Complement inhibition in pre-clinical models of periodontitis and prospects for clinical application

Abstract

Periodontitis is a dysbiotic inflammatory disease leading to the destruction of the tooth-supporting tissues. Current therapies are not always effective and this prevalent oral disease continues to be a significant health and economic burden. Early clinical studies have associated periodontitis with elevated complement activity. Consistently, subsequent genetic and pharmacological studies in rodents have implicated the central complement component C3 and downstream signaling pathways in periodontal host-microbe interactions that promote dysbiosis and inflammatory bone loss. This review discusses these mechanistic advances and moreover focuses on the compstatin family of C3 inhibitors as a novel approach to treat periodontitis. In this regard, local application of the current lead analog Cp40 was recently shown to block both inducible and naturally occurring periodontitis in non-human primates. These promising results from non-human primate studies and the parallel development of Cp40 for clinical use highlight the feasibility for developing an adjunctive, C3-targeted therapy for human periodontitis.

Keywords: C3; Complement; Compstatin cp40; Inflammation; Periodontitis; Primate models; Therapeutics.

Copyright © 2016 Elsevier Ltd. All rights reserved.

Figures

Figure 1. Complement and its involvement in periodontal dysbiosis and inflammatory bone loss

A) Complement cascade: The classic, lectin, and alternative pathways converge to activate C3 leading to the generation of effector molecules. These include the inflammatory anaphylatoxins C3a and C5a, which respectively activate C3aR and C5aR1, which moreover cross-talk with TLRs. Intriguingly, the keystone periodontal pathogen P. gingivalis can directly activate C5aR1 through its arginine-specific gingipains that can cleave C5 to generate biologically active C5a. C3b is an opsonin that promotes microbial opsonization. The cleavage of C5 by its convertase (C3bBb3b) also generates C5b which in the terminal pathway initiates the assembly of the C5b-9 membrane attack complex (MAC), which induces lysis of susceptible targeted microbes. The alternative pathway C3 convertase, C3bBb, is also involved in an amplification loop for all complement pathways. Compstatin and derivative drugs, such as Cp40, block C3 activation, thus inhibiting all activities downstream of C3. B) Dysbiotic inflammation: C5aR1 is involved a subversive crosstalk with Toll-like receptors (TLR) leading to the remodeling of a symbiotic microbiota into a dysbiotic one. This cross-talk is instigated by keystone pathogens (see text for details). The resulting dysbiotic microbial community causes inflammation that is largely dependent on complement (C3aR, C5aR1)-TLR crosstalk. Inflammation and dysbiosis reinforce each other since inflammatory tissue breakdown products are used as nutrients by the dysbiotic microbiota, which thus further exacerbates inflammation and ultimately leads to bone loss, the hallmark of periodontitis. Therapeutic blockade of C3 activation/cleavage using Cp40 has blocked periodontitis in non-human primates.