期刊
SCIENTIFIC REPORTS
卷 5, 期 -, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/srep09526
关键词
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资金
- Royal Society
- MRC
- Baxter Healthcare [BT11-000280]
- Biotechnology and Biological Sciences Research Council
- NSFC [91129000, 11374207, 31370750, 21303104]
- MOST [2010CB529205]
- Research Council of Norway through its Centres of Excellence funding scheme [179573]
- South-Eastern Norway Regional Health Authority [39375]
- Research Council of Norway [230526/F20, 179573/V40]
- BBSRC [BB/K016164/1, BB/F008309/1] Funding Source: UKRI
- MRC [MC_PC_12017] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BB/F008309/1, BB/K016164/1] Funding Source: researchfish
- Engineering and Physical Sciences Research Council [987447] Funding Source: researchfish
- Medical Research Council [MC_PC_12017] Funding Source: researchfish
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 similar to 20 nm oligomeric Fc-based scaffold that we here show binds low-affinity inhibitory receptors (FcRL5, Fc gamma RIIb, 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 providesgreater 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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