Nanobody repertoire generated against the spike protein of ancestral SARS-CoV-2 remains efficacious against the rapidly evolving virus

Author:

Ketaren Natalia E.1ORCID,Mast Fred D.2ORCID,Fridy Peter C.1ORCID,Olivier Jean Paul2ORCID,Sanyal Tanmoy3ORCID,Sali Andrej3ORCID,Chait Brian T.4ORCID,Rout Michael P.1ORCID,Aitchison John D.256ORCID

Affiliation:

1. Laboratory of Cellular and Structural Biology, The Rockefeller University

2. Center for Global Infectious Disease Research, Seattle Children’s Research Institute

3. Department of Bioengineering and Therapeutic Sciences, Department of Pharmaceutical Chemistry, California Institute for Quantitative Biosciences, Byers Hall, 1700 4th Street, Suite 503B, University of California

4. Laboratory of Mass Spectrometry and Gaseous Ion Chemistry, The Rockefeller University

5. Department of Pediatrics, University of Washington

6. Department of Biochemistry, University of Washington

Abstract

To date, all major modes of monoclonal antibody therapy targeting SARS-CoV-2 have lost significant efficacy against the latest circulating variants. As SARS-CoV-2 omicron sublineages account for over 90% of COVID-19 infections, evasion of immune responses generated by vaccination or exposure to previous variants poses a significant challenge. A compelling new therapeutic strategy against SARS-CoV-2 is that of single domain antibodies, termed nanobodies, which address certain limitations of monoclonal antibodies. Here we demonstrate that our high-affinity nanobody repertoire, generated against wild-type SARS-CoV-2 spike protein (Mast, Fridy et al. 2021), remains effective against variants of concern, including omicron BA.4/BA.5; a subset is predicted to counter resistance in emerging XBB and BQ.1.1 sublineages. Furthermore, we reveal the synergistic potential of nanobody cocktails in neutralizing emerging variants. Our study highlights the power of nanobody technology as a versatile therapeutic and diagnostic tool to combat rapidly evolving infectious diseases such as SARS-CoV-2.

Publisher

eLife Sciences Publications, Ltd

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