On-target IgG hexamerisation driven by a C-terminal IgM tail-piece fusion variant confers augmented complement activation
On-target IgG hexamerisation driven by a C-terminal IgM tail-piece fusion variant confers augmented complement activation
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.
Sopp, Joshua M.
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Peters, Shirley J.
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Rowley, Tania F.
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Oldham, Robert J.
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James, Sonya
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Mockridge, Ian
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French, Ruth R.
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Turner, Alison
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Beers, Stephen A.
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Humphreys, David P.
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Cragg, Mark S.
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Sopp, Joshua M.
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Peters, Shirley J.
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Rowley, Tania F.
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Oldham, Robert J.
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James, Sonya
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Mockridge, Ian
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French, Ruth R.
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Turner, Alison
de4cf092-66ae-40bc-89fd-2d8fb5214437
Beers, Stephen A.
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Humphreys, David P.
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Cragg, Mark S.
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Sopp, Joshua M., Peters, Shirley J., Rowley, Tania F., Oldham, Robert J., James, Sonya, Mockridge, Ian, French, Ruth R., Turner, Alison, Beers, Stephen A., Humphreys, David P. and Cragg, Mark S.
(2021)
On-target IgG hexamerisation driven by a C-terminal IgM tail-piece fusion variant confers augmented complement activation.
Communications Biology, 4 (1), [1031].
(doi:10.1038/s42003-021-02513-3).
Abstract
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.
Text
s42003-021-02513-3
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Text
Sopp et al. IgG On-Target IgG Hexamer Manuscript revised final acc
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Accepted/In Press date: 2 August 2021
e-pub ahead of print date: 2 September 2021
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© 2021, The Author(s).
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Local EPrints ID: 494118
URI: http://eprints.soton.ac.uk/id/eprint/494118
ISSN: 2399-3642
PURE UUID: 78bae6be-2b88-4cbb-aeb7-116c2dfcf671
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Date deposited: 24 Sep 2024 16:42
Last modified: 03 Oct 2024 01:50
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Author:
Joshua M. Sopp
Author:
Shirley J. Peters
Author:
Tania F. Rowley
Author:
Robert J. Oldham
Author:
Sonya James
Author:
Ian Mockridge
Author:
Ruth R. French
Author:
Alison Turner
Author:
David P. Humphreys
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