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 VH domain, F6, which we generated by sequentially panning large phage displayed VH 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 a Fc region to a fusion of F6 and ab8, a previously characterized VH 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.
By Chuan Chen, James Saville, Michelle M. Marti, Alexandra Schäfer, Mary Hongying Cheng, Dhiraj Mannar, Xing Zhu, Alison Berezuk, Anupam Banerjee, Michele D. Sobolewski, Andrew Kim, Benjamin R. Treat, Priscila M S Castanha, Nathan Enick, Kevin Dylan McCormick, Xianglei Liu, Cynthia Adams, Margaret Grace Hines, Zehua Sun, Weizao Chen, Jana L. Jacobs, Simon Barratt-Boyes, John W. Mellors, Ralph Baric, Ivet Bahar, Dimiter Dimitrov, Sriram Subramaniam, David R. Martinez, Wei Li