Zhao Fangzhu, Keating Celina, Ozorowski Gabriel, Shaabani Namir, Francino-Urdaniz Irene M, Barman Shawn, Limbo Oliver, Burns Alison, Zhou Panpan, Ricciardi Michael J, Woehl Jordan, Tran Quoc, Turner Hannah L, Peng Linghang, Huang Deli, Nemazee David, Andrabi Raiees, Sok Devin, Teijaro John R, Whitehead Timothy A, Ward Andrew B, Burton Dennis R, Jardine Joseph G
Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA.
IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA 92037, USA.
iScience. 2022 Sep 16;25(9):104914. doi: 10.1016/j.isci.2022.104914. Epub 2022 Aug 11.
The rapid spread of SARS-CoV-2 variants poses a constant threat of escape from monoclonal antibody and vaccine countermeasures. Mutations in the ACE2 receptor binding site on the surface S protein have been shown to disrupt antibody binding and prevent viral neutralization. Here, we used a directed evolution-based approach to engineer three neutralizing antibodies for enhanced binding to S protein. The engineered antibodies showed increased functional activity in terms of neutralization potency and/or breadth of neutralization against viral variants. Deep mutational scanning revealed that higher binding affinity reduces the total number of viral escape mutations. Studies in the Syrian hamster model showed two examples where the affinity-matured antibody provided superior protection compared to the parental antibody. These data suggest that monoclonal antibodies for antiviral indications would benefit from affinity maturation to reduce viral escape pathways and appropriate affinity maturation in vaccine immunization could help resist viral variation.
严重急性呼吸综合征冠状病毒2（SARS-CoV-2）变体的迅速传播对单克隆抗体和疫苗对策构成了持续的逃逸威胁。已证明表面S蛋白上的血管紧张素转换酶2（ACE2）受体结合位点的突变会破坏抗体结合并阻止病毒中和。在此，我们采用基于定向进化的方法设计了三种中和抗体，以增强与S蛋白的结合。这些工程抗体在中和效力和/或针对病毒变体的中和广度方面显示出增强的功能活性。深度突变扫描表明，更高的结合亲和力会减少病毒逃逸突变的总数。在叙利亚仓鼠模型中的研究显示了两个例子，其中亲和力成熟的抗体比亲本抗体提供了更好的保护。这些数据表明，用于抗病毒适应症的单克隆抗体将受益于亲和力成熟以减少病毒逃逸途径，并且疫苗免疫中适当的亲和力成熟有助于抵抗病毒变异。
