CD47 – SIRPalpha Pathway Inhibitors – Target Pipeline List 09/2020
CD47 – SIRPalpha Pathway Inhibitors – Target Pipeline List 09/2020
Target: CD47; SIRPα; Signal Regulatory Protein Alpha; CD172a
This Target Pipeline List provides an overview of inhibitors of the CD47-SIRPα pathway in development as a next generation immuno-oncology treatment of cancer
The phagocytic activity of macrophages is regulated by both activating (“eat me”) and inhibitory (“don’t eat me”) signals. CD47 serves as a critical “don’t eat me” signal inhibiting phagocytosis by binding to signal regulatory protein alpha (SIRPα) on the surface of macrophages. The CD47-SIRPα interaction represents an important mechanism by which malignant cells evade macrophage-mediated destruction. CD47 is overexpressed in numerous hematological cancers and solid tumors, and high CD47 expression correlates with more aggressive disease and poorer clinical outcomes. Preclinical studies have shown that interrupting the CD47-SIRPα signaling pathway promotes anti-tumor activity against human cancers, both in vitro and in vivo. Thus, blocking CD47 has emerged as a promising therapeutic strategy with early clinical data demonstrating benefit to cancer patients.
Dual function molecules are designed to 1) bind CD47 and neutralize its suppressive signal, and 2) deliver a pro-phagocytic (“eat me”) signal through the Fc region, which binds to activating Fc receptors on the surface of macrophages. We believe the combination of these two events – blockade of the negative CD47 “don’t eat me” signal and delivery of a positive Fc “eat me” signal – is a particularly effective way to enable macrophages to destroy tumor cells. Thus, there are differences to be expected whether the Fc is of the IgG1 or IgG4 isotype or even inert (inactivated Fc).
However, development of CD47 antibody as a cancer therapy is hampered by its hematologic side effects, such as severe anemia, caused by natural binding of CD47 antibody to red blood cells. A differentiation factor among competitor molecules is the virtue of not binding or reduced binding to CD47 on human red blood cells. This lowers the risk of serious anemia in patients, avoids the removal of the drug from the circulation by red blood cells (“antigen sink effect”) and minimizes interference with laboratory blood typing tests.
The development pipeline is full of directly acting specific and bispecific CD47 and SIRPα inhibitors or indirect modulators of the CD47-SIRPα pathway. Molecules include monoclonal antibodies, fusion proteins, RNA or small molecules. At least 22 distinct molecules targeting the CD47-SIRPα pathway are in clinical development.
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