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Novel ACE2-IgG1 fusions with improved activity against SARS-CoV2

View ORCID ProfileNaoki Iwanaga, Laura Cooper, Lijun Rong, Brandon Beddingfield, Jackelyn Crabtree, Ralph A. Tripp, View ORCID ProfileJay K. Kolls
doi: https://doi.org/10.1101/2020.06.15.152157
Naoki Iwanaga
1Departments of Pediatrics & Medicine, Center for Translational Research in Infection and Inflammation, Tulane University School of Medicine, New Orleans, LA 70112, USA
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Laura Cooper
2Departments of Microbiology and Immunology, College of Medicine University of Illinois at Chicago, Chicago, IL 60612 USA
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Lijun Rong
2Departments of Microbiology and Immunology, College of Medicine University of Illinois at Chicago, Chicago, IL 60612 USA
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Brandon Beddingfield
3Departments of Microbiology & Immunology, Tulane University School of Medicine, New Orleans, LA 70112, USA
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Jackelyn Crabtree
4Departments of Infectious Diseases, Animal Health Research Center, University of Georgia, Athens, GA 30602 USA
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Ralph A. Tripp
4Departments of Infectious Diseases, Animal Health Research Center, University of Georgia, Athens, GA 30602 USA
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Jay K. Kolls
1Departments of Pediatrics & Medicine, Center for Translational Research in Infection and Inflammation, Tulane University School of Medicine, New Orleans, LA 70112, USA
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  • For correspondence: jkolls1@tulane.edu
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Abstract

SARS-CoV2, the etiologic agent of COVID-19, uses ACE2 as a cell entry receptor. Soluble ACE2 has been shown to have neutralizing antiviral activity but has a short half-life and no active transport mechanism from the circulation into the alveolar spaces of the lung. To overcome this, we constructed an ACE2-human IgG1 fusion protein with mutations in the catalytic domain of ACE2. This fusion protein contained a LALA mutation that abrogates Fcrγ binding, but retains FcRN binding to prolong the half-life, as well as achieve therapeutic concentrations in the lung lavage. Interestingly, a mutation in the catalytic domain of ACE2, MDR504, completely abrogated catalytic activity, but significantly increased binding to SARS-CoV2 spike protein in vitro. This feature correlated with more potent viral neutralization in a plaque assay. Parental administration of the protein showed stable serum concentrations with a serum half-life of ∼ 145 hours with excellent bioavailability in the epithelial lining fluid of the lung. These data support that the MDR504 hACE2-Fc is an excellent candidate for pre or post-exposure prophylaxis or treatment of COVID-19.

Competing Interest Statement

Tulane University has filed a provisional patent listing Drs. Kolls and Iwanaga as inventors of MDR504

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Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted June 15, 2020.
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Novel ACE2-IgG1 fusions with improved activity against SARS-CoV2
Naoki Iwanaga, Laura Cooper, Lijun Rong, Brandon Beddingfield, Jackelyn Crabtree, Ralph A. Tripp, Jay K. Kolls
bioRxiv 2020.06.15.152157; doi: https://doi.org/10.1101/2020.06.15.152157
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Novel ACE2-IgG1 fusions with improved activity against SARS-CoV2
Naoki Iwanaga, Laura Cooper, Lijun Rong, Brandon Beddingfield, Jackelyn Crabtree, Ralph A. Tripp, Jay K. Kolls
bioRxiv 2020.06.15.152157; doi: https://doi.org/10.1101/2020.06.15.152157

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