Mounho-Zamora B, Weissman I, Volkmer J, Willingham S, Prohaska S, Howard M, Jie L, Majeti R.2015. Nonclinical safety assessment of a monoclonal antibody against CD47. Presented at the Society of Toxicology’s 54th Annual Meeting, March 22-26, San Diego, CA.
CD47 is a cell surface protein that functions as a regulator of phagocytosis mediated by cells of the innate immune system. CD47 binds to SIRP-alpha, a receptor on innate immune cells that delivers an inhibitory signal for phagocytosis. Effective phagocytosis requires silencing the CD47/SIRP-alpha inhibition pathway, and cancer cells exhibit an increased expression of CD47, presumably to prevent phagocytic elimination by innate immune cells. Thus, when CD47 is blocked from interacting with SIRP-alpha, pro-phagocytic signals dominate, which results in phagocytosis of the cancer cells. Hu5F9-G4 is an IgG4 monoclonal antibody that targets human CD47, thereby blocking the interaction of CD47 with its receptor and resulting in phagocytosis of human cancer cells. Hu5F9-G4 is being developed as a novel therapeutic for cancer. In support of administration of Hu5F9-G4 in clinical trials, a comprehensive toxicology program was conducted in cynomolgus monkeys. The primary treatment-related finding observed in monkeys was anemia, as reflected in decreased red blood cell (RBC) counts and hemoglobin levels. The anemia, however, was considered related to the pharmacological activity of Hu5F9-G4 since CD47 plays major role in the normal clearance of aging RBCs. Therefore, administration of Hu5F9-G4 likely accelerates the process of elimination of aging RBCs by blocking CD47 on aging RBCs. Pilot toxicology studies revealed that the anemia associated with Hu5F9-G4 could be managed using a priming/maintenance dose schedule, where a low dose of Hu5F9-G4 is administered in week 1 (priming dose) followed by twice-weekly dosing at higher doses (maintenance doses). This presentation will describe the strategy in establishing the priming/maintenance dose schedule in the toxicology program to support the clinical administration of Hu5F9-G4 for the treatment of cancer.