Discovery and Preclinical Activity of BMS-986351, an Antibody to SIRPα that Enhances Macrophage-Mediated Tumor Phagocytosis when Combined with Opsonizing Antibodies.

In normal cells, binding of the transmembrane protein CD47 to signal regulatory protein-α (SIRPα) on macrophages induces an anti-phagocytic signal. Tumor cells hijack this pathway and overexpress CD47 to evade immune destruction. Macrophage antitumor activity can be restored by simultaneously blocking the CD47-SIRPα signaling axis and inducing a pro-phagocytic signal via tumor opsonizing antibodies. We identified a novel, fully human monoclonal antibody (BMS-986351) that binds SIRPα with high affinity. BMS-986351 demonstrated broad binding coverage across SIRPα polymorphisms and potently blocked CD47-SIRPα binding at the CD47 binding site in a dose-dependent manner. In vitro, BMS-986351 increased phagocytic activity against cell lines from solid tumors and hematological malignancies, and this effect was markedly enhanced when BMS-986351 was combined with the opsonizing antibodies cetuximab and rituximab. A phase I dose escalation/ expansion study of BMS-986351 for the treatment of advanced solid and hematologic malignancies is underway (NCT03783403).