A potent SARS-CoV-2 neutralising nanobody shows therapeutic efficacy in the Syrian golden hamster model of COVID-19

Jiandong Huo; Halina Mikolajek; Audrey Le Bas; Jordan J. Clark; Parul Sharma; Anja Kipar; Joshua Dormon; Chelsea Norman; Miriam Weckener; Daniel K. Clare; Peter J. Harrison; Julia A. Tree; Karen R. Buttigieg; Francisco J. Salguero; Robert Watson; Daniel Knott; Oliver Carnell; Didier Ngabo; Michael J. Elmore; Susan Fotheringham; Adam Harding; Lucile Moynié; Philip N. Ward; Maud Dumoux; Tessa Prince; Yper Hall; Julian A. Hiscox; Andrew Owen; William James; Miles W. Carroll; James P. Stewart; James H. Naismith; Raymond J. Owens

doi:10.1038/s41467-021-25480-z

A potent SARS-CoV-2 neutralising nanobody shows therapeutic efficacy in the Syrian golden hamster model of COVID-19

Jiandong Huo, Halina Mikolajek, Audrey Le Bas, Jordan J. Clark, Parul Sharma, Anja Kipar, Joshua Dormon, Chelsea Norman, Miriam Weckener, Daniel K. Clare, Peter J. Harrison, Julia A. Tree, Karen R. Buttigieg, Francisco J. Salguero, Robert Watson, Daniel Knott, Oliver Carnell, Didier Ngabo, Michael J. Elmore, Susan FotheringhamAdam Harding, Lucile Moynié, Philip N. Ward, Maud Dumoux, Tessa Prince, Yper Hall, Julian A. Hiscox, Andrew Owen, William James, Miles W. Carroll, James P. Stewart, James H. Naismith^*, Raymond J. Owens

^*Corresponding author for this work

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Abstract

SARS-CoV-2 remains a global threat to human health particularly as escape mutants emerge. There is an unmet need for effective treatments against COVID-19 for which neutralizing single domain antibodies (nanobodies) have significant potential. Their small size and stability mean that nanobodies are compatible with respiratory administration. We report four nanobodies (C5, H3, C1, F2) engineered as homotrimers with pmolar affinity for the receptor binding domain (RBD) of the SARS-CoV-2 spike protein. Crystal structures show C5 and H3 overlap the ACE2 epitope, whilst C1 and F2 bind to a different epitope. Cryo Electron Microscopy shows C5 binding results in an all down arrangement of the Spike protein. C1, H3 and C5 all neutralize the Victoria strain, and the highly transmissible Alpha (B.1.1.7 first identified in Kent, UK) strain and C1 also neutralizes the Beta (B.1.35, first identified in South Africa). Administration of C5-trimer via the respiratory route showed potent therapeutic efficacy in the Syrian hamster model of COVID-19 and separately, effective prophylaxis. The molecule was similarly potent by intraperitoneal injection.

Original language	English
Article number	5469
Journal	Nature Communications
Volume	12
Issue number	1
Early online date	22 Sept 2021
DOIs	https://doi.org/10.1038/s41467-021-25480-z
Publication status	Published - Dec 2021

