iScience (Jan 2022)
ACE2-IgG1 fusions with improved in vitro and in vivo activity against SARS-CoV-2
- Naoki Iwanaga,
- Laura Cooper,
- Lijun Rong,
- Nicholas J. Maness,
- Brandon Beddingfield,
- Zhongnan Qin,
- Jackelyn Crabtree,
- Ralph A. Tripp,
- Haoran Yang,
- Robert Blair,
- Sonia Jangra,
- Adolfo García-Sastre,
- Michael Schotsaert,
- Sruti Chandra,
- James E. Robinson,
- Akhilesh Srivastava,
- Felix Rabito,
- Xuebin Qin,
- Jay K. Kolls
Affiliations
- Naoki Iwanaga
- Departments of Pediatrics and Medicine, Center for Translational Research in Infection and Inflammation, Tulane University School of Medicine, New Orleans, LA 70112, USA
- Laura Cooper
- Departments of Microbiology and Immunology, College of Medicine University of Illinois at Chicago, Chicago, IL 60612, USA
- Lijun Rong
- Departments of Microbiology and Immunology, College of Medicine University of Illinois at Chicago, Chicago, IL 60612, USA
- Nicholas J. Maness
- Departments of Microbiology and Immunology, Tulane University School of Medicine, New Orleans, LA 70112, USA
- Brandon Beddingfield
- Departments of Microbiology and Immunology, Tulane University School of Medicine, New Orleans, LA 70112, USA
- Zhongnan Qin
- Departments of Microbiology and Immunology, Tulane University School of Medicine, New Orleans, LA 70112, USA; Tulane National Primate Research Center, Covington, LA 70433, USA
- Jackelyn Crabtree
- Departments of Infectious Diseases, Animal Health Research Center, University of Georgia, Athens, GA 30602,USA
- Ralph A. Tripp
- Departments of Infectious Diseases, Animal Health Research Center, University of Georgia, Athens, GA 30602,USA
- Haoran Yang
- Departments of Pediatrics and Medicine, Center for Translational Research in Infection and Inflammation, Tulane University School of Medicine, New Orleans, LA 70112, USA
- Robert Blair
- Departments of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, LA 70112, USA; Tulane National Primate Research Center, Covington, LA 70433, USA
- Sonia Jangra
- Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
- Adolfo García-Sastre
- Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Medicine, Division of Infectious Diseases, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Department of Pathology, Molecular and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
- Michael Schotsaert
- Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
- Sruti Chandra
- Departments of Pediatrics, Tulane University School of Medicine, New Orleans, LA 70112, USA
- James E. Robinson
- Departments of Pediatrics, Tulane University School of Medicine, New Orleans, LA 70112, USA
- Akhilesh Srivastava
- Departments of Pediatrics and Medicine, Center for Translational Research in Infection and Inflammation, Tulane University School of Medicine, New Orleans, LA 70112, USA
- Felix Rabito
- Departments of Pediatrics and Medicine, Center for Translational Research in Infection and Inflammation, Tulane University School of Medicine, New Orleans, LA 70112, USA
- Xuebin Qin
- Departments of Microbiology and Immunology, Tulane University School of Medicine, New Orleans, LA 70112, USA; Tulane National Primate Research Center, Covington, LA 70433, USA
- Jay K. Kolls
- Departments of Pediatrics and Medicine, Center for Translational Research in Infection and Inflammation, Tulane University School of Medicine, New Orleans, LA 70112, USA; Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Corresponding author
- Journal volume & issue
-
Vol. 25,
no. 1
p. 103670
Abstract
Summary: SARS-CoV-2, 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. A mutation in the catalytic domain of ACE2, MDR504, significantly increased binding to SARS-CoV-2 spike protein, as well as to a spike variant, in vitro with more potent viral neutralization in plaque assays. Parental administration of the protein showed stable serum concentrations with excellent bioavailability in the epithelial lining fluid of the lung, and ameliorated lung SARS-CoV-2 infection in vivo. These data support that the MDR504 hACE2-Fc is an excellent candidate for treatment or prophylaxis of COVID-19 and potentially emerging variants.
