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Developing the IVIG biomimetic, Hexa-Fc, for drug and vaccine applications
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Czajkowsky, Daniel M., Andersen, J. T., Fuchs, Anne, Wilson, T. J., Mekhaie, D., Colonna, M., He, J., Shao, Zhiyuan, Mitchell, Daniel A., Wu, Gang, Dell, Anne, Haslam, S., Lloyd, K. A., Moore, Stephen J., Sandlie, I., Blundell, P. A. and Richard, J. P. (2015) Developing the IVIG biomimetic, Hexa-Fc, for drug and vaccine applications. Scientific Reports, Volume 5 . Article number 5926. doi:10.1038/srep09526
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Official URL: http://dx.doi.org/10.1038/srep09526
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.
| Item Type: | Journal Article | ||||||||
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| Subjects: | Q Science > QC Physics Q Science > QD Chemistry Q Science > QR Microbiology |
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| Divisions: | Faculty of Medicine > Warwick Medical School > Health Sciences Faculty of Medicine > Warwick Medical School |
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| Library of Congress Subject Headings (LCSH): | Immunological adjuvants, Molecules--Models , Vaccines | ||||||||
| Journal or Publication Title: | Scientific Reports | ||||||||
| Publisher: | Nature Publishing Group | ||||||||
| ISSN: | 2045-2322 | ||||||||
| Official Date: | 27 April 2015 | ||||||||
| Dates: |
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| Volume: | Volume 5 | ||||||||
| Number of Pages: | 11 | ||||||||
| Article Number: | Article number 5926 | ||||||||
| DOI: | 10.1038/srep09526 | ||||||||
| Status: | Peer Reviewed | ||||||||
| Publication Status: | Published | ||||||||
| Access rights to Published version: | Open Access | ||||||||
| Funder: | Royal Society (Great Britain), Medical Research Council (Great Britain) (MRC), Baxter International Inc., Biotechnology and Biological Sciences Research Council (Great Britain) (BBSRC), Guo jia zi ran ke xue ji jin wei yuan hui (China) [National Natural Science Foundation of China] (NSFC), Large Sky Area Multi-Object Fibre Spectroscopic Telescope (LAMOST), Norges forskningsråd [Norwegian Research Council], Norway. Helse- og omsorgsdepartementet [Ministry of Health and Care Services] | ||||||||
| Grant number: | BT11-000280 (Baxter), 91129000 (NSFC), 11374207 (NSFC), 31370750 (NSFC), 21303104 (NSFC), 2010CB529205 (MOST), 179573 (Norwegian Research Council, 230526/F20 ((Norwegian Research Council), 179573/V40 (Norwegian Research Council), 39375 (Norway. Helse- og |
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