Definition

A bispecific antibody directed against both the human tyrosine kinase receptor epidermal growth factor receptor 2 (HER2; ErbB2; HER-2) and the human cell surface antigen CD47, with potential immunostimulating, phagocytosis-inducing and antineoplastic activities. Upon administration of anti-CD47/anti-HER2 bispecific antibody D3L-001, the anti-HER2 moiety selectively targets and binds to HER2 on HER2-expressing tumor cells, thereby improving the binding of the anti-CD47 moiety to the HER2-expressing tumor cells. The CD47 binding by D3L-001 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 the HER2-expressing tumor cells. Additionally, blocking CD47 signaling activates an anti-tumor T-lymphocyte immune response and T-cell-mediated killing of HER2-expressing tumor cells. CD47, also called integrin-associated protein (IAP), is widely expressed on normal, healthy cells, such as red blood cells 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. HER-2, a tumor-associated antigen (TAA) overexpressed on a variety of tumor cell types, plays an important role in tumor cell proliferation, differentiation and survival. Co-targeting CD47 and HER2 may limit the binding of D3L-001 to CD47 on healthy hematopoietic stem cells (HSCs) and may minimize any associated adverse effects.