Shark nanobodies with potent SARS-CoV-2 neutralizing activity and broad sarbecovirus reactivity

Wei-Hung Chen, Agnes Hajduczki, Elizabeth J. Martinez, Hongjun Bai, Hanover Matz, Thomas M. Hill, Eric Lewitus, William C. Chang, Layla Dawit, Caroline E. Peterson, Phyllis A. Rees, Adelola B. Ajayi, Emily S. Golub, Isabella Swafford, Vincent Dussupt, Sapna David, Sandra V. Mayer, Sandrine Soman, Caitlin Kuklis, Courtney Corbitt, Jocelyn King, Misook Choe, Rajeshwer S. Sankhala, Paul V. Thomas, Michelle Zemil, Lindsay Wieczorek, Tricia Hart, Debora Duso, Larry Kummer, Lianying Yan, Spencer L. Sterling, Eric D. Laing, Christopher C. Broder, Jazmean K. Williams, Edgar Davidson, Benjamin J. Doranz, Shelly J. Krebs, Victoria R. Polonis, Dominic Paquin-Proulx, Morgane Rolland, William W. Reiley, Gregory D. Gromowski, Kayvon Modjarrad, Helen Dooley () and M. Gordon Joyce ()
Additional contact information
Wei-Hung Chen: Walter Reed Army Institute of Research
Agnes Hajduczki: Walter Reed Army Institute of Research
Elizabeth J. Martinez: Walter Reed Army Institute of Research
Hongjun Bai: Walter Reed Army Institute of Research
Hanover Matz: University of Maryland School of Medicine
Thomas M. Hill: University of Maryland School of Medicine
Eric Lewitus: Walter Reed Army Institute of Research
William C. Chang: Walter Reed Army Institute of Research
Layla Dawit: Walter Reed Army Institute of Research
Caroline E. Peterson: Walter Reed Army Institute of Research
Phyllis A. Rees: Walter Reed Army Institute of Research
Adelola B. Ajayi: Walter Reed Army Institute of Research
Emily S. Golub: Walter Reed Army Institute of Research
Isabella Swafford: Walter Reed Army Institute of Research
Vincent Dussupt: Walter Reed Army Institute of Research
Sapna David: Walter Reed Army Institute of Research
Sandra V. Mayer: Henry M. Jackson Foundation for the Advancement of Military Medicine
Sandrine Soman: Viral Diseases Branch, Walter Reed Army Institute of Research
Caitlin Kuklis: Viral Diseases Branch, Walter Reed Army Institute of Research
Courtney Corbitt: Walter Reed Army Institute of Research
Jocelyn King: Walter Reed Army Institute of Research
Misook Choe: Walter Reed Army Institute of Research
Rajeshwer S. Sankhala: Walter Reed Army Institute of Research
Paul V. Thomas: Walter Reed Army Institute of Research
Michelle Zemil: U.S. Military HIV Research Program, Walter Reed Army Institute of Research
Lindsay Wieczorek: Henry M. Jackson Foundation for the Advancement of Military Medicine
Tricia Hart: Trudeau Institute
Debora Duso: Trudeau Institute
Larry Kummer: Trudeau Institute
Lianying Yan: Uniformed Services University
Spencer L. Sterling: Uniformed Services University
Eric D. Laing: Uniformed Services University
Christopher C. Broder: Uniformed Services University
Jazmean K. Williams: Integral Molecular
Edgar Davidson: Integral Molecular
Benjamin J. Doranz: Integral Molecular
Shelly J. Krebs: Walter Reed Army Institute of Research
Victoria R. Polonis: U.S. Military HIV Research Program, Walter Reed Army Institute of Research
Dominic Paquin-Proulx: Walter Reed Army Institute of Research
Morgane Rolland: Walter Reed Army Institute of Research
William W. Reiley: Trudeau Institute
Gregory D. Gromowski: Viral Diseases Branch, Walter Reed Army Institute of Research
Kayvon Modjarrad: Walter Reed Army Institute of Research
Helen Dooley: University of Maryland School of Medicine
M. Gordon Joyce: Walter Reed Army Institute of Research

Nature Communications, 2023, vol. 14, issue 1, 1-18

Abstract: Abstract Despite rapid and ongoing vaccine and therapeutic development, SARS-CoV-2 continues to evolve and evade, presenting a need for next-generation diverse therapeutic modalities. Here we show that nurse sharks immunized with SARS-CoV-2 recombinant receptor binding domain (RBD), RBD-ferritin (RFN), or spike protein ferritin nanoparticle (SpFN) immunogens elicit a set of new antigen receptor antibody (IgNAR) molecules that target two non-overlapping conserved epitopes on the spike RBD. Representative shark antibody variable NAR-Fc chimeras (ShAbs) targeting either of the two epitopes mediate cell-effector functions, with high affinity to all SARS-CoV-2 viral variants of concern, including the divergent Omicron strains. The ShAbs potently cross-neutralize SARS-CoV-2 WA-1, Alpha, Beta, Delta, Omicron BA.1 and BA.5, and SARS-CoV-1 pseudoviruses, and confer protection against SARS-CoV-2 challenge in the K18-hACE2 transgenic mouse model. Structural definition of the RBD-ShAb01-ShAb02 complex enabled design and production of multi-specific nanobodies with enhanced neutralization capacity, and picomolar affinity to divergent sarbecovirus clade 1a, 1b and 2 RBD molecules. These shark nanobodies represent potent immunotherapeutics both for current use, and future sarbecovirus pandemic preparation.

Date: 2023
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DOI: 10.1038/s41467-023-36106-x

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