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  • Review Article
  • Published:

Complement, a target for therapy in inflammatory and degenerative diseases

Nature Reviews Drug Discovery volume 14, pages 857–877 (2015)Cite this article

Subjects

Key Points

  • Complement is a key component of immunity with crucial inflammatory and opsonic properties; inappropriate activation of complement triggers or exacerbates inflammatory disease.

  • Complement dysregulation is a core feature of some diseases and contributes to pathology in many others.

  • Approved agents have been developed for and are highly effective in some orphan applications, but their progress to use in more common diseases has been slow.

  • Numerous challenges, such as target concentration or high turnover, limit the efficacy of these agents in humans.

  • Numerous novel agents targeting different parts of the complement system in different ways are now emerging from pre-clinical studies and are entering Phase I/II trials; these agents bring the potential for more-effective and more-specific anti-complement therapies in disease.

  • Other agents, both biologic and small molecule, are in Phase II or III trials for both rare and common diseases — administration routes include localized (for example, intravitreal) and systemic routes.

  • There is an urgent need to develop biomarkers and imaging methods that enable monitoring of the effects and efficacy of anti-complement agents.

Abstract

The complement system is a key innate immune defence against infection and an important driver of inflammation; however, these very properties can also cause harm. Inappropriate or uncontrolled activation of complement can cause local and/or systemic inflammation, tissue damage and disease. Complement provides numerous options for drug development as it is a proteolytic cascade that involves nine specific proteases, unique multimolecular activation and lytic complexes, an arsenal of natural inhibitors, and numerous receptors that bind to activation fragments. Drug design is facilitated by the increasingly detailed structural understanding of the molecules involved in the complement system. Only two anti-complement drugs are currently on the market, but many more are being developed for diseases that include infectious, inflammatory, degenerative, traumatic and neoplastic disorders. In this Review, we describe the history, current landscape and future directions for anti-complement therapies.

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Figure 1: Targets for inhibition in the complement pathway.
Figure 2: Controlling the alternative-pathway amplification loop.
Figure 3: Progress of complement therapeutics towards clinical use.

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Acknowledgements

The authors thank K. Miller of GlaxoSmithKline, for her thoughtful review and discussion of the manuscript.

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Authors and Affiliations

  1. Institute of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, CF14 4XN, UK

    B. Paul Morgan & Claire L. Harris

  2. Cytokine, Chemokine and Complement Discovery Performance Unit, Immunoinflammation Therapy Area, GlaxoSmithKline, Medicines Research Centre, Stevenage, SG1 2NY, UK

    Claire L. Harris

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  1. B. Paul Morgan
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Correspondence to B. Paul Morgan or Claire L. Harris.

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Competing interests

B.P.M. has undertaken paid consultancy work and sponsored research for GlaxoSmithKline, Swedish Orphan Biovitrum and Achillion Pharma. C.L.H. is employed by GlaxoSmithKline.

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Glossary

Tickover

The spontaneous low-level complement activation that occurs continuously in the plasma of normal individuals and assists in the rapid response to pathogens.

Opsonins

Proteins and protein fragments that coat pathogens and dead or dying host cells to label them for recognition and elimination by phagocytes. The principle complement opsonins are C3b and iC3b.

Short consensus repeats

Structural units comprising approximately 60 amino acids held in a globular domain by 2 invariant disulfide bonds; they are the key building blocks for the assembly of proteins in the regulators of complement activation (RCA) family — including Factor H (FH) and the FH-related (FHR) proteins, C4b-binding protein (C4BP), complement receptor type 1 (CR1) and CR2 — but are also found in other complement proteins and proteins unrelated to complement.

Oligosaccharide sialyl Lewis X epitopes

Carbohydrate structures that are expressed on cell surfaces and act as ligands for cell adhesion molecules of the selectin family.

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Morgan, B., Harris, C. Complement, a target for therapy in inflammatory and degenerative diseases. Nat Rev Drug Discov 14, 857–877 (2015). https://doi.org/10.1038/nrd4657

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