@article{7505f39a962f448cb388cacd3f3728f8,
title = "Developing the IVIG biomimetic, Hexa-Fc, for drug and vaccine applications",
abstract = "The remarkable clinical success of Fc-fusion proteins has driven intense investigation for even more potent replacements. Using quality-by-design (QbD) approaches, we generated hexameric-Fc (hexa-Fc), a ∼20 nm oligomeric Fc-based scaffold that we here show binds low-affinity inhibitory receptors (FcRL5, FcγRIIb, and DC-SIGN) with high avidity and specificity, whilst eliminating significant clinical limitations of monomeric Fc-fusions for vaccine and/or cancer therapies, in particular their poor ability to activate complement. Mass spectroscopy of hexa-Fc reveals high-mannose, low-sialic acid content, suggesting that interactions with these receptors are influenced by the mannose-containing Fc. Molecular dynamics (MD) simulations provides insight into the mechanisms of hexa-Fc interaction with these receptors and reveals an unexpected orientation of high-mannose glycans on the human Fc that provides greater accessibility to potential binding partners. Finally, we show that this biosynthetic nanoparticle can be engineered to enhance interactions with the human neonatal Fc receptor (FcRn) without loss of the oligomeric structure, a crucial modification for these molecules in therapy and/or vaccine strategies where a long plasma half-life is critical.",
author = "Czajkowsky, {Daniel M.} and Andersen, {Jan Terje} and Anja Fuchs and Wilson, {Timothy J.} and David Mekhaiel and Marco Colonna and Jianfeng He and Zhifeng Shao and Mitchell, {Daniel A.} and Gang Wu and Anne Dell and Stuart Haslam and Lloyd, {Katy A.} and Moore, {Shona C.} and Inger Sandlie and Blundell, {Patricia A.} and Pleass, {Richard J.}",
note = "Funding Information: We gratefully acknowledge the Royal Society for funding this work through a Theo Murphy Blue Skies award to R.P, and the MRC Confidence in Concepts for funding P.A.B. We also thank Baxter Healthcare for IVIg through an investigator led grant BT11-000280. We thank Dr John Hodkinson of Biotest for supplying Pentaglobin. Malawian IVIG was a kind gift from Professor Alister Craig. Purified recombinant HIV gp120 was a kind gift of Dr Max Crispin (University of Oxford). This work was also supported by grants from the Biotechnology and Biological Sciences Research Council (to A.D. and S.M.H.). D.M.C. and Z.S. were supported by NSFC (91129000, 11374207, 31370750, 21303104) and MOST (2010CB529205). I.S. and J.T.A. were supported by the Research Council of Norway through its Centres of Excellence funding scheme (project number 179573). J.T.A. was supported by the Research Council of Norway (Grant no. 230526/F20 and 179573/V40) and the South-Eastern Norway Regional Health Authority (Grant no. 39375). Publisher Copyright: {\textcopyright} 2015 Scientific Reports.",
year = "2015",
month = apr,
day = "27",
doi = "10.1038/srep09526",
language = "English",
volume = "5",
journal = "Scientific Reports",
issn = "2045-2322",
}