Neutralizing antibodies (nAbs) hold promise as effective therapeutics against COVID-19. Here, we describe protein engineering and modular design principles that have led to the development of synthetic bivalent and tetravalent nAbs against SARS-CoV-2. The best nAb targets the host receptor binding site of the viral S-protein and its tetravalent versions can block entry with a potency that exceeds the bivalent nAbs by an order of magnitude. Structural studies show that both the bivalent and tetravalent nAbs can make multivalent interactions with a single S-protein trimer, observations consistent with the avidity and potency of these molecules. Significantly, we show that the tetravalent nAbs show much increased tolerance to potential virus escape mutants. Bivalent and tetravalent nAbs can be produced at large-scale and are as stable and specific as approved antibody drugs. Our results provide a general framework for developing potent antiviral therapies against COVID-19 and related viral threats, and our strategy can be readily applied to any antibody drug currently in development.

中文翻译：

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四价 SARS-CoV-2 中和抗体显示出增强的效力和对逃逸突变的抵抗力

中和抗体 (nAb) 有望成为针对 COVID-19 的有效疗法。在这里，我们描述了导致开发针对 SARS-CoV-2 的合成二价和四价 nAb 的蛋白质工程和模块化设计原则。最好的 nAb 靶向病毒 S 蛋白的宿主受体结合位点，其四价版本可以阻止进入，其效力超过二价 nAb 一个数量级。结构研究表明，二价和四价 nAb 都可以与单个 S 蛋白三聚体进行多价相互作用，观察结果与这些分子的亲和力和效力一致。值得注意的是，我们表明四价 nAb 对潜在病毒逃逸突变体的耐受性大大提高。二价和四价 nAb 可以大规模生产，并且与批准的抗体药物一样稳定和特异性。我们的结果为开发针对 COVID-19 和相关病毒威胁的有效抗病毒疗法提供了一个总体框架，我们的策略可以很容易地应用于目前正在开发的任何抗体药物。