Shark nanobodies with potent SARS-CoV-2 neutralizing activity and broad sarbecovirus reactivity
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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Feb 03, 2023
- Source ID
- 10.1038/s41467-023-36106-x
Entities
People
- Adelola B. Ajayi
- Agnes Hajduczki
- Benjamin J Doranz
- Caitlin Kuklis
- Caroline E. Peterson
- Christopher C Broder
- Courtney Corbitt
- Debora Duso
- Dominic Paquin Proulx
- Edgar Davidson
- Elizabeth J. Martinez
- Emily S. Golub
- Eric D. Laing
- Eric Lewitus
- Gregory D. Gromowski
- Hanover Matz
- Helen Dooley
- Hongjun Bai
- Isabella Swafford
- Jazmean K. Williams
- Jocelyn King
- Kayvon Modjarrad
- Larry Kummer
- Layla Dawit
- Lianying Yan
- Lindsay Wieczorek
- M Gordon Joyce
- Michelle Zemil
- Misook Choe
- Morgane Rolland
- Paul V. Thomas
- Phyllis A. Rees
- Rajeshwer S. Sankhala
- Sandra V. Mayer
- Sandrine Soman
- Sapna David
- Shelly J. Krebs
- Spencer L. Sterling
- Thomas M. Hill
- Tricia Hart
- Victoria R. Polonis
- Vincent Dussupt
- Wei‐Hung Chen
- William C Chang
- William W. Reiley
Organizations
- Defense Health Agency