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

Chen, Wei-Hung; Hajduczki, Agnes; Martinez, Elizabeth J.; Bai, Hongjun; Matz, Hanover; Hill, Thomas M.; Lewitus, Eric; Chang, William C.; Dawit, Layla; Peterson, Caroline E.; Rees, Phyllis A.; Ajayi, Adelola B.; Golub, Emily S.; Swafford, Isabella; Dussupt, Vincent; David, Sapna; Mayer, Sandra V.; Soman, Sandrine; Kuklis, Caitlin; Corbitt, Courtney; King, Jocelyn; Choe, Misook; Sankhala, Rajeshwer S.; Thomas, Paul V.; Zemil, Michelle; Wieczorek, Lindsay; Hart, Tricia; Duso, Debora; Kummer, Larry; Yan, Lianying; Sterling, Spencer L.; Laing, Eric D.; Broder, Christopher C.; Williams, Jazmean K.; Davidson, Edgar; Doranz, Benjamin J.; Krebs, Shelly J.; Polonis, Victoria R.; Paquin-Proulx, Dominic; Rolland, Morgane; Reiley, William W.; Gromowski, Gregory D.; Modjarrad, Kayvon; Dooley, Helen; Joyce, M. Gordon

doi:10.1038/s41467-023-36106-x

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

Journal Article · Thu Feb 02 23:00:00 EST 2023 · Nature Communications

DOI:https://doi.org/10.1038/s41467-023-36106-x· OSTI ID:2423606

^[1]; Hajduczki, Agnes ^[1]; ^[1]; ^[1]; Matz, Hanover ^[2]; Hill, Thomas M. ^[2]; Lewitus, Eric ^[1]; ^[1]; Dawit, Layla ^[1]; Peterson, Caroline E. ^[1]; Rees, Phyllis A. ^[1]; Ajayi, Adelola B. ^[1]; Golub, Emily S. ^[1]; ^[1]; ^[1]; David, Sapna ^[1]; Mayer, Sandra V. ^[3]; Soman, Sandrine ^[4]; ^[4]; Corbitt, Courtney ^[1] more »

Walter Reed Army Institute of Research, Silver Spring, MD (United States); Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD (United States)
Univ. of Maryland, Baltimore, MD (United States). School of Medicine
Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD (United States); Walter Reed Army Institute of Research, Silver Spring, MD (United States)
Walter Reed Army Institute of Research, Silver Spring, MD (United States)
Trudeau Institute, Saranac Lake, NY (United States)
Uniformed Services University, Bethesda, MD (United States)
Integral Molecular, Philadelphia, PA (United States)

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.

View Accepted Manuscript (DOE)

Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES). Scientific User Facilities (SUF)

Grant/Contract Number:: AC02-06CH11357

OSTI ID:: 2423606

Journal Information:: Nature Communications, Journal Name: Nature Communications Journal Issue: 1 Vol. 14; ISSN 2041-1723

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: English

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