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Developing the IVIG biomimetic, Hexa-Fc, for drug and vaccine applications

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Czajkowsky, Daniel M., Andersen, Jan Terje, Fuchs, Anja, Wilson, Timothy J., Mekhaiel, David, Colonna, Marco, He, Jianfeng, Shao, Zhifeng, Mitchell, Daniel A., Wu, Gang, Dell, Anne, Haslam, Stuart, Lloyd, Katy, Moore, Shona C., Sandlie, Inger, Blundell, Pat ORCID: https://orcid.org/0000-0003-3386-5660 and Pleass, Richard ORCID: https://orcid.org/0000-0001-7438-8296 (2015) 'Developing the IVIG biomimetic, Hexa-Fc, for drug and vaccine applications'. Scientific Reports, Vol 5, e9526.

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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: Article
Subjects: QU Biochemistry > Cells and Genetics > QU 300 General works
QU Biochemistry > Proteins. Amino Acids. Peptides > QU 55 Proteins
QW Microbiology and Immunology > Immunotherapy and Hypersensitivity > QW 806 Vaccination
Faculty: Department: Biological Sciences > Department of Tropical Disease Biology
Digital Object Identifer (DOI): https://doi.org/10.1038/srep09526
Depositing User: Lynn Roberts-Maloney
Date Deposited: 30 Jun 2015 08:29
Last Modified: 22 Aug 2019 12:52
URI: https://archive.lstmed.ac.uk/id/eprint/5228

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