Definition

A human bispecific antibody directed against the human cell surface glycoproteins CD38 and CD47, with potential immunostimulating, phagocytosis-inducing and antineoplastic activities. Upon administration, the biparatopic anti-CD38 moiety of anti-CD38/anti-CD47 bispecific antibody ISB 1442 targets and binds to different regions of CD38 on CD38-expressing tumor cells, and enables the binding of the anti-CD47 moiety to CD38/CD47-expressing tumor cells. The CD47 binding by ISB 1442 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 CD38/CD47-expressing tumor cells. In addition, the CD38 binding by ISB 1442 may trigger antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cell mediated phagocytosis (ADCP) and antibody-mediated complement dependent cytotoxicity (CDC) in CD38-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. CD38, a type II transmembrane glycoprotein, is present on various immune cells and hematologic malignancies. ISB 1442 enables CD47 binding only upon CD38 crosslinking. This may prevent side effects that would have resulted from the binding of the anti-CD47 moiety to CD47 expressed on healthy hematopoietic stem cells (HSCs).