Novel COVID-19 therapeutics are urgently needed. We generated a phage-displayed human antibody V_H domain library from which we identified a high-affinity V_H binder ab8. Bivalent V_H, V_H-Fc ab8, bound with high avidity to membrane-associated S glycoprotein and to mutants found in patients. It potently neutralized mouse-adapted SARS-CoV-2 in wild-type mice at a dose as low as 2 mg/kg and exhibited high prophylactic and therapeutic efficacy in a hamster model of SARS-CoV-2 infection, possibly enhanced by its relatively small size. Electron microscopy combined with scanning mutagenesis identified ab8 interactions with all three S protomers and showed how ab8 neutralized the virus by directly interfering with ACE2 binding. V_H-Fc ab8 did not aggregate and did not bind to 5,300 human membrane-associated proteins. The potent neutralization activity of V_H-Fc ab8 combined with good developability properties and cross-reactivity to SARS-CoV-2 mutants provide a strong rationale for its evaluation as a COVID-19 therapeutic.

迫切需要新型COVID-19治疗剂。我们生成了噬菌体展示的人抗体V _H结构域文库，从中我们鉴定出了高亲和力的V _H结合蛋白ab8。二价V _H，V _H -Fc ab8高亲和力与膜相关的S糖蛋白和患者中发现的突变体结合。它以低至2 mg / kg的剂量有效中和了野生型小鼠中适应小鼠的SARS-CoV-2，并且在SARS-CoV-2仓鼠模型中表现出较高的预防和治疗功效，可能相对于其增强小尺寸。电子显微镜与扫描诱变相结合，鉴定了与所有三个S启动子的ab8相互作用，并显示了ab8如何通过直接干扰ACE2结合来中和病毒。V _{^ h}-Fc ab8没有聚集并且不结合5,300种人膜相关蛋白。V _H -Fc ab8的有效中和活性与良好的可显影性和与SARS-CoV-2突变体的交叉反应性相结合，为其评估为COVID-19治疗剂提供了有力的依据。