Complement, a target for therapy in inflammatory and degenerative diseases

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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.

Supplementary information

The online version of this article (doi:10.1038/nrd4657) contains supplementary material, which is available to authorized users.

Abstract

The complement cascade, a key regulator of innate immunity, is a rich source of potential therapeutic targets for diseases including autoimmune, inflammatory and degenerative disorders. Morgan and Harris discuss the progress made in modulating the complement system and the existing challenges, including dosing, localization of the drug to the target and how to interfere with protein–protein interactions.

Supplementary information

The online version of this article (doi:10.1038/nrd4657) contains supplementary material, which is available to authorized users.

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.

Supplementary information

The online version of this article (doi:10.1038/nrd4657) contains supplementary material, which is available to authorized users.

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Most cited references 173

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STEC-HUS, atypical HUS and TTP are all diseases of complement activation.

Marina Noris, Giuseppe Remuzzi, Federica Mescia (2012)

Haemolytic uraemic syndrome (HUS) and thrombotic thrombocytopaenic purpura (TTP) are diseases characterized by microvascular thrombosis, with consequent thrombocytopaenia, haemolytic anaemia and dysfunction of affected organs. Advances in our understanding of the molecular pathology led to the recognition of three different diseases: typical HUS caused by Shiga toxin-producing Escherichia coli (STEC-HUS); atypical HUS (aHUS), associated with genetic or acquired disorders of regulatory components of the complement system; and TTP that results from a deficiency of ADAMTS13, a plasma metalloprotease that cleaves von Willebrand factor. In this Review, we discuss data indicating that complement hyperactivation is a common pathogenetic effector that leads to endothelial damage and microvascular thrombosis in all three diseases. In STEC-HUS, the toxin triggers endothelial complement deposition through the upregulation of P-selectin and possibly interferes with the activity of complement regulatory molecules. In aHUS, mutations in the genes coding for complement components predispose to hyperactivation of the alternative pathway of complement. In TTP, severe ADAMTS13 deficiency leads to generation of massive platelet thrombi, which might contribute to complement activation. More importantly, evidence is emerging that pharmacological targeting of complement with the anti-C5 monoclonal antibody eculizumab can effectively treat not only aHUS for which it is indicated, but also STEC-HUS and TTP in some circumstances.

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Atypical Hemolytic Uremic Syndrome

David J Kavanagh, Tim H J Goodship, Anna Richards (2013)

Summary Hemolytic uremic syndrome (HUS) is a triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure. The atypical form of HUS is a disease characterized by complement overactivation. Inherited defects in complement genes and acquired autoantibodies against complement regulatory proteins have been described. Incomplete penetrance of mutations in all predisposing genes is reported, suggesting that a precipitating event or trigger is required to unmask the complement regulatory deficiency. The underlying genetic defect predicts the prognosis both in native kidneys and after renal transplantation. The successful trials of the complement inhibitor eculizumab in the treatment of atypical HUS will revolutionize disease management.

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Dynamics of complement activation in aHUS and how to monitor eculizumab therapy.

Marina Noris, Miriam Galbusera, Sara Gastoldi … (2014)

Atypical hemolytic-uremic syndrome (aHUS) is associated with genetic complement abnormalities/anti-complement factor H antibodies, which paved the way to treatment with eculizumab. We studied 44 aHUS patients and their relatives to (1) test new assays of complement activation, (2) verify whether such abnormality occurs also in unaffected mutation carriers, and (3) search for a tool for eculizumab titration. An abnormal circulating complement profile (low C3, high C5a, or SC5b-9) was found in 47% to 64% of patients, irrespective of disease phase. Acute aHUS serum, but not serum from remission, caused wider C3 and C5b-9 deposits than control serum on unstimulated human microvascular endothelial cells (HMEC-1). In adenosine 5'-diphosphate-activated HMEC-1, also sera from 84% and 100% of patients in remission, and from all unaffected mutation carriers, induced excessive C3 and C5b-9 deposits. At variance, in most patients with C3 glomerulopathies/immune complex-associated membranoproliferative glomerulonephritis, serum-induced endothelial C5b-9 deposits were normal. In 8 eculizumab-treated aHUS patients, C3/SC5b-9 circulating levels did not change posteculizumab, whereas serum-induced endothelial C5b-9 deposits normalized after treatment, paralleled or even preceded remission, and guided drug dosing and timing. These results point to efficient complement inhibition on endothelium for aHUS treatment. C5b-9 endothelial deposits might help monitor eculizumab effectiveness, avoid drug overexposure, and save money considering the extremely high cost of the drug.

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Author and article information

Contributors

B. Paul Morgan: morganbp@cardiff.ac.uk

Bio :

B. Paul Morgan is Professor of Immunology and Director of the Systems Immunity University Research Institute at Cardiff University, UK. He is a chemical pathologist but has worked on the complement system for over 30 years. His Ph.D. explored the biology of the terminal pathway and the mechanisms of cell escape from complement killing, work that he consolidated during 2 years of post-doctoral training in US complement labs. He returned to Cardiff to complete clinical training and build a research group, generously supported by the Wellcome Trust. He has published over 400 papers and reviews exploring different aspects of the complement system, particularly the biology of complement regulation and the roles of complement in disease. In recent years he has focused primarily on the roles of complement in neurological diseases and novel approaches to therapy. 10.1038/nrd4657.

Claire L. Harris: harriscl@cardiff.ac.uk

Bio :

Claire L. Harris holds a Personal Chair at Cardiff University, UK, and is also Head of Complement in the Cytokine, Chemokine and Complement Discovery Performance Unit (C3 DPU) at GlaxoSmithKline. She graduated from the University of Cambridge with a PhD in the biochemistry of the complement system and moved to Cardiff in 1993 to join the Complement Biology Group at the University of Wales College of Medicine, Cardiff, UK. After a postdoctoral period working in the biochemistry of complement in humans and other species, she obtained a University Award from the Wellcome Trust and established a research group focused on structure–function relationships in complement activators and regulators. She has a longstanding interest in the mechanisms underlying complement dysregulation and disease and in designing improved and targeted therapies for diseases driven by complement. Her recent work includes functional characterization of complement protein variants linked to diseases such as age-related macular degeneration, this has led to the concept of the 'complotype' — the influence of complement genetic makeup on inflammation & infection. She joined the C3 DPU at GSK in June 2013 to drive development of a differentiated portfolio in complement therapies. Claire L. Harris's homepage.

Journal

Journal ID (nlm-ta): Nat Rev Drug Discov

Journal ID (iso-abbrev): Nat Rev Drug Discov

Title: Nature Reviews. Drug Discovery

Publisher: Nature Publishing Group UK (London )

ISSN (Print): 1474-1776

ISSN (Electronic): 1474-1784

Publication date (Electronic): 23 October 2015

Publication date (Print): 2015

Volume: 14

Issue: 12

Pages: 857-877

Affiliations

[1 ]GRID grid.5600.3, ISNI 0000 0001 0807 5670, Institute of Infection and Immunity, School of Medicine, Cardiff University, ; Cardiff, CF14 4XN UK

[2 ]GRID grid.418236.a, ISNI 0000 0001 2162 0389, Cytokine, Chemokine and Complement Discovery Performance Unit, Immunoinflammation Therapy Area, GlaxoSmithKline, Medicines Research Centre, ; Stevenage, SG1 2NY UK

Article

Publisher ID: BFnrd4657

DOI: 10.1038/nrd4657

PMC ID: 7098197

PubMed ID: 26493766

SO-VID: 412efb47-2c32-4f9e-a45f-57bba79b9baa

License:

This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.