Bibliographical note

Funding Information: This work was supported by the Rosalind Franklin Institute, funding delivery partner EPSRC. PPUK is funded by the Rosalind Franklin Institute EPSRC grant no. EP/ S025243/1. J.H.N., A.L.B., P.J.H., M.W. and P.W. are supported by Wellcome Trust (100209/Z/12/Z). J.H. is supported by the EPA Cephalosporin Fund. X-ray data were obtained using Diamond Light Source COVID-19 Rapid Access time on Beamline I03, I04 and I24 (proposal MX27031). The core virus neutralisation facility is supported by gifts to the Oxford COVID-19 Research Response Fund. EM results were obtained at the national EM facility at Diamond, eBIC, through rapid access proposal BI27051. Work at the University of Liverpool is supported by MRC grant MR/W005611/1, G2P-UK; A National Virology Consortium to address phenotypic consequences of SARSCoV-2 genomic variation (JPS and JAH) and by the US Food and Drug Administration (USA) 75F40120C00085, Characterisation of severe coronavirus infection in humans and model systems for medical countermeasure development and evaluation (JAH). We wish to thank the laboratory staff of the Histology Laboratory, Institute of Veterinary Pathology, Vetsuisse Faculty, University of Zurich, and the laboratory staff of the Pathology Laboratory and Biological Investigations Group Public Health England, Porton Down for excellent technical support. We are grateful to Josep Monné Rodriguez for his assistance in the design of the apps for the morphometric assessment. We thank Tomas Mal-inauskas (Oxford University) and colleagues at the CMB (Oxford University) for assistance with protein production and Professor Gary Stephens, Barney Jones and Hong Lin (Reading University) for expertise in llama immunisation.

Open Access: This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

Publisher Copyright: © The Author(s) 2021

Citation: Huo, J., Mikolajek, H., Le Bas, A. et al. A potent SARS-CoV-2 neutralising nanobody shows therapeutic efficacy in the Syrian golden hamster model of COVID-19. Nat Commun 12, 5469 (2021).

DOI: https://doi.org/10.1038/s41467-021-25480-z

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Huo, J., Mikolajek, H., Le Bas, A., Clark, J. J., Sharma, P., Kipar, A., Dormon, J., Norman, C., Weckener, M., Clare, D. K., Harrison, P. J., Tree, J. A., Buttigieg, K. R., Salguero, F. J., Watson, R., Knott, D., Carnell, O., Ngabo, D., Elmore, M. J., ... Owens, R. J. (2021). A potent SARS-CoV-2 neutralising nanobody shows therapeutic efficacy in the Syrian golden hamster model of COVID-19. Nature Communications, 12(1), Article 5469. https://doi.org/10.1038/s41467-021-25480-z

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title = "A potent SARS-CoV-2 neutralising nanobody shows therapeutic efficacy in the Syrian golden hamster model of COVID-19",

abstract = "SARS-CoV-2 remains a global threat to human health particularly as escape mutants emerge. There is an unmet need for effective treatments against COVID-19 for which neutralizing single domain antibodies (nanobodies) have significant potential. Their small size and stability mean that nanobodies are compatible with respiratory administration. We report four nanobodies (C5, H3, C1, F2) engineered as homotrimers with pmolar affinity for the receptor binding domain (RBD) of the SARS-CoV-2 spike protein. Crystal structures show C5 and H3 overlap the ACE2 epitope, whilst C1 and F2 bind to a different epitope. Cryo Electron Microscopy shows C5 binding results in an all down arrangement of the Spike protein. C1, H3 and C5 all neutralize the Victoria strain, and the highly transmissible Alpha (B.1.1.7 first identified in Kent, UK) strain and C1 also neutralizes the Beta (B.1.35, first identified in South Africa). Administration of C5-trimer via the respiratory route showed potent therapeutic efficacy in the Syrian hamster model of COVID-19 and separately, effective prophylaxis. The molecule was similarly potent by intraperitoneal injection.",

author = "Jiandong Huo and Halina Mikolajek and {Le Bas}, Audrey and Clark, {Jordan J.} and Parul Sharma and Anja Kipar and Joshua Dormon and Chelsea Norman and Miriam Weckener and Clare, {Daniel K.} and Harrison, {Peter J.} and Tree, {Julia A.} and Buttigieg, {Karen R.} and Salguero, {Francisco J.} and Robert Watson and Daniel Knott and Oliver Carnell and Didier Ngabo and Elmore, {Michael J.} and Susan Fotheringham and Adam Harding and Lucile Moyni{\'e} and Ward, {Philip N.} and Maud Dumoux and Tessa Prince and Yper Hall and Hiscox, {Julian A.} and Andrew Owen and William James and Carroll, {Miles W.} and Stewart, {James P.} and Naismith, {James H.} and Owens, {Raymond J.}",

