Mechanism of Small Molecule Inhibitors of Phagocytosis

Abstract

Immune cytopenias occur when the body produces antibodies that target specific hematopoietic cells, inducing extravascular antibody-mediated phagocytosis by monocyte-macrophages in the spleen and/or liver through activation of Fcγ Receptors (FcγRs). Immune cytopenias include Immune Thrombocytopenia (ITP), Autoimmune Hemolytic Anemia (AIHA), Hemolytic Transfusion Reactions (HTR), Hemolytic Disease of the Fetus and Newborn (HDFN), and Autoimmune Neutropenia (AIN). Thus, novel therapeutics that inhibit phagocytosis would be useful, especially for short-term use while other therapies are being evaluated. In our earlier studies, we successfully identified two small-molecule drugs able to inhibit in vitro phagocytosis with a low IC50 concentration and negligible toxicity. These drugs, known as KB-151 and KB-208, have the potential to be utilized as lead compounds for further studies, once their mechanism of action is more clearly understood. In this regard, we have developed preliminary results that suggest that these small molecules may bind to the Fc receptors on monocyte macrophages and block the subsequent attachment of antibody-opsonized red blood cells to prevent phagocytosis.