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

• Published in: Nature communications Vol. 14; no. 1; pp. 580 - 18
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 03.02.2023; Nature Publishing Group; Nature Portfolio
• Subjects: 101/47; 13/1; 60 APPLIED LIFE SCIENCES; 631/154/51/1568; 631/250/255/2514; 631/535/1266; 631/61/24; 64/110; 82/80; 9/10; Affinity; Animals; Antibodies; Antibodies, Neutralizing; Antibodies, Viral; antibody therapy; Antigens; applied immunology; Chimeras; COVID-19; COVID-19 - prevention & control; Epitopes; Ferritin; Ferritins - genetics; Humanities and Social Sciences; Immunization; Immunoglobulin Fc Fragments; Mice; Mice, Transgenic; multidisciplinary; Nanobodies; Nanoparticles; Neutralization; Pandemics; Receptors; SARS-CoV-2 - genetics; Science; Science (multidisciplinary); Severe acute respiratory syndrome coronavirus 2; Severe acute respiratory syndrome-related coronavirus; Sharks; Single-Domain Antibodies; Spike Glycoprotein, Coronavirus - genetics; Spike protein; Transgenic mice; Vaccine efficacy; Vaccines; Viral diseases; viral infection; x-ray crystallography
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-023-36106-x

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. SARS-CoV-2 variants of concern continue to emerge, reducing vaccine efficacy and limiting therapeutic options. Here, Chen and colleagues describe the identification and design of shark nanobodies with pansarbecovirus activity.