Optimizing CD47 Blockade in Cancer Immunotherapy: The Case for Wild Type SIRPαFc to Minimize Erythrocyte Interactions

CD47 is known to interact with SIRPα on macrophages, preventing the immune system from attacking cancer cells. This interaction is a target for cancer immunotherapy. Multiple strategies to block CD47 are being explored, such as SIRPαFc fusion proteins and monoclonal antibodies. A potential issue with CD47 therapies is their impact on red blood cells (RBCs), which could lead to anemia.

In this study, different CD47-targeting biologics were assessed for their binding affinity to erythrocytes and other cell types using flow cytometry. The SIRPαFc fusion proteins with wild type sequences, which have a high affinity for CD47, showed minimal binding to human RBCs, contrasting with both blocking and non-blocking CD47 antibodies. This effect was consistent across blood types but not observed with other cells like tumor cell lines. The presence of wild type SIRPα sequences was crucial for the low RBC binding, as mutated versions with increased CD47 affinity bound strongly to human RBCs. The binding of wild type SIRPαFc to RBCs could be enhanced by first clustering CD47 with a non-blocking antibody, indicating that wild type SIRPαFc does not naturally aggregate CD47 on RBCs. This low binding specificity to human RBCs is unique to humans, as mouse SIRPαFc can bind mouse RBCs, and human SIRPαFc can interact with CD47 on non-human primate and porcine RBCs.

The findings suggest that wild type SIRPαFc is less likely to bind to human RBCs compared to other CD47 blockers, which could result in better pharmacokinetics and reduced toxicity for cancer patients. Additionally, the strong binding of wild type SIRPαFc to monkey RBCs implies that preclinical studies involving non-human primates may not accurately reflect the hematological toxicity risks in humans. The research was presented at the 105th Annual Meeting of the American Association for Cancer Research and published in Cancer Research.