CR1-based inhibitors for prevention of complement-mediated immune hemolysis

Abstract

Complement receptor 1 (CR1) is a single pass transmembrane glycoprotein that, through its ability to bind key components of the complement cascade, can inhibit both the classical and alternative pathways. Using several animal models, a recombinant form of CR1 has been documented to be effective in reducing tissue damage that occurs as a result of complement activation in various inflammatory conditions. This strategy is currently being explored in human clinical trials. Activation of complement cascade via the antibody-mediated classical pathway can initiate red blood cell destruction, causing transfusion reactions and hemolytic anemia. We discuss here our approach of using CR1 derivatives as therapeutic targets for prevention of complement-dependent immune hemolysis. Using a mouse model of hemolytic transfusion reaction, we have found that sCR1 treatment reduces complement activation and prolongs the survival of transfused red blood cells. Through structure-function analysis, we have identified a complement inhibitory domain located at the amino-terminal region of CR1 that mediates its antihemolytic activity in vivo. Collectively, our data highlight a potential use for CR1 to control complement-dependent immune hemolysis and identify its functional domains for the future design of CR1-based inhibitors.