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The study has been published in Science. YES, it is PEER-REVIEWED.
• www.science.org/doi/10.1126/...
Abstract The ongoing emergence of severe acute respiratory syndrome coronavirus (SARS-CoV-2) variants of concern (VOCs) that reduce the effectiveness of antibody therapeutics necessitates development of next-generation antibody modalities that are resilient to viral evolution. Here, we characterized amino-terminal domain (NTD)- and receptor binding domain (RBD) -specific 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-electron microscopy structural analysis revealing recognition of a distinct NTD epitope outside of the site i antigenic supersite. Given C1596's 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 bAbs offer promising potential for the design of resilient, next-generation antibody therapeutics against SARS-CoV-2 VOCs. An illustration of the bispecific antibodies the Stanford-led research team developed to neutralize the virus that causes COVID-19. Named “CoV2-biRN,” these two antibodies work together by attaching to different areas of the virus. Credit: Christopher O. Barnes/Adonis Rubi The bispecific antibodies target two areas of the virus: One attaches to the “NTD,” or Spike N-terminal domain, an area on the virus that does not change very much. This allows the second antibody to attach to the “RBD,” or receptor-binding domain, essentially preventing the virus from infecting human cells. Credit: Christopher O. Barnes/Adonis Rubio
March 9, 2025 at 4:01 PM