Title |
Developing the IVIG biomimetic, Hexa-Fc, for drug and vaccine applications
|
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Published in |
Scientific Reports, April 2015
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DOI | 10.1038/srep09526 |
Pubmed ID | |
Authors |
Daniel M. Czajkowsky, Jan Terje Andersen, Anja Fuchs, Timothy J. Wilson, David Mekhaiel, Marco Colonna, Jianfeng He, Zhifeng Shao, Daniel A. Mitchell, Gang Wu, Anne Dell, Stuart Haslam, Katy A. Lloyd, Shona C. Moore, Inger Sandlie, Patricia A. Blundell, Richard J. Pleass |
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. |
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Geographical breakdown
Country | Count | As % |
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United Kingdom | 3 | 43% |
Spain | 1 | 14% |
Unknown | 3 | 43% |
Demographic breakdown
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Members of the public | 5 | 71% |
Practitioners (doctors, other healthcare professionals) | 1 | 14% |
Scientists | 1 | 14% |
Mendeley readers
Geographical breakdown
Country | Count | As % |
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Spain | 1 | 2% |
Unknown | 62 | 98% |
Demographic breakdown
Readers by professional status | Count | As % |
---|---|---|
Student > Ph. D. Student | 27 | 43% |
Researcher | 10 | 16% |
Student > Master | 7 | 11% |
Student > Bachelor | 3 | 5% |
Professor | 3 | 5% |
Other | 7 | 11% |
Unknown | 6 | 10% |
Readers by discipline | Count | As % |
---|---|---|
Immunology and Microbiology | 17 | 27% |
Agricultural and Biological Sciences | 13 | 21% |
Medicine and Dentistry | 8 | 13% |
Biochemistry, Genetics and Molecular Biology | 7 | 11% |
Chemistry | 3 | 5% |
Other | 6 | 10% |
Unknown | 9 | 14% |