CD20/CD47 bispecific fusion protein CPO107

A bispecific fusion protein composed of the anti-CD20 antibody ofatumumab fused to the CD47 binding fragment signal regulatory protein alpha (SIRPalpha), and 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 fusion protein CPO107, the anti-CD20 moiety selectively targets and binds to CD20 on CD20-positive tumor cells, thereby inducing antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) in CD20-positive tumor cells, and improving the binding of its SIRPalpha moiety to CD47 expressed by CD20-positive tumor cells. The CD47 binding by CPO107 blocks the interaction of CD47 with endogenous 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. 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. CD20 is a membrane antigen that is overexpressed in B-cell malignancies. By co-targeting CD47 and CD20, CPO107 has the potential to overcome the limitations of existing CD47-targeted therapies by possibly avoiding the side effects caused by binding to CD47 expressed on healthy hematopoietic stem cells (HSCs).