Multivalent Fcγ-receptor engagement by a hexameric Fc-fusion protein triggers Fcγ-receptor internalisation and modulation of Fcγ-receptor functions. Issue 1 (December 2017)

• Record Type: Journal Article
• Authors: Qureshi, O.; Rowley, T.; Junker, F.; Peters, S.; Crilly, S.; Compson, J.; Eddleston, A.; Björkelund, H.; Greenslade, K.; Parkinson, M.; Davies, N.; Griffin, R.; Pither, T.; Cain, K.; Christodoulou, L.; Staelens, L.; Ward, E.; Tibbitts, J.; Kiessling, A.; Smith, B.; Brennan, F.; Malmqvist, M.; Fallah-Arani, F.; Humphreys, D.
• Is Part Of: Scientific reports. Volume 7:Issue 1(2017)
• Page Start: 1
• Page End: 15
• Publication Date: 2017-12
• Subjects: Natural history -- Research -- Periodicals; Biology -- Research -- Periodicals; Physical sciences -- Research -- Periodicals; Earth sciences -- Research -- Periodicals; Environmental sciences -- Research -- Periodicals; 502.85
• DOI: 10.1038/s41598-017-17255-8
• Languages: English
• ISSNs: 2045-2322

Abstract

Abstract 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 inin vitro andin 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.