Definition

A bi-functional, trimeric, fusion protein consisting of the extracellular domains (ECDs) of human signal-regulatory protein alpha (SIRPalpha; SIRPa; CD172a) fused to a 4-1BB ligand (4-1BBL), with potential immune checkpoint inhibitory, immunostimulating and antineoplastic activities. Upon administration, the SIRPa-4-1BBL fusion protein DSP107 selectively targets and binds to both CD47 expressed on tumor cells and 4-1BB (CD137; tumor necrosis factor receptor superfamily member 9; TNFRSF9) expressed on T cells and natural killer (NK) cells. 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 4-1BBL to 4-1BB activates 4-1BB-mediated signaling, induces cytotoxic T-lymphocyte (CTL) proliferation, cytokine production and promotes a CTL-mediated anti-tumor immune response as well as NK-mediated tumor cell killing. The crosslinking specifically enables the activation of 4-1BB-mediated signaling in T-cells and NK cells in the tumor microenvironment (TME), allowing targeted immune responses in the TME. 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. 4-1BB, a surface glycoprotein of the tumor necrosis factor receptor superfamily, is an inducible costimulatory receptor that plays a key role in T-cell proliferation, survival and cytolytic activity.