Definition

A bispecific antibody directed against both the tumor-associated antigen (TAA) delta-like protein 3 (DLL3) and the human cell surface antigen CD47, with potential immunostimulating, phagocytosis-inducing and antineoplastic activities. Upon administration of anti-DLL3/anti-CD47 bispecific antibody PT217, the anti-DLL3 moiety selectively targets and binds to DLL3 on DLL3-expressing tumor cells, thereby improving the binding of the anti-CD47 moiety to DLL3-expressing tumor cells. The CD47 binding by PT217 blocks the interaction of CD47 with signal regulatory protein alpha (SIRPalpha), an inhibitory protein expressed on macrophages and dendritic cells (DCs), which prevents CD47/SIRPalpha-mediated signaling and abrogates the CD47/SIRPalpha-mediated inhibition of phagocytosis. 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 (LRP), expressed on macrophages, which results in macrophage activation and the specific phagocytosis of DLL3-expressing tumor cells. Additionally, blocking CD47 signaling activates an anti-tumor T-lymphocyte immune response and T-cell-mediated killing of DLL3-expressing tumor cells. PT217 may also induce an anti-tumor activity through the induction of antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP). CD47, also called integrin-associated protein (IAP), is widely expressed on normal, healthy cells, such as red blood cells (RBCs) and platelets, and overexpressed on the surface of a variety of cancer cells. Expression of CD47, and its interaction with SIRPalpha, leads to the inhibition of macrophage activation and protects cancer cells from phagocytosis, which allows cancer cells to proliferate. DLL3, a Notch pathway protein, is overexpressed on a variety of cancer cell types. It plays a key role in embryonic development and in tumor initiation and proliferation. Co-targeting CD47 and DLL3 may limit the binding of PT217 to CD47 on healthy hematopoietic stem cells (HSCs) and may minimize the associated adverse effects.