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Stable nebulization and muco-trapping properties of Regdanvimab/IN-006 supports its development as a potent, dose-saving inhaled therapy for COVID-19

View ORCID ProfileMorgan McSweeney, Ian Stewart, Zach Richardson, Hyunah Kang, Yoona Park, Cheolmin Kim, View ORCID ProfileKarthik Tiruthani, Whitney Wolf, Alison Schaefer, Priya Kumar, Harendra Aurora, Jeff Hutchins, Jong Moon Cho, Anthony J. Hickey, Soo Young Lee, View ORCID ProfileSamuel Lai
doi: https://doi.org/10.1101/2022.02.27.482162
Morgan McSweeney
1Inhalon Biopharma Inc, Research Triangle Park, NC 27709, USA
2Mucommune LLC, Research Triangle Park, NC 27709, USA
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  • ORCID record for Morgan McSweeney
Ian Stewart
3RTI International, Research Triangle Park, NC 27709, USA
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Zach Richardson
1Inhalon Biopharma Inc, Research Triangle Park, NC 27709, USA
2Mucommune LLC, Research Triangle Park, NC 27709, USA
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Hyunah Kang
4Biotechnology Research Institute, Celltrion Inc, Incheon 22014, Republic of Korea
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Yoona Park
4Biotechnology Research Institute, Celltrion Inc, Incheon 22014, Republic of Korea
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Cheolmin Kim
4Biotechnology Research Institute, Celltrion Inc, Incheon 22014, Republic of Korea
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Karthik Tiruthani
5Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina-Chapel Hill, Chapel Hill, NC, 27599, USA
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Whitney Wolf
5Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina-Chapel Hill, Chapel Hill, NC, 27599, USA
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Alison Schaefer
6UNC/NCSU Joint Department of Biomedical Engineering, University of North Carolina-Chapel Hill, Chapel Hill, NC, 27599, USA
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Priya Kumar
7Dept of Anesthesiology, School of Medicine, University of North Carolina, Chapel Hill, NC, USA
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Harendra Aurora
7Dept of Anesthesiology, School of Medicine, University of North Carolina, Chapel Hill, NC, USA
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Jeff Hutchins
1Inhalon Biopharma Inc, Research Triangle Park, NC 27709, USA
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Jong Moon Cho
4Biotechnology Research Institute, Celltrion Inc, Incheon 22014, Republic of Korea
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Anthony J. Hickey
3RTI International, Research Triangle Park, NC 27709, USA
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Soo Young Lee
4Biotechnology Research Institute, Celltrion Inc, Incheon 22014, Republic of Korea
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Samuel Lai
1Inhalon Biopharma Inc, Research Triangle Park, NC 27709, USA
2Mucommune LLC, Research Triangle Park, NC 27709, USA
5Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina-Chapel Hill, Chapel Hill, NC, 27599, USA
6UNC/NCSU Joint Department of Biomedical Engineering, University of North Carolina-Chapel Hill, Chapel Hill, NC, 27599, USA
8Department of Microbiology & Immunology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA
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  • ORCID record for Samuel Lai
  • For correspondence: lai@unc.edu
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Abstract

The respiratory tract represents the key target for antiviral delivery in early interventions to prevent severe COVID-19. While neutralizing monoclonal antibodies (mAb) possess considerable efficacy, their current reliance on parenteral dosing necessitates very large doses and places a substantial burden on the healthcare system. In contrast, direct inhaled delivery of mAb therapeutics offers the convenience of self-dosing at home, as well as much more efficient mAb delivery to the respiratory tract. Here, building on our previous discovery of Fc-mucin interactions crosslinking viruses to mucins, we showed that regdanvimab, a potent neutralizing mAb already approved for COVID-19 in several countries around the world, can effectively trap SARS-CoV-2 virus-like-particles in fresh human airway mucus. IN-006, a reformulation of Regdanvimab, was stably nebulized across a wide range of concentrations, with no loss of activity and no formation of aggregates. Finally, nebulized delivery of IN-006 resulted in 100-fold greater mAb levels in the lungs of rats compared to serum, in marked contrast to intravenously dosed mAbs. These results not only support our current efforts to evaluate the safety and efficacy of IN-006 in clinical trials, but more broadly substantiate nebulized delivery of human antiviral mAbs as a new paradigm in treating SARS-CoV-2 and other respiratory pathologies.

Competing Interest Statement

MM, ZR, and JH are employees of Inhalon Biopharma/Mucommune, and hold shares in Inhalon Biopharma. HK, ML, CK, and KK are employees of Celltrion, Inc. SKL is founder of Mucommune, LLC and currently serves as its interim CEO. SKL is also founder of Inhalon Biopharma, Inc, and currently serves as its CSO as well as on its Board of Director and Scientific Advisory Board. SKL has equity interests in both Mucommune and Inhalon Biopharma; SKL's relationships with Mucommune and Inhalon are subject to certain restrictions under University policy. The terms of these arrangements are managed by UNC-CH in accordance with its conflict of interest policies.

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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 01, 2022.
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Stable nebulization and muco-trapping properties of Regdanvimab/IN-006 supports its development as a potent, dose-saving inhaled therapy for COVID-19
Morgan McSweeney, Ian Stewart, Zach Richardson, Hyunah Kang, Yoona Park, Cheolmin Kim, Karthik Tiruthani, Whitney Wolf, Alison Schaefer, Priya Kumar, Harendra Aurora, Jeff Hutchins, Jong Moon Cho, Anthony J. Hickey, Soo Young Lee, Samuel Lai
bioRxiv 2022.02.27.482162; doi: https://doi.org/10.1101/2022.02.27.482162
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Stable nebulization and muco-trapping properties of Regdanvimab/IN-006 supports its development as a potent, dose-saving inhaled therapy for COVID-19
Morgan McSweeney, Ian Stewart, Zach Richardson, Hyunah Kang, Yoona Park, Cheolmin Kim, Karthik Tiruthani, Whitney Wolf, Alison Schaefer, Priya Kumar, Harendra Aurora, Jeff Hutchins, Jong Moon Cho, Anthony J. Hickey, Soo Young Lee, Samuel Lai
bioRxiv 2022.02.27.482162; doi: https://doi.org/10.1101/2022.02.27.482162

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