Journal Article Ppublish
PubMed: 39746041 DOI: 10.1073/pnas.2417544121
Affinity maturation endows potent activity onto class 6 SARS-CoV-2 broadly neutralizing antibodies.
Proc Natl Acad Sci U S A 122(1):e2417544121
Authors: Ohan Mazigi, David B Langley, Jake Y Henry, Deborah L Burnett, Meghna Sobti, Gregory J Walker, Romain Rouet, Harikrishnan Balachandran, Helen Lenthall, Jennifer Jackson, Stephanie Ubiparipovic, Peter Schofield, Simon H J Brown, Sebastian R Schulz, Markus Hoffmann, Stefan Pöhlmann, Jeffrey Post, Marianne Martinello, Golo Ahlenstiel, Anthony Kelleher, William D Rawlinson, Stuart G Turville, Rowena A Bull, Alastair G Stewart, Hans-Martin Jäck, Christopher C Goodnow, Daniel Christ
Affiliations
- Garvan Institute of Medical Research, Sydney, NSW 2010, Australia.
- University of New South Wales Sydney, St. Vincent's Clinical School, Faculty of Medicine, Sydney, NSW 2010, Australia.
- University of New South Wales Sydney, School of Biomedical Sciences, Faculty of Medicine, Sydney, NSW 2052, Australia.
- Victor Chang Cardiac Research Institute, Sydney, NSW 2010, Australia.
- Prince of Wales Hospital, Sydney, NSW 2031, Australia.
- Kirby Institute, University of New South Wales Sydney, Sydney, NSW 2033, Australia.
- School of Chemistry and Molecular Bioscience, Molecular Horizons, and Australian Research Council Centre for Cryo-electron Microscopy of Membrane Proteins, University of Wollongong, Wollongong, NSW 2522, Australia.
- Division of Molecular Immunology, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen-Nürnberg 91054, Germany.
- University Hospital Erlangen, Erlangen-Nürnberg 91054, Germany.
- Infection Biology Unit, German Primate Center-Leibniz Institute for Primate Research, Göttingen 37077, Germany.
- Faculty of Biology and Psychology, Georg-August University Göttingen, Göttingen 37073, Germany.
- Prince of Wales Clinical School, Faculty of Medicine, University of New South Wales Australia, Sydney, NSW 2031, Australia.
- Blacktown Mt. Druitt Hospital, Blacktown, NSW 2148, Australia.
Abstract
The emergence of SARS-CoV-2 variants of concern (VOCs) has greatly diminished the neutralizing activity of previously FDA-approved monoclonal antibodies (mAbs), including that of antibody cocktails and of first-generation broadly neutralizing antibodies such as S309 (Sotrovimab). In contrast, antibodies targeting cryptic conformational epitopes of the receptor binding domain (RBD) have demonstrated broad activity against emerging variants, but exert only moderate neutralizing activity, which has so far hindered clinical development. Here, we utilize in vitro display technology to identify and affinity-mature antibodies targeting the cryptic class 6 epitope, accessible only in the "up" conformation of the SARS-CoV-2 spike trimer. Increasing antibody affinity into the low picomolar range endowed potent neutralization of VOCs and protection of hACE2 mice from viral challenge. Cryoelectron microscopy and crystal structures of two affinity-matured antibodies (4C12-B12 and 4G1-C2) in complex with RBD highlighted binding modes and epitopes distal from mutational hotspots commonly overserved in VOCs, providing direct structural insights into the observed mutational resistance. Moreover, we further demonstrate that antibodies targeting the class 6 epitope, rather than being an artifact of in vitro selection, are common in the IgG1 memory B cell repertoire of convalescent patients and can be induced in human antibody V-gene transgenic mice through immunization. Our results highlight the importance of very high (picomolar) affinity in the development of neutralizing antibodies and vaccines and suggest an affinity threshold in the provision of broad and long-lasting immunity against SARS-CoV-2.
MeSH
Genes, Broadly Neutralizing Antibodies, Sars-Cov-2, Epitopes, Antibodies, Antibodies, Neutralizing, Immunity, Severe Acute Respiratory Syndrome-Related Coronavirus