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In vivo characterisation and therapeutic efficacy of a C5-specific inhibitor [Abstract]

Hepburn, Natalie J., Williams, Anwen Sian, Chamberlain, Jayne C., Hamer, Joseph, Nunn, M. A., Morgan, Bryan Paul and Harris, Claire Louise 2007. In vivo characterisation and therapeutic efficacy of a C5-specific inhibitor [Abstract]. Molecular Immunology 44 (1-3) , p. 183. 10.1016/j.molimm.2006.07.087

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Abstract

The involvement of complement in the perpetuation and exacerbation of many inflammatory diseases has driven the search for therapeutic agents capable of inhibiting dysregulated complement activation. Many of these reagents regulate the early stages of the complement cascade by inhibiting the C3 convertases and have demonstrated therapeutic effect in animal models of disease and in clinical trials in humans. However, the drawback of systemic and total C inhibition, particularly in long-term treatment of chronic inflammatory disease, is potentiation of infection and immune complex disease due to an inability to opsonise complexes and foreign cells and to lyse pathogens. The terminal pathway of complement has been implicated in pathology in animal models of arthritis, multiple sclerosis and myasthenia gravis. Specific inhibition of the terminal pathway should ameliorate disease whilst leaving key physiological processes, such as opsonisation, unaffected. Recent identification of a C5-binding protein in the salivary gland of the soft tick Ornithodoros moubata has enabled development of a recombinant terminal pathway-specific reagent, rEV576. This reagent binds C5 to form a stable complex preventing C5 participation in the complement cascade. We have further investigated the characteristics of this reagent and here describe its binding to C5 in vitro and in vivo, circulating half-life in rats and effect on complement CH50. Its therapeutic effect in rat models of myasthenia gravis (EAMG) and arthritis has been investigated. In EAMG, this reagent inhibited end plate damage, C9 deposition and cellular infiltration and ablated clinical disease. Such reagents offer exciting prospects for targeted treatment of complement-mediated diseases without inhibition of the physiological roles of complement.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Systems Immunity Research Institute (SIURI)
Subjects: Q Science > QR Microbiology > QR180 Immunology
R Medicine > RC Internal medicine
R Medicine > RM Therapeutics. Pharmacology
Publisher: Elsevier
Last Modified: 04 Jun 2017 04:43
URI: http://orca-mwe.cf.ac.uk/id/eprint/43471

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