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Development and characterisation of novel anti-C5 monoclonal antibodies capable of inhibiting complement in multiple species

Zelek, Wioleta M., Taylor, Philip R. and Morgan, B. Paul 2019. Development and characterisation of novel anti-C5 monoclonal antibodies capable of inhibiting complement in multiple species. Immunology 157 (4) , pp. 283-295. 10.1111/imm.13083

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Abstract

Over the last decade there has been an explosion in complement therapies; one third of the drugs in the clinic or in development target C5 protein. Eculizumab, a monoclonal antibody (mAb) that binds C5 and blocks its cleavage by the convertase, is the current gold standard treatment for atypical haemolytic uremic syndrome (aHUS) and paroxysmal nocturnal haemoglobinuria (PNH) and in clinical trials for many other diseases. Here we describe a panel of novel anti‐C5 mAb, including mAb that, like Eculizumab, are efficient inhibitors of complement but, unlike Eculizumab, inhibit across species, including human, rat, rabbit and guinea pig. Several inhibitory anti‐C5 mAb were identified and characterised for C5 binding and lytic inhibitory capacity in comparison to current therapeutic anti‐C5 mAb; three clones, 4G2, 7D4 and 10B6, were selected and further characterised for ligand specificity and affinity and cross‐species inhibitory activity. The mAb 10B6 was human‐specific while mAb 4G2 and 7D4 efficiently inhibited lysis by human, rabbit and rat serum, and weakly inhibited guinea pig complement; 7D4 also weakly inhibited mouse complement in vitro The rat C5‐cross‐reactive mAb 4G2, when administered intraperitoneally in a rat model of myasthenia gravis, effectively blocked the disease and protected muscle endplates from destruction. To our knowledge this is the first report of an anti‐C5 function blocking mAb that permits preclinical studies in rats.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Systems Immunity Research Institute (SIURI)
Publisher: Wiley
ISSN: 0019-2805
Funders: Wellcome Trust
Date of First Compliant Deposit: 20 May 2019
Date of Acceptance: 14 May 2019
Last Modified: 11 Sep 2019 08:02
URI: http://orca-mwe.cf.ac.uk/id/eprint/122673

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