Engineering SARS-CoV-2 neutralizing antibodies for increased potency and reduced viral escape pathways.
Engineering SARS-CoV-2 neutralizing antibodies for increased potency and reduced viral escape pathways.
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DOI：
10.1016/j.isci.2022.104914
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发表时间：
2022-09-16
期刊：
影响因子：
5.8
通讯作者：
Jardine, Joseph G.
中科院分区：
文献类型：
--
作者：
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.
SARS-CoV-2变种的快速传播构成了单克隆抗体和疫苗对策的持续威胁。表面S蛋白上ACE 2受体结合位点的突变已显示破坏抗体结合并阻止病毒中和。在这里，我们使用了一种基于定向进化的方法来设计三种中和抗体，以增强与S蛋白的结合。工程化抗体在针对病毒变体的中和效力和/或中和宽度方面显示出增加的体外功能活性。深度突变扫描显示，较高的结合亲和力减少了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实例，其中亲和力成熟的抗体与亲本抗体相比提供了上级保护。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可以帮助抵抗病毒变异。2类和3类SARS-CoV-2中和单克隆抗体的冷冻电镜分析具有更高亲和力的工程抗体中和新出现的SARS-CoV-2变体更高亲和力的抗体减少病毒逃逸的途径工程抗体提高仓鼠模型的保护免疫学;病毒学;结构生物学。
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 in vitro 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. Cryo-EM analysis of Class 2 and Class 3 SARS-CoV-2 neutralizing monoclonal antibodies Engineered antibodies with higher affinity neutralize emerging SARS-CoV-2 variants The higher affinity antibodies reduce the pathways for viral escape Engineered antibodies improve protection in hamster model Immunology; Virology; Structural biology.
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影响因子：
48
作者：
Barad BA;Echols N;Wang RY;Cheng Y;DiMaio F;Adams PD;Fraser JS
通讯作者：
Fraser JS
影响因子：
64.8
作者：
Barnes CO;Jette CA;Abernathy ME;Dam KA;Esswein SR;Gristick HB;Malyutin AG;Sharaf NG;Huey-Tubman KE;Lee YE;Robbiani DF;Nussenzweig MC;West AP Jr;Bjorkman PJ
通讯作者：
Bjorkman PJ
影响因子：
64.8
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Gaebler C;Wang Z;Lorenzi JCC;Muecksch F;Finkin S;Tokuyama M;Cho A;Jankovic M;Schaefer-Babajew D;Oliveira TY;Cipolla M;Viant C;Barnes CO;Bram Y;Breton G;Hägglöf T;Mendoza P;Hurley A;Turroja M;Gordon K;Millard KG;Ramos V;Schmidt F;Weisblum Y;Jha D;Tankelevich M;Martinez-Delgado G;Yee J;Patel R;Dizon J;Unson-O'Brien C;Shimeliovich I;Robbiani DF;Zhao Z;Gazumyan A;Schwartz RE;Hatziioannou T;Bjorkman PJ;Mehandru S;Bieniasz PD;Caskey M;Nussenzweig MC
通讯作者：
Nussenzweig MC
影响因子：
8.8
作者：
Francino-Urdaniz IM;Steiner PJ;Kirby MB;Zhao F;Haas CM;Barman S;Rhodes ER;Leonard AC;Peng L;Sprenger KG;Jardine JG;Whitehead TA
通讯作者：
Whitehead TA
影响因子：
56.9
作者：
Hsieh, Ching-Lin;Goldsmith, Jory A.;McLellan, Jason S.
通讯作者：
McLellan, Jason S.