Bispecific antibodies with broad neutralization potency against SARS-CoV-2 variants of concern.

Autor:	Rubio AA; Stanford Biosciences, Stanford School of Medicine; Stanford, USA.; Department of Biology, Stanford University; Stanford, USA., Baharani VA; Laboratory of Retrovirology, The Rockefeller University; New York, USA.; Laboratory of Molecular Immunology, The Rockefeller University; New York, USA., Dadonaite B; Basic Sciences Division and Computational Biology Program, Fred Hutchinson Cancer Center; Seattle, USA., Parada M; Department of Biology, Stanford University; Stanford, USA., Abernathy ME; Department of Biology, Stanford University; Stanford, USA., Wang Z; Laboratory of Molecular Immunology, The Rockefeller University; New York, USA., Lee YE; Department of Biology, Stanford University; Stanford, USA., Eso MR; Department of Biology, Stanford University; Stanford, USA., Phung J; Department of Biology, Stanford University; Stanford, USA., Ramos I; Department of Biology, Stanford University; Stanford, USA., Chen T; Department of Biology, Stanford University; Stanford, USA., Nesr GE; Stanford Biosciences, Stanford School of Medicine; Stanford, USA., Bloom JD; Basic Sciences Division and Computational Biology Program, Fred Hutchinson Cancer Center; Seattle, USA.; Howard Hughes Medical Institute; Chevy Chase, USA., Bieniasz PD; Laboratory of Retrovirology, The Rockefeller University; New York, USA.; Howard Hughes Medical Institute; Chevy Chase, USA., Nussenzweig MC; Laboratory of Molecular Immunology, The Rockefeller University; New York, USA.; Howard Hughes Medical Institute; Chevy Chase, USA., Barnes CO; Department of Biology, Stanford University; Stanford, USA.; ChEM-H Institute, Stanford University; Stanford, CA.; Chan Zuckerberg Biohub; San Francisco, USA.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2024 May 06. Date of Electronic Publication: 2024 May 06.
DOI:	10.1101/2024.05.05.592584
Abstrakt:	The ongoing emergence of 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 N-terminal domain (NTD) and receptor binding domain (RBD)-specific monoclonal antibodies previously isolated from 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-EM 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. Notably, 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, EG.5.1, and BA.2.86, contrasting the diminished potency of parental antibodies delivered as monotherapies or as a cocktail. Furthermore, prophylactic delivery of CoV2-biRN5 significantly reduced the viral load within the lungs of K18-hACE2 mice following challenge with SARS-CoV-2 XBB.1.5. In conclusion, our NTD-RBD bsAbs offer promising potential for the design of resilient, next-generation antibody therapeutics against SARS-CoV-2 VOCs. Competing Interests: Competing interests: The Rockefeller University has filed a provisional patent application in connection with monoclonal antibodies described in this work on which Z.W. and M.C.N. are inventors (US patent 17/575,246). J.D.B. is on the scientific advisory boards of Invivyd, Aerium Therapeutics, Apriori Bio, and the Vaccine Company. J.D.B. consults for GSK and Moderna. B.D. consults for Moderna. J.D.B. and B.D. are inventors on Fred Hutch licensed patents related to viral deep mutational scanning.
Databáze:	MEDLINE
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