Rappazzo C Garrett, Tse Longping V, Kaku Chengzi I, Wrapp Daniel, Sakharkar Mrunal, Huang Deli, Deveau Laura M, Yockachonis Thomas J, Herbert Andrew S, Battles Michael B, O'Brien Cecilia M, Brown Michael E, Geoghegan James C, Belk Jonathan, Peng Linghang, Yang Linlin, Scobey Trevor D, Burton Dennis R, Nemazee David, Dye John M, Voss James E, Gunn Bronwyn M, McLellan Jason S, Baric Ralph S, Gralinski Lisa E, Walker Laura M
Adimab LLC, Lebanon, NH 03766, USA.
Department of Epidemiology, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
bioRxiv. 2020 Nov 17:2020.11.17.385500. doi: 10.1101/2020.11.17.385500.
The recurrent zoonotic spillover of coronaviruses (CoVs) into the human population underscores the need for broadly active countermeasures. Here, we employed a directed evolution approach to engineer three SARS-CoV-2 antibodies for enhanced neutralization breadth and potency. One of the affinity-matured variants, ADG-2, displays strong binding activity to a large panel of sarbecovirus receptor binding domains (RBDs) and neutralizes representative epidemic sarbecoviruses with remarkable potency. Structural and biochemical studies demonstrate that ADG-2 employs a unique angle of approach to recognize a highly conserved epitope overlapping the receptor binding site. In murine models of SARS-CoV and SARS-CoV-2 infection, passive transfer of ADG-2 provided complete protection against respiratory burden, viral replication in the lungs, and lung pathology. Altogether, ADG-2 represents a promising broad-spectrum therapeutic candidate for the treatment and prevention of SARS-CoV-2 and future emerging SARS-like CoVs.
冠状病毒（CoV）反复发生人畜共患的溢出感染进入人类群体，这凸显了采取广泛有效的应对措施的必要性。在此，我们采用定向进化方法改造了三种严重急性呼吸综合征冠状病毒2（SARS-CoV-2）抗体，以增强中和广度和效力。亲和力成熟的变体之一ADG-2，对一大组沙贝病毒受体结合域（RBD）表现出强结合活性，并以显著的效力中和代表性的流行沙贝病毒。结构和生化研究表明，ADG-2采用独特的接近角度来识别与受体结合位点重叠的高度保守表位。在严重急性呼吸综合征冠状病毒（SARS-CoV）和SARS-CoV-2感染的小鼠模型中，被动转移ADG-2可提供完全保护，防止出现呼吸负担、肺部病毒复制和肺部病理变化。总之，ADG-2是一种有前景的广谱治疗候选药物，可用于治疗和预防SARS-CoV-2以及未来出现的类似SARS的冠状病毒。
