C3-targeted therapy in periodontal disease: moving closer to the clinic

Abstract

Complement plays a key role in immunosurveillance and homeostasis. When dysregulated or overactivated, complement can become a pathological effector, as seen in several inflammatory disorders, including periodontal disease. Recently, clinical correlative studies and preclinical mechanistic investigations have collectively demonstrated that complement is hyperactivated during periodontitis and that targeting its central component (C3) provides therapeutic benefit in nonhuman primates (NHPs). The preclinical efficacy of a C3-targeted drug candidate combined with excellent safety and pharmacokinetic profiles supported its use in a recent Phase IIa clinical study in which C3 inhibition resolved gingival inflammation in patients with periodontal disease. We posit that C3-targeted intervention might represent a novel and transformative host-modulation therapy meriting further investigation in Phase III clinical trials for the treatment of periodontitis.

Trial registration: ClinicalTrials.gov NCT03316521 NCT03694444.

Figure 1:. Complement activation and its effects in periodontitis.

The complement cascade can be triggered by distinct initiation mechanisms: The classical pathway is initiated by antigen (Ag) – antibody (Ab) complex–mediated activation of the C1 complex. The lectin pathway is activated when complexes of mannose-binding lectin (MBL) and MBL-associated serine proteases (MASPs) bind to microbial surfaces. The alternative pathway can be triggered by a ‘tick-over’ mechanism involving spontaneous hydrolysis of C3, if a regulatory mechanism is absent (as is typically the case with microbial surfaces). The so-called ‘alternative pathway (AP)-amplification loop’ (in which more C3 is cleaved into more C3b which further fuels the loop) amplifies complement activation independently of the initiating mechanism, thereby contributing most of the downstream terminal pathway-mediated effector responses (i.e., C5a, membrane attack complex [MAC]). All three mechanisms of complement activation and amplification converge at C3, which is thus an attractive target of pharmacological interception, e.g., by the cyclic inhibitory peptide AMY-101. If C3 is not blocked, downstream effects include the generation of effectors (C3a and C5a) that promote inflammation and the generation the C5b-C9 MAC with potential antimicrobial but also tissue destructive capacity. Whereas the role of MAC in periodontitis is uncertain, C3a and C5a activate their cognate G-protein-coupled receptors (C3aR and C5aR1), which cross-talk with Toll-like receptors. This cross-talk synergistically activates inflammatory leukocytes, which can directly or indirectly mediate destructive periodontal tissue inflammation and bone loss in periodontitis [46, 56]. Complement-mediated inflammation also promotes the dysbiosis of the periodontal microbial community [32, 33]. C3 blockade can prevent these downstream effects and thereby offer broader protection against periodontitis [33, 37]. TLR, toll-like receptor.

Figure 2:. Milestones to the development of complement C3-targeted intervention in periodontitis.

A timeline is shown of key preclinical and clinical studies leading to the development of complement C3-targeted host-modulation using the peptide-based C3 therapeutic AMY-101 as an adjunctive therapy in mammalian periodontal disease (see text for details) [24, 32, 33, 37, 41, 51]. NHP, non-human primates.