SIRPα (Signal regulatory protein alpha)

Class

Anti-SIRPα monoclonal antibody (pan-allele, humanized IgG2)

Pathway

Innate immune checkpoint; blocks SIRPα-CD47 interaction on myeloid cells to promote macrophage phagocytosis of tumor cells without interfering with T-cell activation

SIRPα is an inhibitory receptor on macrophages and other myeloid cells. Its ligand, CD47, is broadly expressed on both healthy and cancer cells and engages SIRPα to deliver a restraining, or 'don't eat me,' signal that limits phagocytosis. Many tumors upregulate CD47 to evade innate immune clearance. Blocking the SIRPα-CD47 interaction is intended to remove this checkpoint, allowing macrophages to engulf and destroy tumor cells, particularly those already marked by antibodies or other immune signals. Because SIRPα, unlike CD47, is expressed mainly on myeloid-lineage cells rather than red blood cells, targeting SIRPα instead of CD47 aims to disrupt the checkpoint on the immune-cell side while limiting the antigen sink and hematologic effects associated with agents that bind CD47 broadly across blood cells. The SIRPα gene is also polymorphic across the population, so binding designed to cover multiple allelic variants helps ensure consistent activity regardless of a given individual's receptor form. This mechanism functions as an innate immune checkpoint, complementary to T-cell checkpoint inhibition, and is broadly relevant in oncology, where tumor cells resist immune clearance through CD47 overexpression and where enhancing macrophage-mediated killing may complement antibody- or T-cell-based approaches.