Novel SIRPα Antibodies That Induce Single-Agent Phagocytosis of Tumor Cells while Preserving T Cells

The signal regulatory protein alpha (SIRP alpha)/CD47 axis has emerged as an important innate immune checkpoint that enables cancer cell escape from macrophage phagocytosis. SIRP alpha expression is limited to macrophages, dendritic cells, and neutrophils-cells enriched in the tumor microenvironment. In this study, we present novel anti-SIRP Abs, SIRP-1 and SIRP-2, as an approach to targeting the SIRP alpha/CD47 axis. Both SIRP-1 and SIRP-2 bind human macrophage SIRP alpha variants 1 and 2, the most common variants in the human population. SIRP-1 and SIRP-2 are differentiated among reported anti-SIRP Abs in that they induce phagocytosis of solid and hematologic tumor cell lines by human monocyte-derived macrophages as single agents. We demonstrate that SIRP-1 and SIRP-2 disrupt SIRP alpha/CD47 interaction by two distinct mechanisms: SIRP-1 directly blocks SIRP alpha/CD47 and induces internalization of SIRP alpha/Ab complexes that reduce macrophage SIRP alpha surface levels and SIRP-2 acts via disruption of higher-order SIRP alpha structures on macrophages. Both SIRP-1 and SIRP-2 engage Fc gamma RII, which is required for single-agent phagocytic activity. Although SIRP-1 and SIRP-2 bind SIRP gamma with varying affinity, they show no adverse effects on T cell proliferation. Finally, both Abs also enhance phagocytosis when combined with tumor-opsonizing Abs, including a highly differentiated anti-CD47 Ab, AO-176, currently being evaluated in phase 1 clinical trials, NCT03834948 and NCT04445701. SIRP-1 and SIRP-2 are novel, differentiated SIRP Abs that induce in vitro single-agent and combination phagocytosis and show no adverse effects on T cell functionality. These data support their future development, both as single agents and in combination with other anticancer drugs.