Definition

A humanized immunoglobulin G1 (IgG1) affinity-tuned bispecific antibody directed against both the B-cell-specific membrane protein and tumor-associated antigen (TAA) CD20, and the human cell surface antigen CD47, with potential immunostimulating, phagocytosis-inducing and antineoplastic activities. Upon administration of anti-CD47/CD20 bispecific antibody CC-96673, the anti-CD20 moiety selectively targets and binds with high affinity to CD20 on CD20-positive B cells, and the anti-CD47 moiety targets and binds with optimally lowered affinity to CD47 expressed on the CD20-positive malignant B-cells. The CD47 binding by CC-96673 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 CD20/CD47-expressing tumor cells. Additionally, blocking CD47 signaling activates an anti-tumor T-lymphocyte immune response and T-cell-mediated killing of CD20/CD47-expressing tumor cells. CC-96673 may also induce an anti-tumor activity through the induction of antibody dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) against CD20-positive tumor cells. CD20 is a non-glycosylated cell surface phosphoprotein which is exclusively expressed on B cells during most stages of B-cell development. It is often overexpressed in B-cell malignancies. 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.