SIRP-alpha/4-1BBL fusion protein

Class

fusion protein

This fusion protein joins two distinct immune-modulating domains into a single molecule. One domain is derived from SIRP-alpha, a receptor normally found on macrophages that recognizes CD47, a protein many tumor cells overexpress to send a "do not eat me" signal that suppresses phagocytosis. By presenting this domain as a soluble decoy, the fusion protein intercepts CD47 on tumor cells, removing that inhibitory signal and permitting macrophages to engulf and destroy the tumor cells. The second domain is 4-1BB ligand (4-1BBL), which engages 4-1BB, a costimulatory receptor on T cells and natural killer cells that, when activated, enhances their proliferation, survival, and cytotoxic activity. Combining both functions in one molecule allows the construct to simultaneously disable a tumor's innate-immune evasion strategy and stimulate adaptive and innate lymphocyte killing, engaging two complementary arms of the immune system rather than one. This dual-engagement design is relevant to cancers that both overexpress CD47 and reside in an immunosuppressed microenvironment where added T-cell and NK-cell costimulation could improve tumor clearance. The general rationale for pairing checkpoint blockade with costimulation is to convert a tumor from immunologically "invisible" to actively targeted by multiple effector pathways.