly maintenance dose; part C, to study a loading dose in week 2; and a tumor biopsy cohort. RESULTS Sixty-two patients were treated: 11 in part A, 14 in B, 22 in C, and 15 in the biopsy cohort. Part A used doses that ranged from 0.1 to 3 mg/kg. On the basis of tolerability and receptor occupancy studies that showed 100% CD47 saturation on RBCs, 1 mg/kg was selected as the priming dose. In subsequent groups, patients were treated with maintenance doses that ranged from 3 to 45 mg/kg, and most toxicities were mild to moderate. These included transient anemia (57% of patients), hemagglutination on peripheral blood smear (36%), fatigue (64%), headaches (50%), fever (45%), chills (45%), hyperbilirubinemia (34%), lymphopenia (34%), infusion-related reactions (34%), and arthralgias (18%). No maximum tolerated dose was reached with maintenance doses up to 45 mg/kg. At doses of 10 mg/kg or more, the CD47 antigen sink was saturated by 5F9, and a 5F9 half-life of approximately 13 days was observed. Strong antibody staining of tumor tissue was observed in a patient at 30 mg/kg. Two patients with ovarian/fallopian tube cancers had partial remissions for 5.2 and 9.2 months. CONCLUSION 5F9 is well tolerated using a priming dose at 1 mg/kg on day 1 followed by maintenance doses of up to 45 mg/kg weekly.

Tumor-associated macrophages and macrophage-related immune checkpoint expression in sarcomas

“…66 Early clinical trials with CD47/SIRPα axis inhibitors have shown promising activity in B-cell lymphoma and some solid tumors. [40][41][42]66 Our findings, demonstrating frequent expression of CD47 in many sarcomas, suggest that targeting the CD47/SIRPα axis in these tumors may be worthwhile, for example, in chordoma and dedifferentiated liposarcoma. However, it should be noted that some relatively common sarcoma types (including leiomyosarcoma, undifferentiated pleomorphic sarcoma, and Ewing sarcoma) expressed CD47 infrequently, reiterating the potential for false-negative results when trials lump together different soft tissue sarcomas.…”

“…In phase 1 studies targeting CD47/ SIRPα signaling, encouraging responses were seen in both lymphoma and advanced solid tumors. [39][40][41][42] Overexpression of CD47 has been observed across most cancers, [32][33][34][35][36][43][44][45] including in osteosarcoma, 46 but has never been systematically examined in soft tissue sarcomas.…”

Contribution of Macrophages and T Cells in Skeletal Metastasis

“…Studies showed that CD47 blockade promotes macrophage reprogramming, which drives macrophage phagocytosis of cancer cells in xenograft mouse models [180,181]. Hu5F9-G4 and CC-90002 are CD47 antibodies that are currently being studied in phase I clinical trials with promising results [182]. TTI-621, a recombinant protein that blocks the CD47-SIRPα signaling in humans, is currently being studied in clinical trials including multiple solid tumors based on previous xenograft studies where it improved macrophage phagocytosis of cancer but not normal cells [183].…”

A drug development perspective on targeting tumor‐associated myeloid cells

“…Several molecules targeting CD47/SIRPa axis are being developed as therapeutic agents for treatment of different tumor types (Table 1). However, initial data from phase 1 trials are not as promising as the preclinical data suggested [80].…”