Developing the IVIG biomimetic, hexa-Fc, for drug and vaccine applications.
Developing the IVIG biomimetic, hexa-Fc, for drug and vaccine applications.
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开发用于药物和疫苗应用的 IVIG 仿生物质 hexa-Fc。
DOI：
10.1038/srep09526
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发表时间：
2015-04-27
影响因子：
4.6
通讯作者：
Pleass RJ
中科院分区：
文献类型：
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作者：
Czajkowsky DM;Andersen JT;Fuchs A;Wilson TJ;Mekhaiel D;Colonna M;He J;Shao Z;Mitchell DA;Wu G;Dell A;Haslam S;Lloyd KA;Moore SC;Sandlie I;Blundell PA;Pleass RJ
Fc融合蛋白的显著临床成功推动了对更有效替代物的深入研究。使用设计质量（QbD）方法，我们生成了六聚体Fc（hexa-Fc），这是一种约20 nm的寡聚Fc基支架，我们在此显示其以高亲合力和特异性结合低亲和力抑制性受体（FcRL 5，FcγRIIb和DC-SIGN），同时消除了单体Fc融合物用于疫苗和/或癌症治疗的重大临床限制，特别是其激活补体的能力差。 hexa-Fc的质谱显示高甘露糖、低唾液酸含量，表明与这些受体的相互作用受到含甘露糖Fc的影响。分子动力学（MD）模拟提供了对hexa-Fc与这些受体相互作用机制的深入了解，并揭示了人Fc上高甘露糖聚糖的意想不到的方向，这为潜在的结合伴侣提供了更大的可及性。最后，我们表明，这种生物合成的纳米颗粒可以被工程化，以增强与人类新生儿Fc受体（FcRn）的相互作用，而不损失的寡聚体结构，这些分子在治疗和/或疫苗策略中的一个重要的修改，其中长的血浆半衰期是至关重要的。
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.