Complete Mapping of Mutations to the SARS-CoV-2 Spike Receptor-Binding Domain that Escape Antibody Recognition.
Complete Mapping of Mutations to the SARS-CoV-2 Spike Receptor-Binding Domain that Escape Antibody Recognition.
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DOI：
10.1101/2020.09.10.292078
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发表时间：
2021-01-13
影响因子：
30.3
通讯作者：
Bloom, Jesse D
中科院分区：
文献类型：
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作者：
Greaney, Allison J;Starr, Tyler N;Bloom, Jesse D
靶向SARS-CoV-2刺突受体结合结构域（RBD）的抗体正被开发为治疗剂，并对感染引起的中和抗体应答做出重大贡献。在这里，我们描述了一种深度突变扫描方法来映射RBD中的所有氨基酸突变如何影响抗体结合，并将此方法应用于10种人单克隆抗体。逃逸突变聚集在RBD的几个表面上，这些表面大致对应于结构上定义的抗体表位。然而，即使是靶向相同RBD表面的抗体也常常具有不同的逃逸突变。完整的逃逸图预测在单一抗体存在下病毒生长期间选择哪些突变，并使我们能够设计逃逸抗性抗体鸡尾酒-包括竞争结合RBD相同表面但具有不同逃逸突变的抗体鸡尾酒。因此，完整的逃逸突变图谱使合理设计抗体治疗和评估病毒进化的抗原后果。靶向SARS-CoV-2刺突受体结合域（RBD）的抗体正在开发作为治疗药物，是中和感染引起的抗体反应的主要贡献者。在这里，我们描述了一种深度突变扫描方法来映射RBD中的所有氨基酸突变如何影响抗体结合，并将该方法应用于10种人单克隆抗体。逃逸突变聚集在RBD的几个表面上，这些表面大致对应于结构上定义的抗体表位。然而，即使是靶向相同表面的抗体也常常具有不同的逃逸突变。完整的逃逸图预测在存在单一抗体的情况下，在病毒生长期间选择哪些突变。它们进一步使设计逃逸抗性抗体鸡尾酒成为可能，包括竞争结合相同RBD表面但具有不同逃逸突变的抗体鸡尾酒。因此，完整的逃逸-突变图谱使得能够合理设计抗体疗法和评估病毒进化的抗原性后果。
Antibodies targeting the SARS-CoV-2 spike receptor-binding domain (RBD) are being developed as therapeutics and make a major contribution to the neutralizing antibody response elicited by infection. Here, we describe a deep mutational scanning method to map how all amino-acid mutations in the RBD affect antibody binding, and apply this method to 10 human monoclonal antibodies. The escape mutations cluster on several surfaces of the RBD that broadly correspond to structurally defined antibody epitopes. However, even antibodies targeting the same RBD surface often have distinct escape mutations. The complete escape maps predict which mutations are selected during viral growth in the presence of single antibodies, and enable us to design escape-resistant antibody cocktails-including cocktails of antibodies that compete for binding to the same surface of the RBD but have different escape mutations. Therefore, complete escape-mutation maps enable rational design of antibody therapeutics and assessment of the antigenic consequences of viral evolution.Antibodies targeting the SARS-CoV-2 spike receptor-binding domain (RBD) are being developed as therapeutics and are a major contributor to neutralizing antibody responses elicited by infection. Here, we describe a deep mutational scanning method to map how all amino-acid mutations in the RBD affect antibody binding and apply this method to 10 human monoclonal antibodies. The escape mutations cluster on several surfaces of the RBD that broadly correspond to structurally defined antibody epitopes. However, even antibodies targeting the same surface often have distinct escape mutations. The complete escape maps predict which mutations are selected during viral growth in the presence of single antibodies. They further enable the design of escape-resistant antibody cocktails-including cocktails of antibodies that compete for binding to the same RBD surface but have different escape mutations. Therefore, complete escape-mutation maps enable rational design of antibody therapeutics and assessment of the antigenic consequences of viral evolution.