Complement in immune and inflammatory disorders: therapeutic interventions

Abstract

With the awareness that immune-inflammatory cross-talk is at the heart of many disorders, the desire for novel immunomodulatory strategies in the therapy of such diseases has grown dramatically. As a prime initiator and important modulator of immunological and inflammatory processes, the complement system has emerged as an attractive target for early and upstream intervention in inflammatory diseases and has moved into the spotlight of drug discovery. Although prevalent conditions such as age-related macular degeneration have attracted the most attention, the diverse array of complement-mediated pathologies, with distinct underlying mechanisms, demands a multifaceted arsenal of therapeutic strategies. Fortunately, efforts in recent years have not only introduced the first complement inhibitors to the clinic but also filled the pipelines with promising candidates. With a focus on immunomodulatory strategies, in this review we discuss complement-directed therapeutic concepts and highlight promising candidate molecules.

FIGURE 1

Simplified scheme of the complement cascade with currently exploited targets of complement-directed therapeutic intervention. Abbreviations: AP, alternative pathway; C1-INH, C1 inhibitor; C3aR, C3a receptor; C3(H₂O), hydrolyzed C3; C5aR, C5a receptor; C5L2, C5a receptor-like 2; CP, classical pathway; CR, complement receptor; FB, factor B; Fcn, ficolins; FD, factor D; FH, factor H; FP, properdin; GPCR, G protein-coupled receptor; LP, lectin pathway; MAC, membrane attack complex; MASP, MBL-associated protease; MBL, mannose-binding lectin.