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Characterising the original anti-C5 function-blocking antibody, BB5.1, for species specificity, mode of action and interactions with C5

Zelek, Wioleta M., Menzies, Georgina E., Brancale, Andrea, Stockinger, Brigitta and Morgan, B. Paul 2020. Characterising the original anti-C5 function-blocking antibody, BB5.1, for species specificity, mode of action and interactions with C5. Immunology 161 (2) , pp. 103-113. 10.1111/imm.13228

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Abstract

The implication of complement in multiple diseases over the last twenty years has fuelled interest in developing anti‐complement drugs. To date, the focus has been on C5; blocking cleavage of C5 prevents formation of two pro‐inflammatory activities, C5a anaphylatoxin and membrane attack complex. The concept of C5 blockade to inhibit inflammation dates back thirty years to the description of BB5.1, an anti‐C5 blocking monoclonal antibody raised in C5‐deficient mice. This antibody proved an invaluable tool to demonstrate complement involvement in mouse disease models and catalysed enthusiasm for anti‐complement drug development, culminating in the anti‐human C5 monoclonal antibody ecuizumab, the most successful anti‐complement drug to date, already in the clinic for several rare diseases. Despite its key role in providing proof‐of‐concept for C5 blockade, the mechanism of BB5.1 inhibition remains poorly understood. Here we characterised BB5.1 cross‐species inhibition, C5 binding affinity and chain specificity. BB5.1 efficiently inhibited C5 in mouse serum but not in human or other rodent sera; it prevented C5 cleavage and C5a generation. BB5.1 bound the C5 α‐chain with high affinity and slow off‐rate. BB5.1 complementarity determining regions were obtained and docking algorithms used to predict the likely binding interface on mouse C5.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Pharmacy
Biosciences
Medicine
Publisher: Wiley
ISSN: 0019-2805
Funders: Wellcome Trust, MRC, CRUK
Date of First Compliant Deposit: 22 June 2020
Date of Acceptance: 10 June 2020
Last Modified: 16 Oct 2020 10:00
URI: http://orca-mwe.cf.ac.uk/id/eprint/132680

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