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Broad and potent activity against SARS-like viruses by an engineered human monoclonal antibody
Science ( IF 44.7 ) Pub Date : 2021-01-25 , DOI: 10.1126/science.abf4830
C Garrett Rappazzo 1 , Longping V Tse 2 , Chengzi I Kaku 1 , Daniel Wrapp 3 , Mrunal Sakharkar 1 , Deli Huang 4 , Laura M Deveau 1 , Thomas J Yockachonis 5 , Andrew S Herbert 6, 7 , Michael B Battles 1 , Cecilia M O'Brien 6, 7 , Michael E Brown 1 , James C Geoghegan 1 , Jonathan Belk 1 , Linghang Peng 4 , Linlin Yang 4 , Yixuan Hou 2 , Trevor D Scobey 2 , Dennis R Burton 4, 8, 9, 10 , David Nemazee 4 , John M Dye 6 , James E Voss 4 , Bronwyn M Gunn 5 , Jason S McLellan 3 , Ralph S Baric 2, 11 , Lisa E Gralinski 2 , Laura M Walker 1, 12
Affiliation  

The recurrent zoonotic spillover of coronaviruses (CoVs) into the human population underscores the need for broadly active countermeasures. 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 high potency. Structural and biochemical studies demonstrate that ADG-2 employs a distinct angle of approach to recognize a highly conserved epitope overlapping the receptor binding site. In immunocompetent mouse models of SARS and COVID-19, prophylactic administration 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 against clade 1 sarbecoviruses.

中文翻译:


工程化人单克隆抗体对 SARS 样病毒具有广泛而有效的活性



冠状病毒(CoV)反复向人群传播人畜共患疾病,这凸显了采取广泛积极对策的必要性。我们采用定向进化方法设计了三种 SARS-CoV-2 抗体,以增强中和广度和效力。其中一种亲和力成熟的变体 ADG-2 对大量 sarbecovirus 受体结合域 (RBD) 显示出强大的结合活性,并高效中和代表性流行性 sarbecovirus。结构和生化研究表明 ADG-2 采用独特的方法角度来识别与受体结合位点重叠的高度保守的表位。在 SARS 和 COVID-19 免疫功能正常的小鼠模型中,预防性施用 ADG-2 提供了针对呼吸负担、肺部病毒复制和肺部病理的完全保护。总而言之,ADG-2 代表了一种有前途的针对 1 型 sarbecoviruses 的广谱治疗候选药物。
更新日期:2021-01-25
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