Tissue-targeted complement therapeutics

Abstract

Complement activation contributes to the pathogenesis of numerous inflammatory and autoimmune diseases. Therapeutic complement inhibitors have proven effective in several of these diseases and have now entered clinical use. Complement activation has multiple different biologic effects, however, and the currently available drugs can have undesirable side-effects, such as an increased risk of infection. Several different complement inhibitors have been developed that bind to target molecules, thereby concentrating the drug at a specific anatomic site. This approach appears to be both more effective than untargeted drugs and to have fewer side effects. In this article we review different targeting strategies that have been developed and the evidence supporting the use and benefits of targeted drugs.

Keywords: Complement; Inflammation; Targeted; Therapeutics.

Figure 1.. Sites of complement activation and inhibition.

Complement activation can occur in the fluid phase or on the surface of cells and tissues. Monoclonal antibodies, small molecules, and recombinant proteins have access to complement proteins in plasma and can block fluid phase activation. siRNA can reduce levels of complement proteins in plasma and decrease fluid phase activation. These same strategies also block complement activation on cell and tissue surfaces. Targeted inhibitors block activation in the fluid phase while they are still in the plasma, and effectively block the activity of convertases on cell and tissue surfaces. Monoclonal antibodies may prevent cells from endocytosing complement proteins. Small molecules may block the extracellular activity of complement fragments that are generated inside cells.