Neutralizing antibodies (nAbs) hold promise as 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 tetravalent versions block entry with a potency exceeding 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, consistent with the avidity and potency of these molecules. Significantly, we show that the tetravalent nAbs show increased tolerance to potential virus escape mutants and an emerging variant of concern. 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 enhancing antiviral therapies against COVID-19 and related viral threats, and our strategy can be applied to virtually any antibody drug.

中和抗体 (nAb) 有望成为 COVID-19 的治疗药物。在这里，我们描述了蛋白质工程和模块化设计原理，这些原理导致了针对 SARS-CoV-2 的合成二价和四价 nAb 的开发。最好的 nAb 靶向病毒 S 蛋白的宿主受体结合位点，四价版本阻断进入的能力比二价 nAb 强一个数量级。结构研究表明，二价和四价 nAb 都可以与单个 S 蛋白三聚体产生多价相互作用，这与这些分子的亲合力和效力一致。值得注意的是，我们发现四价 nAb 对潜在的病毒逃逸突变体和新出现的令人关注的变体表现出更高的耐受性。二价和四价 nAb 可以大规模生产，并且与已批准的抗体药物一样稳定和特异。我们的结果为增强针对 COVID-19 和相关病毒威胁的抗病毒治疗提供了总体框架，并且我们的策略几乎可以应用于任何抗体药物。