note = "Funding Information: This work was supported by the Rosalind Franklin Institute, funding delivery partner EPSRC. PPUK is funded by the Rosalind Franklin Institute EPSRC grant no. EP/ S025243/1. J.H.N., A.L.B., P.J.H., M.W. and P.W. are supported by Wellcome Trust (100209/Z/12/Z). J.H. is supported by the EPA Cephalosporin Fund. X-ray data were obtained using Diamond Light Source COVID-19 Rapid Access time on Beamline I03, I04 and I24 (proposal MX27031). The core virus neutralisation facility is supported by gifts to the Oxford COVID-19 Research Response Fund. EM results were obtained at the national EM facility at Diamond, eBIC, through rapid access proposal BI27051. Work at the University of Liverpool is supported by MRC grant MR/W005611/1, G2P-UK; A National Virology Consortium to address phenotypic consequences of SARSCoV-2 genomic variation (JPS and JAH) and by the US Food and Drug Administration (USA) 75F40120C00085, Characterisation of severe coronavirus infection in humans and model systems for medical countermeasure development and evaluation (JAH). We wish to thank the laboratory staff of the Histology Laboratory, Institute of Veterinary Pathology, Vetsuisse Faculty, University of Zurich, and the laboratory staff of the Pathology Laboratory and Biological Investigations Group Public Health England, Porton Down for excellent technical support. We are grateful to Josep Monn{\'e} Rodriguez for his assistance in the design of the apps for the morphometric assessment. We thank Tomas Mal-inauskas (Oxford University) and colleagues at the CMB (Oxford University) for assistance with protein production and Professor Gary Stephens, Barney Jones and Hong Lin (Reading University) for expertise in llama immunisation. Open Access: This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article{\textquoteright}s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article{\textquoteright}s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. Publisher Copyright: {\textcopyright} The Author(s) 2021 Citation: Huo, J., Mikolajek, H., Le Bas, A. et al. A potent SARS-CoV-2 neutralising nanobody shows therapeutic efficacy in the Syrian golden hamster model of COVID-19. Nat Commun 12, 5469 (2021). DOI: https://doi.org/10.1038/s41467-021-25480-z",

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Huo, J, Mikolajek, H, Le Bas, A, Clark, JJ, Sharma, P, Kipar, A, Dormon, J, Norman, C, Weckener, M, Clare, DK, Harrison, PJ, Tree, JA , Buttigieg, KR , Salguero, FJ, Watson, R, Knott, D, Carnell, O, Ngabo, D , Elmore, MJ , Fotheringham, S, Harding, A, Moynié, L, Ward, PN, Dumoux, M, Prince, T, Hall, Y, Hiscox, JA, Owen, A, James, W, Carroll, MW, Stewart, JP, Naismith, JH & Owens, RJ 2021, 'A potent SARS-CoV-2 neutralising nanobody shows therapeutic efficacy in the Syrian golden hamster model of COVID-19', Nature Communications, vol. 12, no. 1, 5469. https://doi.org/10.1038/s41467-021-25480-z

TY - JOUR

T1 - A potent SARS-CoV-2 neutralising nanobody shows therapeutic efficacy in the Syrian golden hamster model of COVID-19

AU - Huo, Jiandong

AU - Mikolajek, Halina

AU - Le Bas, Audrey

AU - Clark, Jordan J.

AU - Sharma, Parul

AU - Kipar, Anja

AU - Dormon, Joshua

AU - Norman, Chelsea

AU - Weckener, Miriam

AU - Clare, Daniel K.

AU - Harrison, Peter J.

AU - Tree, Julia A.

AU - Buttigieg, Karen R.

AU - Salguero, Francisco J.

