Complement has long been considered a key innate immune effector system that mediates host defence and tissue homeostasis. Yet, growing evidence has illuminated a broader involvement of complement in fundamental biological processes extending far beyond its traditional realm in innate immunity. Complement engages in intricate crosstalk with multiple pattern-recognition and signalling pathways both in the extracellular and intracellular space. Besides modulating host–pathogen interactions, this crosstalk guides early developmental processes and distinct cell trajectories, shaping tissue immunometabolic and regenerative programmes in different physiological systems. This Review provides a guide to the system-wide functions of complement. It highlights illustrative paradigm shifts that have reshaped our understanding of complement pathobiology, drawing examples from evolution, development of the central nervous system, tissue regeneration and cancer immunity. Despite its tight spatiotemporal regulation, complement activation can be derailed, fuelling inflammatory tissue pathology. The pervasive contribution of complement to disease pathophysiology has inspired a resurgence of complement therapeutics with major clinical developments, some of which have challenged long-held dogmas. We thus highlight major therapeutic concepts and milestones in clinical complement intervention.
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This work was supported by the Dr Ralph and Sallie Weaver Professorship of Research Medicine to J.D.L. and by a grant from the US National Institutes of Health (DE026152 to G.H.).
J.D.L. is the founder of Amyndas Pharmaceuticals, which is developing complement inhibitors (including third-generation compstatin analogues such as AMY-101). J.D.L. is an inventor of patents or patent applications that describe the use of complement inhibitors for therapeutic purposes, some of which are developed by Amyndas Pharmaceuticals. J.D.L. and G.H. have a joint patent that describes the use of complement inhibitors for therapeutic purposes in periodontitis. J.D.L. is also the inventor of the compstatin technology licensed to Apellis Pharmaceuticals (namely 4(1MeW)7W/POT-4/APL-1 and PEGylated derivatives such as APL-2/pegcetacoplan/Empaveli/Aspaveli/Syfovre). D.C.M. has provided paid consulting services to 4D Molecular Therapeutics and Merck KGaA.
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Mastellos, D.C., Hajishengallis, G. & Lambris, J.D. A guide to complement biology, pathology and therapeutic opportunity. Nat Rev Immunol (2023). https://doi.org/10.1038/s41577-023-00926-1