Applying complement therapeutics to rare diseases

Abstract

Around 350 million people worldwide suffer from rare diseases. These may have a genetic, infectious, or autoimmune basis, and several include an inflammatory component. Launching of effective treatments can be very challenging when there is a low disease prevalence and limited scientific insights into the disease mechanisms. As a key trigger of inflammatory processes, complement has been associated with a variety of diseases and has become an attractive therapeutic target for conditions involving inflammation. In view of the clinical experience acquired with drugs licensed for the treatment of rare diseases such as hereditary angioedema and paroxysmal nocturnal hemoglobinuria, growing evidence supports the safety and efficacy of complement therapeutics in restoring immune balance and preventing aggravation of clinical outcomes. This review provides an overview of the candidates currently in the pharmaceutical pipeline with potential to treat orphan diseases and discusses the molecular mechanisms triggered by complement involved with the disease pathogenesis.

Keywords: Autoimmune diseases; C1 inhibitor; Complement; Compstatin; Eculizumab; Orphan drugs; Rare diseases.

Figure 1

Complement acts as a key mediator of several pathophysiological processes.

Figure 2

Simplified scheme of the complement cascade. In blue: proteins of the classical and lectins pathways; green: convertases of the classical and lectins pathways; orange: proteins of the alternative pathway; purple: convertases of the alternative pathway; red: proteins common to all the pathways; gray: soluble regulators. Complement cell receptors are depicted at the surface of the host cell. Red symbols: points of therapeutic interventions in rare diseases. Abbreviations: C1INH-C1 inhibitor, C4BP-C4b binding protein, CR-complement receptor, DAF-decay accelerating factor, FB-factor B, FD-factor D, FH-factor H, FI-factor I, MAC-membrane attack complex, MBL-mannose binding lectin, MCP-membrane cofactor protein. *ALN-CC5 inhibits C5 expression.

Figure 3

Impact of drug candidates on complement-mediated functions. Abbreviations: AP-alternative pathway, CP-classical pathway, C5aR-C5a receptor 1, C1-INH-C1 inhibitor, FD-factor D, FH-factor H, LP-lectin pathway, MAC-membrane attack complex, MASP-2-mannose binding lectin. Dotted lines indicate impact in the complement functions downstream of C3 due to less generation of C3b. Full lines indicate impact on C5-mediated functions due to inhibited amplification loop.