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：

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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。