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标题：Potent and broad neutralization of SARS-CoV-2 variants of concern (VOCs) including omicron sub-lineages BA.1 and BA.2 by biparatopic human VH domains
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作者：Chuan Chen ; James W. Saville ; Michelle M. Marti 等
期刊名称：iScience
印刷版ISSN：2589-0042
出版年度：2022
卷号：25
期号：8
页码：1-21
DOI：10.1016/j.isci.2022.104798
语种：English
出版社：Elsevier
摘要：SummaryThe 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 VHdomain, F6, which we generated by sequentially panning large phage-displayed VHlibraries 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 VHdomain, 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.Graphical abstractDisplay OmittedHighlights•Identification of a human VHwith broad neutralization against SARS-CoV-2 VOCs•CryoEM reveals a unique binding paratope of F6 involving the framework region•The biparatopic antibody (F6-ab8-Fc) enhances the neutralization potency•F6-ab8-Fc reduces disease burden and protects mice from the Beta variant mortalityImmunology; Virology.