State Key Laboratory for Diagnosis and Treatment of Infectious Diseases/National Clinical Research Center for Infectious Diseases, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310003, China.
CAS Key Laboratory of Infection and Immunity, National Laboratory of Macromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China.
Cell Res. 2021 Jan;31(1):25-36. doi: 10.1038/s41422-020-00444-y. Epub 2020 Dec 1.
Structural principles underlying the composition and synergistic mechanisms of protective monoclonal antibody cocktails are poorly defined. Here, we exploited antibody cooperativity to develop a therapeutic antibody cocktail against SARS-CoV-2. On the basis of our previously identified humanized cross-neutralizing antibody H014, we systematically analyzed a fully human naive antibody library and rationally identified a potent neutralizing antibody partner, P17, which confers effective protection in animal model. Cryo-EM studies dissected the nature of the P17 epitope, which is SARS-CoV-2 specific and distinctly different from that of H014. High-resolution structure of the SARS-CoV-2 spike in complex with H014 and P17, together with functional investigations revealed that in a two-antibody cocktail, synergistic neutralization was achieved by S1 shielding and conformational locking, thereby blocking receptor attachment and viral membrane fusion, conferring high potency as well as robustness against viral mutation escape. Furthermore, cluster analysis identified a hypothetical 3rd antibody partner for further reinforcing the cocktail as pan-SARS-CoVs therapeutics.
保护性单克隆抗体鸡尾酒的组成和协同作用机制的结构原理还没有明确界定。在这里，我们利用抗体协同作用开发了一种针对 SARS-CoV-2 的治疗性抗体鸡尾酒。基于我们之前鉴定的人源化中和抗体 H014，我们系统地分析了一个完全人源的原始抗体文库，并合理地鉴定了一个有效的中和抗体伙伴 P17，它在动物模型中提供了有效的保护。冷冻电镜研究剖析了 P17 表位的性质，它是 SARS-CoV-2 特异性的，与 H014 的表位明显不同。SARS-CoV-2 刺突与 H014 和 P17 的高分辨率结构以及功能研究表明，在双抗体鸡尾酒中，通过 S1 屏蔽和构象锁定实现协同中和，从而阻断受体附着和病毒膜融合，赋予高效力和对病毒突变逃逸的稳健性。此外，聚类分析确定了一个假设的第 3 个抗体伙伴，以进一步加强鸡尾酒作为泛 SARS-CoV 治疗药物。
