Multivalent Fcγ-receptor engagement by a hexameric Fc-fusion protein triggers Fcγ-receptor internalisation and modulation of Fcγ-receptor functions.

Autor:	Qureshi OS; UCB Pharma, 216 Bath Road, Slough, SL1 3WE, UK., Rowley TF; UCB Pharma, 216 Bath Road, Slough, SL1 3WE, UK., Junker F; UCB Pharma, 216 Bath Road, Slough, SL1 3WE, UK., Peters SJ; UCB Pharma, 216 Bath Road, Slough, SL1 3WE, UK., Crilly S; UCB Pharma, 216 Bath Road, Slough, SL1 3WE, UK., Compson J; UCB Pharma, 216 Bath Road, Slough, SL1 3WE, UK., Eddleston A; UCB Pharma, 216 Bath Road, Slough, SL1 3WE, UK., Björkelund H; Ridgeview Diagnostics AB, Uppsala Science Park, SE75183, Uppsala, Sweden., Greenslade K; UCB Pharma, 216 Bath Road, Slough, SL1 3WE, UK., Parkinson M; UCB Pharma, 216 Bath Road, Slough, SL1 3WE, UK., Davies NL; UCB Pharma, 216 Bath Road, Slough, SL1 3WE, UK., Griffin R; UCB Pharma, 216 Bath Road, Slough, SL1 3WE, UK., Pither TL; UCB Pharma, 216 Bath Road, Slough, SL1 3WE, UK., Cain K; UCB Pharma, 216 Bath Road, Slough, SL1 3WE, UK., Christodoulou L; UCB Pharma, 216 Bath Road, Slough, SL1 3WE, UK., Staelens L; UCB Biopharma Sprl., Chemin du Foriest, Braine l'Alleud, Belgium., Ward E; UCB Pharma, 216 Bath Road, Slough, SL1 3WE, UK., Tibbitts J; UCB Pharma, 216 Bath Road, Slough, SL1 3WE, UK., Kiessling A; UCB Pharma, 216 Bath Road, Slough, SL1 3WE, UK., Smith B; UCB Pharma, 216 Bath Road, Slough, SL1 3WE, UK., Brennan FR; UCB Pharma, 216 Bath Road, Slough, SL1 3WE, UK., Malmqvist M; Ridgeview Diagnostics AB, Uppsala Science Park, SE75183, Uppsala, Sweden., Fallah-Arani F; UCB Pharma, 216 Bath Road, Slough, SL1 3WE, UK., Humphreys DP; UCB Pharma, 216 Bath Road, Slough, SL1 3WE, UK. david.humphreys@ucb.com.
Jazyk:	angličtina
Zdroj:	Scientific reports [Sci Rep] 2017 Dec 06; Vol. 7 (1), pp. 17049. Date of Electronic Publication: 2017 Dec 06.
DOI:	10.1038/s41598-017-17255-8
Abstrakt:	Engagement of Fcγ-receptors triggers a range of downstream signalling events resulting in a diverse array of immune functions. As a result, blockade of Fc-mediated function is an important strategy for the control of several autoimmune and inflammatory conditions. We have generated a hexameric-Fc fusion protein (hexameric-Fc) and tested the consequences of multi-valent Fcγ-receptor engagement in in vitro and in vivo systems. In vitro engagement of hexameric-Fc with FcγRs showed complex binding interactions that altered with receptor density and triggered the internalisation and degradation of Fcγ-receptors. This caused a disruption of Fc-binding and phagocytosis. In vivo, in a mouse ITP model we observed a short half-life of hexameric-Fc but were nevertheless able to observe inhibition of platelet phagocytosis several days after hexameric-Fc dosing. In cynomolgus monkeys, we again observed a short half-life, but were able to demonstrate effective FcγR blockade. These findings demonstrate the ability of multi-valent Fc-based therapeutics to interfere with FcγR function and a potential mechanism through which they could have a sustained effect; the internalisation and degradation of FcγRs.
Databáze:	MEDLINE
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