On-target IgG hexamerisation driven by a C-terminal IgM tail-piece fusion variant confers augmented complement activation.

Autor: Sopp JM; Antibody and Vaccine Group, Centre for Cancer Immunology, Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton, UK., Peters SJ; UCB Pharma, Slough, UK., Rowley TF; UCB Pharma, Slough, UK., Oldham RJ; Antibody and Vaccine Group, Centre for Cancer Immunology, Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton, UK., James S; Antibody and Vaccine Group, Centre for Cancer Immunology, Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton, UK., Mockridge I; Antibody and Vaccine Group, Centre for Cancer Immunology, Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton, UK., French RR; Antibody and Vaccine Group, Centre for Cancer Immunology, Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton, UK., Turner A; UCB Pharma, Slough, UK., Beers SA; Antibody and Vaccine Group, Centre for Cancer Immunology, Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton, UK., Humphreys DP; UCB Pharma, Slough, UK., Cragg MS; Antibody and Vaccine Group, Centre for Cancer Immunology, Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton, UK. msc@soton.ac.uk.
Jazyk: angličtina
Zdroj: Communications biology [Commun Biol] 2021 Sep 02; Vol. 4 (1), pp. 1031. Date of Electronic Publication: 2021 Sep 02.
DOI: 10.1038/s42003-021-02513-3
Abstrakt: The majority of depleting monoclonal antibody (mAb) drugs elicit responses via Fc-FcγR and Fc-C1q interactions. Optimal C1q interaction is achieved through hexameric Fc:Fc interactions at the target cell surface. Herein is described an approach to exploit the tailpiece of the naturally multimeric IgM to augment hexamerisation of IgG. Fusion of the C-terminal tailpiece of IgM promoted spontaneous hIgG hexamer formation, resulting in enhanced C1q recruitment and complement-dependent cytotoxicity (CDC) but with off-target complement activation and reduced in-vivo efficacy. Mutation of the penultimate tailpiece cysteine to serine (C575S) ablated spontaneous hexamer formation, but facilitated reversible hexamer formation after concentration in solution. C575S mutant tailpiece antibodies displayed increased complement activity only after target binding, in-line with the concept of 'on-target hexamerisation', whilst retaining efficient in-vivo efficacy and augmented target cell killing in the lymph node. Hence, C575S-tailpiece technology represents an alternative format for promoting on-target hexamerisation and enhanced CDC.
(© 2021. The Author(s).)
Databáze: MEDLINE
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