Chen Chuan, Saville James W, Marti Michelle M, Schäfer Alexandra, Cheng Mary Hongying, Mannar Dhiraj, Zhu Xing, Berezuk Alison M, Banerjee Anupam, Sobolewski Michele D, Kim Andrew, Treat Benjamin R, Da Silva Castanha Priscila Mayrelle, Enick Nathan, McCormick Kevin D, Liu Xianglei, Adams Cynthia, Hines Margaret Grace, Sun Zehua, Chen Weizao, Jacobs Jana L, Barratt-Boyes Simon M, Mellors John W, Baric Ralph S, Bahar Ivet, Dimitrov Dimiter S, Subramaniam Sriram, Martinez David R, Li Wei
Center for Antibody Therapeutics, Division of Infectious Diseases, Department of Medicine, University of Pittsburgh Medical School, Pittsburgh, PA, USA.
Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC V6T 1Z3, Canada.
iScience. 2022 Aug 19;25(8):104798. doi: 10.1016/j.isci.2022.104798. Epub 2022 Jul 20.
The emergence of SARS-CoV-2 variants of concern (VOCs) requires the development of next-generation biologics with high neutralization breadth. Here, we characterized a human V domain, F6, which we generated by sequentially panning large phage-displayed V libraries against receptor binding domains (RBDs) containing VOC mutations. Cryo-EM analyses reveal that F6 has a unique binding mode that spans a broad surface of the RBD and involves the antibody framework region. Attachment of an Fc region to a fusion of F6 and ab8, a previously characterized V domain, resulted in a construct (F6-ab8-Fc) that broadly and potently neutralized VOCs including Omicron. Additionally, prophylactic treatment using F6-ab8-Fc reduced live Beta (B.1.351) variant viral titers in the lungs of a mouse model. Our results provide a new potential therapeutic against SARS-CoV-2 variants including Omicron and highlight a vulnerable epitope within the spike that may be exploited to achieve broad protection against circulating variants.
值得关注的严重急性呼吸综合征冠状病毒2（SARS-CoV-2）变异株（VOC）的出现，需要开发具有高中和广度的下一代生物制剂。在此，我们对一种人V结构域F6进行了表征，该结构域是通过针对含有VOC突变的受体结合域（RBD）对大型噬菌体展示V文库进行连续淘选而产生的。冷冻电镜分析表明，F6具有独特的结合模式，跨越RBD的广泛表面并涉及抗体框架区。将Fc区域连接到F6与先前表征的V结构域ab8的融合体上，产生了一种构建体（F6-ab8-Fc），该构建体能够广泛且有效地中和包括奥密克戎在内的VOC。此外，使用F6-ab8-Fc进行预防性治疗可降低小鼠模型肺部活的贝塔（B.1.351）变异株病毒滴度。我们的结果为针对包括奥密克戎在内的SARS-CoV-2变异株提供了一种新的潜在治疗方法，并突出了刺突蛋白内一个可能被利用来实现对循环变异株广泛保护的易损表位。
