Opportunities for new therapies based on the natural regulators of complement activation

While the complement system is an essential component of immunity, shutting down all or part of it could be beneficial in a wide range of clinical situations. Designer, small-molecule, protease inhibitors and antagonists of protein-protein interactions are under development, while an approach based on a humanized monoclonal antibody to the C5 component works effectively against the later stages of complement activation and is close to completing clinical trials. The cobra venom factor depletes plasma of essential complement components, and a humanized (nonimmunogenic) version is being sought. Perhaps the most promising approach to comprehensive complement downregulation, however, is the exploitation of innate regulators of complement activation, with two products in clinical trials. The potential for more efficacious complement blockers of this kind is growing because of better targeting, but a deeper knowledge at the atomic level of mechanisms of action of these regulators is needed to underpin a rational approach to design of still more potent complement inhibitors.