Complement therapeutics in inflammatory diseases: promising drug candidates for C3-targeted intervention

Abstract

There is increasing appreciation that complement dysregulation lies at the heart of numerous immune-mediated and inflammatory disorders. Complement inhibitors are therefore being evaluated as new therapeutic options in various clinical translation programs and the first clinically approved complement-targeted drugs have profoundly impacted the management of certain complement-mediated diseases. Among the many members of the intricate protein network of complement, the central component C3 represents a 'hot-spot' for complement-targeted therapeutic intervention. C3 modulates both innate and adaptive immune responses and is linked to diverse immunomodulatory systems and biological processes that affect human pathophysiology. Compelling evidence from preclinical disease models has shown that C3 interception may offer multiple benefits over existing therapies or even reveal novel therapeutic avenues in disorders that are not commonly regarded as complement-driven, such as periodontal disease. Using the clinically developed compstatin family of C3 inhibitors and periodontitis as illustrative examples, this review highlights emerging therapeutic concepts and developments in the design of C3-targeted drug candidates as novel immunotherapeutics for oral and systemic inflammatory diseases.

Keywords: C3; complement; compstatin Cp40; inflammation, periodontitis; primate models; therapeutics.

© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Figures

Figure 1. Roadmap of compstatin’s structure-function optimization and important milestones achieved towards its clinical translation

The crossdisciplinary effort placed on compstatin’s molecular characterization and structure-guided refinement culminated in a series of improved, more potent derivatives displaying favourable pharmacokinetic profiles, increased plasma residence and sustained therapeutic efficacy in various NHP disease models. This comprehensive timeline reflects the tight reciprocity and consolidation of key molecular developments (i.e. the resolution of the C3c-compstatin crystal structure by Janssen et al., 2007) with the preclinical and clinical evaluation program of compstatin. (Figure 1 has been adapted from the article “Compstatin: a C3-targeted complement inhibitor reaching its prime for bedside intervention’, Eur J Clin Invest. 2015, 45(4):423–40, with permission from Wiley)

Figure 2. Complement involvement in periodontal dysbiosis and inflammation

Periodontitis is induced by a polymicrobial bacterial community, wherein different members have distinct roles that synergize to cause destructive inflammation in periodontal pockets. Keystone pathogens manipulate the host response (for instance, P. gingivalis induces a subversive complement-Toll-like receptor cross-talk; see text for details) leading to the dysbiotic transformation of the microbiota. In dysbiosis, pathobionts over-activate the inflammatory response in a complement C3-dependent manner resulting in destructive periodontal inflammation and bone loss. Inflammation and dysbiosis reinforce each other since inflammatory tissue breakdown products are used as nutrients by the dysbiotic microbiota, which further exacerbates inflammation and perpetuates a disease-provoking vicious cycle. Therapeutic intervention at the C3 level with specific inhibitors (Cp40) has blocked periodontitis in non-human primates.