Complement therapeutics; history and current progress

Abstract

Complement (C) performs vital roles in immune surveillance, from killing of bacteria to generation of an optimal antibody response. However, the mediators responsible for this protective role can inappropriately target self tissues and cause pathology in many inflammatory diseases, in ischaemia-reperfusion injuries and also as a result of therapeutic intervention, such as in cardiopulmonary bypass. Here we review the history of anti-complement therapeutics and describe the plethora of reagents that have evolved to treat complement-mediated pathologies. These agents range from small compounds, including natural products isolated from plants and synthetic peptides designed to target and inhibit the complement cascade, to large, intricately engineered biological reagents. Recombinant, humanised antibody fragments which inhibit at specific points in the complement cascade have been generated and used successfully in man. Other reagents, mimicking the action of the natural complement regulatory proteins present on the surface of self cells, have also been developed and extensively tested. We discuss the pros and cons of these different reagents and describe recent advances in the field, such as specific targeting of drugs to sites of inflammation, which have opened the door to the use of anti-complement therapy in both acute and chronic inflammatory conditions.