AU - Watson, Robert

AU - Knott, Daniel

AU - Carnell, Oliver

AU - Ngabo, Didier

AU - Elmore, Michael J.

AU - Fotheringham, Susan

AU - Harding, Adam

AU - Moynié, Lucile

AU - Ward, Philip N.

AU - Dumoux, Maud

AU - Prince, Tessa

AU - Hall, Yper

AU - Hiscox, Julian A.

AU - Owen, Andrew

AU - James, William

AU - Carroll, Miles W.

AU - Stewart, James P.

AU - Naismith, James H.

AU - Owens, Raymond J.

N1 - Funding Information: This work was supported by the Rosalind Franklin Institute, funding delivery partner EPSRC. PPUK is funded by the Rosalind Franklin Institute EPSRC grant no. EP/ S025243/1. J.H.N., A.L.B., P.J.H., M.W. and P.W. are supported by Wellcome Trust (100209/Z/12/Z). J.H. is supported by the EPA Cephalosporin Fund. X-ray data were obtained using Diamond Light Source COVID-19 Rapid Access time on Beamline I03, I04 and I24 (proposal MX27031). The core virus neutralisation facility is supported by gifts to the Oxford COVID-19 Research Response Fund. EM results were obtained at the national EM facility at Diamond, eBIC, through rapid access proposal BI27051. Work at the University of Liverpool is supported by MRC grant MR/W005611/1, G2P-UK; A National Virology Consortium to address phenotypic consequences of SARSCoV-2 genomic variation (JPS and JAH) and by the US Food and Drug Administration (USA) 75F40120C00085, Characterisation of severe coronavirus infection in humans and model systems for medical countermeasure development and evaluation (JAH). We wish to thank the laboratory staff of the Histology Laboratory, Institute of Veterinary Pathology, Vetsuisse Faculty, University of Zurich, and the laboratory staff of the Pathology Laboratory and Biological Investigations Group Public Health England, Porton Down for excellent technical support. We are grateful to Josep Monné Rodriguez for his assistance in the design of the apps for the morphometric assessment. We thank Tomas Mal-inauskas (Oxford University) and colleagues at the CMB (Oxford University) for assistance with protein production and Professor Gary Stephens, Barney Jones and Hong Lin (Reading University) for expertise in llama immunisation. Open Access: This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. Publisher Copyright: © The Author(s) 2021 Citation: Huo, J., Mikolajek, H., Le Bas, A. et al. A potent SARS-CoV-2 neutralising nanobody shows therapeutic efficacy in the Syrian golden hamster model of COVID-19. Nat Commun 12, 5469 (2021). DOI: https://doi.org/10.1038/s41467-021-25480-z

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N2 - SARS-CoV-2 remains a global threat to human health particularly as escape mutants emerge. There is an unmet need for effective treatments against COVID-19 for which neutralizing single domain antibodies (nanobodies) have significant potential. Their small size and stability mean that nanobodies are compatible with respiratory administration. We report four nanobodies (C5, H3, C1, F2) engineered as homotrimers with pmolar affinity for the receptor binding domain (RBD) of the SARS-CoV-2 spike protein. Crystal structures show C5 and H3 overlap the ACE2 epitope, whilst C1 and F2 bind to a different epitope. Cryo Electron Microscopy shows C5 binding results in an all down arrangement of the Spike protein. C1, H3 and C5 all neutralize the Victoria strain, and the highly transmissible Alpha (B.1.1.7 first identified in Kent, UK) strain and C1 also neutralizes the Beta (B.1.35, first identified in South Africa). Administration of C5-trimer via the respiratory route showed potent therapeutic efficacy in the Syrian hamster model of COVID-19 and separately, effective prophylaxis. The molecule was similarly potent by intraperitoneal injection.

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DO - 10.1038/s41467-021-25480-z

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A potent SARS-CoV-2 neutralising nanobody shows therapeutic efficacy in the Syrian golden hamster model of COVID-19

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