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Therapeutic activity of an inhaled potent SARS-CoV-2 neutralizing human monoclonal antibody in hamsters

Michael S. Piepenbrink, Jun-Gyu Park, Fatai S. Oladunni, Ashlesha Deshpande, Madhubanti Basu, Sanghita Sarkar, Andreas Loos, Jennifer Woo, Phillip Lovalenti, Derek Sloan, Chengjin Ye, Kevin Chiem, Nathaniel B. Erdmann, Paul A. Goepfert, Vu L. Truong, Mark R. Walter, Luis Martinez-Sobrido, James J. Kobie
doi: https://doi.org/10.1101/2020.10.14.339150
Michael S. Piepenbrink
aDepartment of Medicine, Division of Infectious Diseases, University of Alabama at Birmingham, Birmingham, AL, USA
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Jun-Gyu Park
bTexas Biomedical Research Institute, San Antonio, TX, USA
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Fatai S. Oladunni
bTexas Biomedical Research Institute, San Antonio, TX, USA
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Ashlesha Deshpande
cDepartment of Microbiology, University of Alabama at Birmingham, Birmingham, AL, USA
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Madhubanti Basu
aDepartment of Medicine, Division of Infectious Diseases, University of Alabama at Birmingham, Birmingham, AL, USA
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Sanghita Sarkar
aDepartment of Medicine, Division of Infectious Diseases, University of Alabama at Birmingham, Birmingham, AL, USA
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Andreas Loos
dAridis Pharmaceuticals Inc., San Jose CA, USA
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Jennifer Woo
dAridis Pharmaceuticals Inc., San Jose CA, USA
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Phillip Lovalenti
dAridis Pharmaceuticals Inc., San Jose CA, USA
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Derek Sloan
dAridis Pharmaceuticals Inc., San Jose CA, USA
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Chengjin Ye
bTexas Biomedical Research Institute, San Antonio, TX, USA
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Kevin Chiem
bTexas Biomedical Research Institute, San Antonio, TX, USA
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Nathaniel B. Erdmann
aDepartment of Medicine, Division of Infectious Diseases, University of Alabama at Birmingham, Birmingham, AL, USA
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Paul A. Goepfert
aDepartment of Medicine, Division of Infectious Diseases, University of Alabama at Birmingham, Birmingham, AL, USA
cDepartment of Microbiology, University of Alabama at Birmingham, Birmingham, AL, USA
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Vu L. Truong
dAridis Pharmaceuticals Inc., San Jose CA, USA
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Mark R. Walter
cDepartment of Microbiology, University of Alabama at Birmingham, Birmingham, AL, USA
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Luis Martinez-Sobrido
bTexas Biomedical Research Institute, San Antonio, TX, USA
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  • For correspondence: lmartinez@txbiomed.org jjkobie@uabmc.edu
James J. Kobie
aDepartment of Medicine, Division of Infectious Diseases, University of Alabama at Birmingham, Birmingham, AL, USA
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  • For correspondence: lmartinez@txbiomed.org jjkobie@uabmc.edu
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Abstract

SARS-CoV-2 infection results in viral burden in the upper and lower respiratory tract, enabling transmission and often leading to substantial lung pathology. Delivering the antiviral treatment directly to the lungs has the potential to improve lung bioavailability and dosing efficiency. As the SARS-CoV-2 Receptor Binding Domain (RBD) of the Spike (S) is increasingly deemed to be a clinically validated target, RBD-specific B cells were isolated from patients following SARS-CoV-2 infection to derive a panel of fully human monoclonal antibodies (hmAbs) that potently neutralize SARS-CoV-2. The most potent hmAb, 1212C2 was derived from an IgM memory B cell, has high affinity for SARS-CoV-2 RBD which enables its direct inhibition of RBD binding to ACE2. The 1212C2 hmAb exhibits in vivo prophylactic and therapeutic activity against SARS-CoV-2 in hamsters when delivered intraperitoneally, achieving a meaningful reduction in upper and lower respiratory viral burden and lung pathology. Furthermore, liquid nebulized inhale treatment of SARS-CoV-2 infected hamsters with as low as 0.6 mg/kg of inhaled dose, corresponding to approximately 0.03 mg/kg of lung deposited dose, mediated a reduction in respiratory viral burden that is below the detection limit, and mitigated lung pathology. The therapeutic efficacy achieved at an exceedingly low-dose of inhaled 1212C2 supports the rationale for local lung delivery and achieving dose-sparing benefits as compared to the conventional parenteral route of administration. Taken together, these results warrant an accelerated clinical development of 1212C2 hmAb formulated and delivered via inhalation for the prevention and treatment of SARS-CoV-2 infection.

Competing Interest Statement

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

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Therapeutic activity of an inhaled potent SARS-CoV-2 neutralizing human monoclonal antibody in hamsters
Michael S. Piepenbrink, Jun-Gyu Park, Fatai S. Oladunni, Ashlesha Deshpande, Madhubanti Basu, Sanghita Sarkar, Andreas Loos, Jennifer Woo, Phillip Lovalenti, Derek Sloan, Chengjin Ye, Kevin Chiem, Nathaniel B. Erdmann, Paul A. Goepfert, Vu L. Truong, Mark R. Walter, Luis Martinez-Sobrido, James J. Kobie
bioRxiv 2020.10.14.339150; doi: https://doi.org/10.1101/2020.10.14.339150
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Therapeutic activity of an inhaled potent SARS-CoV-2 neutralizing human monoclonal antibody in hamsters
Michael S. Piepenbrink, Jun-Gyu Park, Fatai S. Oladunni, Ashlesha Deshpande, Madhubanti Basu, Sanghita Sarkar, Andreas Loos, Jennifer Woo, Phillip Lovalenti, Derek Sloan, Chengjin Ye, Kevin Chiem, Nathaniel B. Erdmann, Paul A. Goepfert, Vu L. Truong, Mark R. Walter, Luis Martinez-Sobrido, James J. Kobie
bioRxiv 2020.10.14.339150; doi: https://doi.org/10.1101/2020.10.14.339150

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