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Here, we characterized amino-terminal domain (NTD)\u2013 and receptor binding domain (RBD)\u2013specific monoclonal antibodies previously isolated from coronavirus disease 2019 (COVID-19) convalescent donors for their activity against emergent SARS-CoV-2 VOCs. Among these, the NTD-specific antibody C1596 displayed the greatest breadth of binding to VOCs, with cryo\u2013electron microscopy structural analysis revealing recognition of a distinct NTD epitope outside of the site i antigenic supersite. Given C1596\u2019s favorable binding profile, we designed a series of bispecific antibodies (bsAbs), termed CoV2-biRNs, that featured both NTD and RBD specificities. Two of the C1596-inclusive bsAbs, CoV2-biRN5 and CoV2-biRN7, retained potent in vitro neutralization activity against all Omicron variants tested, including XBB.1.5, BA.2.86, and JN.1, contrasting the diminished potency of parental antibodies delivered as monotherapies or as a cocktail. Furthermore, prophylactic delivery of CoV2-biRN5 reduced the viral load within the lungs of K18-hACE2 mice after challenge with SARS-CoV-2 XBB.1.5. In conclusion, NTD-RBD bsAbs offer promising potential for the design of resilient, next-generation antibody therapeutics against SARS-CoV-2 VOCs.<\/jats:p>","DOI":"10.1126\/scitranslmed.adq5720","type":"journal-article","created":{"date-parts":[[2025,3,5]],"date-time":"2025-03-05T18:58:23Z","timestamp":1741201103000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":20,"title":["Bispecific antibodies targeting the N-terminal and receptor binding domains potently neutralize SARS-CoV-2 variants of concern"],"prefix":"10.1126","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3676-4283","authenticated-orcid":true,"given":"Adonis A.","family":"Rubio","sequence":"first","affiliation":[{"name":"Stanford Biosciences, Stanford School of Medicine, Stanford, CA 94305, USA."},{"name":"Department of Biology, Stanford University, Stanford, CA 94305, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Viren 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