SIRPa-Fc-CD40L fusion protein SL-172154

A bi-functional fusion protein consisting of the extracellular domains (ECDs) of human signal-regulatory protein alpha (SIRPalpha; SIRPa; CD172a) and CD40 ligand (CD40L; CD154; TRAP; TNFSF5) linked via a human Fc domain, with potential immune checkpoint inhibitory and antineoplastic activities. Upon administration, the SIRPa-Fc-CD40L fusion protein SL-172154 selectively targets and binds to both CD47 expressed on tumor cells and CD40, a cell surface receptor that belongs to the tumor necrosis factor (TNF) receptor family, expressed on antigen-presenting cells (APCs). Binding to CD47 blocks the interaction of CD47 with endogenous SIRPa, a cell surface protein expressed on macrophages. This prevents CD47/SIRPa-mediated signaling and abrogates the CD47/SIRPa-mediated inhibition of macrophage activation and phagocytosis of cancer cells. This induces pro-phagocytic signaling mediated by the binding of calreticulin (CRT), which is specifically expressed on the surface of tumor cells, to low-density lipoprotein (LDL) receptor-related protein-1 (LRP-1), which is expressed on macrophages, and results in macrophage activation and the specific phagocytosis of tumor cells. The binding of CD40L to CD40 activates CD40, increases CD40-mediated signaling and induces proliferation and activation of B-lymphocytes, shifts the induction of suppressive macrophages towards immunostimulatory macrophages, activates monocyte-derived dendritic cells (moDCs), and leads to the secretion of inflammatory cytokines. This activates the immune system to induce the proliferation and activation of cytotoxic T lymphocytes (CTLs) against tumor cells. The crosslinking specifically enhances antigen presentation to CD8+ and CD4+ T lymphocytes and tumor cell phagocytosis by the APC. CD47, also called integrin-associated protein (IAP), is a tumor-associated antigen (TAA) expressed on normal, healthy hematopoietic stem cells (HSC) and overexpressed on the surface of a variety of cancer cells. Expression of CD47, and its interaction with SIRPa, leads to the inhibition of macrophage activation and protects cancer cells from phagocytosis, thereby allowing cancer cells to proliferate.