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  • Review Article
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Therapeutic potential of complement modulation

Nature Reviews Drug Discovery volume 9, pages 43–56 (2010)Cite this article

Key Points

  • The complement system is an important part of the innate immune system that participates in tissue injury in a number of inflammatory and autoimmune diseases.

  • Polymorphisms in genes that encode complement proteins involved in activation or regulation of the system are recognized as triggers of diseases such as atypical haemolytic uraemic syndrome and age-related macular degeneration.

  • Modulation of complement activation could be beneficial in reducing tissue injury or even preventing the onset of such diseases.

  • Currently, only a few agents that are known to inhibit complement activation are approved for clinical use for narrow indications. These include an antibody to C5 (eculizumab) aimed at the treatment of paroxysmal nocturnal haemoglobinuria, Serping1 concentrate as a replacement therapy in hereditary angioedema and pooled immunoglobulin G preparations for intravenous use in some autoimmune diseases.

  • Recent literature shows that there is a growing interest in developing new and potent agents that target complement proteins and products of activation. Some examples include humanized monoclonal antibodies to complement proteins, activation products or receptors, synthetic molecules that target complement proteins or receptors, constructs of naturally occurring complement regulators and receptors modified to enhance tissue-directed activity and prolong half-life.

  • Many new agents have been tested in in vitro and in vivo animal models, generally with encouraging results. Some agents have reached clinical trials for indications such as hereditary angioedema, age-related macular degeneration, rheumatoid arthritis and psoriasis.

  • Because of a better understanding of the role of complement in many pathological states, targeting its activation holds promise as an innovative way to approach therapeutic intervention in many patients.

Abstract

The complement system is an essential component of innate immunity that has been more recently recognized as an unexpected player in various pathological states. These include age-related macular degeneration, atypical haemolytic uraemic syndrome, allergy, foetal loss, and axonal and myelin degradation after trauma. Its importance has also been recognized in physiological processes including haematopoietic stem cell homing to the bone marrow, liver regeneration and modulation of adaptive immune responses. Although the complement system has long been known to be involved in autoimmune and inflammatory diseases, few agents that target the complement system are currently approved for clinical use. However, renewed interest in modulating this system in various pathological conditions has emerged, and several agents are now in development.

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Figure 1: Complement activation pathways.
Figure 2: Mechanisms of complement regulation.
Figure 3: Site of action of complement inhibitors.

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Authors and Affiliations

  1. Centre de Recherche en Rhumatologie et Immunologie, Centre Hospitalier Universitaire de Québec and Départment de Microbiologie-Infectiologie et Immunologie, Université Laval, Québec, Canada

    Eric Wagner

  2. Departments of Pediatrics and Immunology, Duke University Medical Center, Box 2611, Durham, 27710, North Carolina, USA

    Michael M. Frank

Authors
  1. Eric Wagner
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  2. Michael M. Frank
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Correspondence to Michael M. Frank.

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DATABASES

Entrez Gene

http://www.ncbi.nlm.nih.gov/gene

OMIM

http://www.ncbi.nlm.nih.gov/omim

idiopathic thrombocytopenic purpura

Kawasaki disease

membranoproliferative glomerulonephritis

Glossary

Age-related macular degeneration

The principal cause of blindness in the elderly in industrialized countries. It is characterized by a loss of retinal pigment epithelium and photoreceptors, and deposits of proteins and lipids (drusen) or neovascularization.

Innate immune system

Innate immunity is said to be nonspecific, but many of its components, including complement, recognize pathogen associated molecular patterns (PAMPs) for initiation of a defence reaction.

Anaphylatoxins

Small peptides derived from C3 and C5 cleavage that promote inflammation by inducing leukocyte chemotaxis and increasing vascular permeability, among other activities.

Kinin pathway

Triggers the generation of bradykinin, a potent vasoactive peptide, upon activation of the contact system of the coagulation cascade.

Decay-accelerating activity

Shortening of the half-lives of convertases of the complement activation cascade by CR1 and DAF by accelerated dissociation of their components.

Immunological memory

The ability of the immune system to recognize and respond rapidly and vigorously to a specific antigen with which it has previously had contact.

Opsonization

Coating of an organism with complement fragments that leads to recognition by specific receptors on phagocytes and elimination by phagocytosis.

Systemic lupus erythematosus

A prototypical autoimmune disease characterized by the presence of antibodies directed against intracellular antigens (for example, DNA) that form immune complexes causing inflammation at sites of deposition such as the skin, joints and kidneys.

Ischaemia–reperfusion injury

A condition that arises upon restoration of blood flow in an organ deprived of oxygen supply.

Hereditary angioedema

Condition that is manifested by recurrent episodes of skin swelling and abdominal pain; may be fatal if swelling affects the larynx.

Atypical haemolytic uraemic syndrome

Renal pathology manifested by a triad of microangiopathic haemolytic anaemia, thrombocytopaenia and acute renal failure. It can be sporadic or familial.

Hyperacute rejection

This occurs within minutes of revascularization of the organ graft and is caused by complement-activating pre-formed antibodies reacting against endothelial cells. By contrast, acute rejection occurs within the first weeks following transplantation because of elicited antibodies.

Cell homing

The process by which haematopoietic stem and progenitor cells are contained within the bone marrow and travel to this site when transplanted.

Regulator of complement activation protein family

These include factor H, C4BP, DAF, MCP, CR1 and CR2. They share a common structure consisting of a number of repetitive units of 60 amino acids called short consensus repeats, or complement control protein modules, which contain binding sites for activated complement proteins.

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Wagner, E., Frank, M. Therapeutic potential of complement modulation. Nat Rev Drug Discov 9, 43–56 (2010). https://doi.org/10.1038/nrd3011

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