Nanobody repertoire generated against the spike protein of ancestral SARS-CoV-2 remains efficacious against the rapidly evolving virus
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 prev...
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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 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. |
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AbstractList | 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 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. |
Audience | Academic |
Author | Olivier, Jean Paul Mast, Fred D Chait, Brian T Sanyal, Tanmoy Aitchison, John D Fridy, Peter C Ketaren, Natalia E Sali, Andrej Rout, Michael P |
Author_xml | – sequence: 1 givenname: Natalia E orcidid: 0000-0002-7869-6162 surname: Ketaren fullname: Ketaren, Natalia E organization: Laboratory of Cellular and Structural Biology, The Rockefeller University, New York, United States – sequence: 2 givenname: Fred D orcidid: 0000-0002-2177-6647 surname: Mast fullname: Mast, Fred D organization: Center for Global Infectious Disease Research, Seattle Children's Research Institute, Seattle, United States – sequence: 3 givenname: Peter C orcidid: 0000-0002-8208-9154 surname: Fridy fullname: Fridy, Peter C organization: Laboratory of Cellular and Structural Biology, The Rockefeller University, New York, United States – sequence: 4 givenname: Jean Paul orcidid: 0000-0002-2197-271X surname: Olivier fullname: Olivier, Jean Paul organization: Center for Global Infectious Disease Research, Seattle Children's Research Institute, Seattle, United States – sequence: 5 givenname: Tanmoy orcidid: 0000-0002-6009-9431 surname: Sanyal fullname: Sanyal, Tanmoy organization: Department of Bioengineering and Therapeutic Sciences, Department of Pharmaceutical Chemistry, California Institute for Quantitative Biosciences, Byers Hall, University of California, San Francisco, San Francisco, United States – sequence: 6 givenname: Andrej orcidid: 0000-0003-0435-6197 surname: Sali fullname: Sali, Andrej organization: Department of Bioengineering and Therapeutic Sciences, Department of Pharmaceutical Chemistry, California Institute for Quantitative Biosciences, Byers Hall, University of California, San Francisco, San Francisco, United States – sequence: 7 givenname: Brian T surname: Chait fullname: Chait, Brian T organization: Laboratory of Mass Spectrometry and Gaseous Ion Chemistry, The Rockefeller University, New York, United States – sequence: 8 givenname: Michael P orcidid: 0000-0003-2010-706X surname: Rout fullname: Rout, Michael P organization: Laboratory of Cellular and Structural Biology, The Rockefeller University, New York, United States – sequence: 9 givenname: John D orcidid: 0000-0002-9153-6497 surname: Aitchison fullname: Aitchison, John D organization: Department of Biochemistry, University of Washington, Seattle, United States |
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Keywords | viruses nanobodies chemical biology infectious disease neutralization betacoronavirus biochemistry SARS-CoV-2 variants microbiology single-domain antibodies human spike |
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Title | Nanobody repertoire generated against the spike protein of ancestral SARS-CoV-2 remains efficacious against the rapidly evolving virus |
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