A nanobody recognizes a unique conserved epitope and potently neutralizes SARS-CoV-2 omicron variants

Naphak Modhiran; Simon Malte Lauer; Alberto A Amarilla; Peter Hewins; Sara Irene Lopes van den Broek; Yu Shang Low; Nazia Thakur; Benjamin Liang; Guillermo Valenzuela Nieto; James Jung; Devina Paramitha; Ariel Isaacs; Julian D J Sng; David Song; Jesper Tranekjær Jørgensen; Yorka Cheuquemilla; Jörg Bürger; Ida Vang Andersen; Johanna Himelreichs; Ronald Jara; Ronan MacLoughlin; Zaray Miranda-Chacon; Pedro Chana-Cuevas; Vasko Kramer; Christian Spahn; Thorsten Mielke; Alexander A Khromykh; Trent Munro; Martina L Jones; Paul R Young; Keith Chappell; Dalan Bailey; Andreas Kjaer; Matthias Manfred Herth; Kellie Ann Jurado; David Schwefel; Alejandro Rojas-Fernandez; Daniel Watterson

doi:10.1016/j.isci.2023.107085

A nanobody recognizes a unique conserved epitope and potently neutralizes SARS-CoV-2 omicron variants

iScience. 2023 Jun 9;26(7):107085. doi: 10.1016/j.isci.2023.107085. eCollection 2023 Jul 21.

Authors

Naphak Modhiran^{1

2}, Simon Malte Lauer³, Alberto A Amarilla¹, Peter Hewins⁴, Sara Irene Lopes van den Broek⁵, Yu Shang Low¹, Nazia Thakur^{6

7}, Benjamin Liang¹, Guillermo Valenzuela Nieto⁸, James Jung¹, Devina Paramitha¹, Ariel Isaacs¹, Julian D J Sng¹, David Song⁴, Jesper Tranekjær Jørgensen^{9

10}, Yorka Cheuquemilla⁸, Jörg Bürger^{3

11}, Ida Vang Andersen^{5

9}, Johanna Himelreichs⁸, Ronald Jara⁸, Ronan MacLoughlin¹², Zaray Miranda-Chacon⁷, Pedro Chana-Cuevas¹³, Vasko Kramer¹⁴, Christian Spahn³, Thorsten Mielke¹¹, Alexander A Khromykh^{1

15}, Trent Munro², Martina L Jones², Paul R Young^{1

2

15}, Keith Chappell^{1

2

15}, Dalan Bailey⁶, Andreas Kjaer^{9

10}, Matthias Manfred Herth^{5

9}, Kellie Ann Jurado⁴, David Schwefel³, Alejandro Rojas-Fernandez^{7

16}, Daniel Watterson^{1

2

15}

Affiliations

¹ School of Chemistry and Molecular Bioscience, the University of Queensland, Brisbane, QLD, Australia.
² Australian Institute for Bioengineering and Nanotechnology, Brisbane, QLD, Australia.
³ Institute of Medical Physics and Biophysics, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt Universität zu Berlin, Berlin, Germany.
⁴ Department of Microbiology, University of Pennsylvania, Philadelphia, PA, USA.
⁵ Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Jagtvej 160, 2100 Copenhagen, Denmark.
⁶ The Pirbright Institute, Ash Road, Guildford, UK.
⁷ Nuffield Department of Medicine, University of Oxford, Oxford, UK.
⁸ Institute of Medicine, Faculty of Medicine & Center for Interdisciplinary Studies on the Nervous System, CISNE, Universidad Austral de Chile, Valdivia, Chile.
⁹ Department of Clinical Physiology, Nuclear Medicine & PET, Copenhagen University Hospital, Rigshospitalet, Blegdamsvej 9, 2100 Copenhagen, Denmark.
¹⁰ Cluster for Molecular Imaging, Department of Biomedical Sciences, University of Copenhagen, Blegdamsvej 3, 2200 Copenhagen, Denmark.
¹¹ Microscopy and Cryo-Electron Microscopy Service Group, Max-Planck-Institute for Molecular Genetics, Berlin, Germany.
¹² Research and Development, Science and Emerging Technologies, Aerogen Limited, Galway Business Park, H91 HE94 Galway, Ireland.
¹³ CETRAM & Faculty of Medical Science Universidad de Santiago de Chile, Chile.
¹⁴ PositronPharma SA, Rancagua 878, 7500921 Providencia, Santiago, Chile.
¹⁵ Australian Infectious Diseases Research Centre, Global Virus Network Centre of Excellence, Brisbane, QLD, Australia.
¹⁶ Berking Biotechnology, Valdivia, Chile.

Abstract

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) Omicron variant sub-lineages spread rapidly worldwide, mostly due to their immune-evasive properties. This has put a significant part of the population at risk for severe disease and underscores the need for effective anti-SARS-CoV-2 agents against emergent strains in vulnerable patients. Camelid nanobodies are attractive therapeutic candidates due to their high stability, ease of large-scale production, and potential for delivery via inhalation. Here, we characterize the receptor binding domain (RBD)-specific nanobody W25 and show superior neutralization activity toward Omicron sub-lineages in comparison to all other SARS-CoV2 variants. Structure analysis of W25 in complex with the SARS-CoV2 spike glycoprotein shows that W25 engages an RBD epitope not covered by any of the antibodies previously approved for emergency use. In vivo evaluation of W25 prophylactic and therapeutic treatments across multiple SARS-CoV-2 variant infection models, together with W25 biodistribution analysis in mice, demonstrates favorable pre-clinical properties. Together, these data endorse W25 for further clinical development.

Keywords: Decision science; Information system model; Public health.

Abstract

Grants and funding