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Potent universal-coronavirus therapeutic activity mediated by direct respiratory administration of a Spike S2 domain-specific human neutralizing monoclonal antibody

Michael S. Piepenbrink, Jun-Gyu Park, Ashlesha Desphande, Andreas Loos, Chengjin Ye, Madhubanti Basu, Sanghita Sarkar, David Chauvin, Jennifer Woo, Philip Lovalenti, Nathaniel B. Erdmann, Paul A. Goepfert, Vu L. Truong, Richard A. Bowen, Mark R. Walter, Luis Martinez-Sobrido, View ORCID ProfileJames J. Kobie
doi: https://doi.org/10.1101/2022.03.05.483133
Michael S. Piepenbrink
1Department of Medicine, Division of Infectious Diseases, University of Alabama at Birmingham, Birmingham, AL, USA
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Jun-Gyu Park
2Texas Biomedical Research Institute, San Antonio, TX, USA
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Ashlesha Desphande
3Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL, USA
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Andreas Loos
4Aridis Pharmaceuticals Inc., Los Gatos, CA, USA
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Chengjin Ye
2Texas Biomedical Research Institute, San Antonio, TX, USA
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Madhubanti Basu
1Department of Medicine, Division of Infectious Diseases, University of Alabama at Birmingham, Birmingham, AL, USA
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Sanghita Sarkar
1Department of Medicine, Division of Infectious Diseases, University of Alabama at Birmingham, Birmingham, AL, USA
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David Chauvin
4Aridis Pharmaceuticals Inc., Los Gatos, CA, USA
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Jennifer Woo
4Aridis Pharmaceuticals Inc., Los Gatos, CA, USA
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Philip Lovalenti
4Aridis Pharmaceuticals Inc., Los Gatos, CA, USA
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Nathaniel B. Erdmann
1Department of Medicine, Division of Infectious Diseases, University of Alabama at Birmingham, Birmingham, AL, USA
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Paul A. Goepfert
1Department of Medicine, Division of Infectious Diseases, University of Alabama at Birmingham, Birmingham, AL, USA
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Vu L. Truong
4Aridis Pharmaceuticals Inc., Los Gatos, CA, USA
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Richard A. Bowen
5Department of Biomedical Sciences, Colorado State University, Fort Collins, CO, USA
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Mark R. Walter
3Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL, USA
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  • For correspondence: jjkobie@uabmc.edu
Luis Martinez-Sobrido
2Texas Biomedical Research Institute, San Antonio, TX, USA
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  • For correspondence: jjkobie@uabmc.edu
James J. Kobie
1Department of Medicine, Division of Infectious Diseases, University of Alabama at Birmingham, Birmingham, AL, USA
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  • ORCID record for James J. Kobie
  • For correspondence: jjkobie@uabmc.edu
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Abstract

Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) marks the third novel β-coronavirus to cause significant human mortality in the last two decades. Although vaccines are available, too few have been administered worldwide to keep the virus in check and to prevent mutations leading to immune escape. To determine if antibodies could be identified with universal coronavirus activity, plasma from convalescent subjects was screened for IgG against a stabilized pre-fusion SARS-CoV-2 spike S2 domain, which is highly conserved between human β-coronavirus. From these subjects, several S2-specific human monoclonal antibodies (hmAbs) were developed that neutralized SARS-CoV-2 with recognition of all variants of concern (VoC) tested (Beta, Gamma, Delta, Epsilon, and Omicron). The hmAb 1249A8 emerged as the most potent and broad hmAb, able to recognize all human β-coronavirus and neutralize SARS-CoV and MERS-CoV. 1249A8 demonstrated significant prophylactic activity in K18 hACE2 mice infected with SARS-CoV-2 lineage A and lineage B Beta, and Omicron VoC. 1249A8 delivered as a single 4 mg/kg intranasal (i.n.) dose to hamsters 12 hours following infection with SARS-CoV-2 Delta protected them from weight loss, with therapeutic activity further enhanced when combined with 1213H7, an S1-specific neutralizing hmAb. As little as 2 mg/kg of 1249A8 i.n. dose 12 hours following infection with SARS-CoV Urbani strain, protected hamsters from weight loss and significantly reduced upper and lower respiratory viral burden. These results indicate in vivo cooperativity between S1 and S2 specific neutralizing hmAbs and that potent universal coronavirus neutralizing mAbs with therapeutic potential can be induced in humans and can guide universal coronavirus vaccine development.

Competing Interest Statement

M.S.P., J.-G.P., A.D., F.S.O., M.B., S.S., N.B.E., P.A.G., M.R.W., L.M.-S., and J.J.K. are co-inventors on patents that include claims related to the hmAbs described. A.L., D.C., J.W., P.L., and V.L.T. are employees of Aridis Pharmaceuticals.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted March 07, 2022.
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Potent universal-coronavirus therapeutic activity mediated by direct respiratory administration of a Spike S2 domain-specific human neutralizing monoclonal antibody
Michael S. Piepenbrink, Jun-Gyu Park, Ashlesha Desphande, Andreas Loos, Chengjin Ye, Madhubanti Basu, Sanghita Sarkar, David Chauvin, Jennifer Woo, Philip Lovalenti, Nathaniel B. Erdmann, Paul A. Goepfert, Vu L. Truong, Richard A. Bowen, Mark R. Walter, Luis Martinez-Sobrido, James J. Kobie
bioRxiv 2022.03.05.483133; doi: https://doi.org/10.1101/2022.03.05.483133
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Potent universal-coronavirus therapeutic activity mediated by direct respiratory administration of a Spike S2 domain-specific human neutralizing monoclonal antibody
Michael S. Piepenbrink, Jun-Gyu Park, Ashlesha Desphande, Andreas Loos, Chengjin Ye, Madhubanti Basu, Sanghita Sarkar, David Chauvin, Jennifer Woo, Philip Lovalenti, Nathaniel B. Erdmann, Paul A. Goepfert, Vu L. Truong, Richard A. Bowen, Mark R. Walter, Luis Martinez-Sobrido, James J. Kobie
bioRxiv 2022.03.05.483133; doi: https://doi.org/10.1101/2022.03.05.483133

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