Harnessing Avidity: Quantifying the Entropic and Energetic Effects of Linker Length and Rigidity for Multivalent Binding of Antibodies to HIV-1
Harnessing Avidity: Quantifying the Entropic and Energetic Effects of Linker Length and Rigidity for Multivalent Binding of Antibodies to HIV-1
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DOI：
10.1016/j.cels.2019.09.007
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发表时间：
2019-11-27
期刊：
影响因子：
9.3
通讯作者：
Phillips, Rob
中科院分区：
文献类型：
--
作者：
Einav, Tal;Yazdi, Shahrzad;Phillips, Rob
IgG抗体通过使用它们的两个Fab同时附着于抗原来增加它们的表观亲和力。HIV-1通过具有很少且高度分离的包膜（Env）针对抗体的刺突靶标来挫败这种策略，迫使大多数IgG结合单核苷酸。在这里，我们开发了一个由不同长度和柔性的DNA接头连接的合成diFab的统计力学模型。该框架使我们能够将接头的能量和熵效应转化为diFab的中和效力。我们证明，预测最强的中和效力需要最佳地跨越Env三聚体上的两个Fab结合位点之间的距离的刚性接头，并且可以通过将更多的Fab并入这些构建体中来进一步增强亲合力。这些结果为多价抗HIV-1治疗剂的设计提供了信息，所述多价抗HIV-1治疗剂在面对Env刺突的快速突变时利用亲合力效应来保持对HIV-1的效力。
IgG antibodies increase their apparent affinities by using both of their Fabs to simultaneously attach to antigens. HIV-1 foils this strategy by having few, and highly separated, Envelope (Env) spike targets for antibodies, forcing most IgGs to bind monovalently. Here, we develop a statistical mechanics model of synthetic diFabs joined by DNA linkers of different lengths and flexibilities. This framework enables us to translate the energetic and entropic effects of the linker into the neutralization potency of a diFab. We demonstrate that the strongest neutralization potencies are predicted to require a rigid linker that optimally spans the distance between two Fab binding sites on an Env trimer and that avidity can be further boosted by incorporating more Fabs into these constructs. These results inform the design of multivalent anti-HIV-1 therapeutics that utilize avidity effects to remain potent against HIV-1 in the face of the rapid mutation of Env spikes.