Complement in human disease: approved and up-and-coming therapeutics

Abstract

The complement system is recognised as a protector against blood-borne pathogens and a controller of immune system and tissue homoeostasis. However, dysregulated complement activity is associated with unwanted or non-resolving immune responses and inflammation, which induce or exacerbate the pathogenesis of a broad range of inflammatory and autoimmune diseases. Although the merit of targeting complement clinically has long been acknowledged, the overall complement drug approval rate has been modest. However, the success of the humanised anti-C5 antibody eculizumab in effectively treating paroxysmal nocturnal haemoglobinuria and atypical haemolytic syndrome has revitalised efforts to target complement therapeutically. Increased understanding of complement biology has led to the identification of novel targets for drug development that, in combination with advances in drug discovery and development technologies, has resulted in a surge of interest in bringing new complement therapeutics into clinical use. The rising number of approved drugs still almost exclusively target rare diseases, but the substantial pipeline of up-and-coming treatment options will possibly provide opportunities to also expand the clinical targeting of complement to common diseases.

Figure 1.. The complement system – activation, function, and regulation.

Complement can be activated through the lectin, classical, and alternative pathway. The pathways activate C3 into C3(H₂O) via hydrolysis (AP) or recognize different PAMPs or DAMPs, or antigen-antibody immune complexes, as triggers, but all cumulate in the formation of initially C3 convertases and then C5 convertases (LP/CP or AP C3 and C5 convertases), which cleavage-activate C3 into C3a and C3b, and C5 into C5a and C5b, respectively. Because C3b can feed into all PW convertases, C3b generation is central to a (pathologically) important amplification loop. C3b opsonizes targets and mediates the phagocytic clearance of noxious antigens via engagement of receptors that recognize C3b (or breakdown products iC3b and C3d (not shown)). C5b, together with components C6 – C9, form the membrane attack complex (MAC) and kill target cells via direct lysis. C3a and C5a mediate several important activities (complement functions are listed in black boxes below) and are central to the general inflammatory reaction. Several fluid-phase or membrane bound complement regulators (depicted in red) control complement activation at central functional nodes of the complement cascade (target recognition, surface deposition, amplification, and MAC formation)). Complement functions depicted are not exhaustive but focused on currently know disease drivers. Approved complement drugs and respective targets are depicted in blue. AP, alternative pathway; C1-INH, C1 and MASP1/2 inhibitor; C4BP, C4b binding protein; CP, classical pathway; CR1, complement receptor 1; DAMP, danger-associated molecular pattern; F, factor; IC, antigen-antibody immune complexes; LP, lectin pathway; MAC, membrane attack complex; MASP1/2, MBL serine proteases 1 and 2; PAMP, pathogen-associated molecular pattern; pathway, PW.