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

doi:10.1016/j.isci.2021.103670

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

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21 Scopus citations

Abstract

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.

Original language	English
Article number	103670
Journal	iScience
Volume	25
Issue number	1
DOIs	https://doi.org/10.1016/j.isci.2021.103670
State	Published - 21 Jan 2022

Keywords

Drugs
Virology

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Iwanaga, N., Cooper, L., Rong, L., Maness, N. J., Beddingfield, B., Qin, Z., Crabtree, J., Tripp, R. A., Yang, H., Blair, R., Jangra, S., García-Sastre, A., Schotsaert, M., Chandra, S., Robinson, J. E., Srivastava, A., Rabito, F., Qin, X., & Kolls, J. K. (2022). ACE2-IgG1 fusions with improved in vitro and in vivo activity against SARS-CoV-2. iScience, 25(1), Article 103670. https://doi.org/10.1016/j.isci.2021.103670

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title = "ACE2-IgG1 fusions with improved in vitro and in vivo activity against SARS-CoV-2",

abstract = "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.",

keywords = "Drugs, Virology",

author = "Naoki Iwanaga and Laura Cooper and Lijun Rong and Maness, {Nicholas J.} and Brandon Beddingfield and Zhongnan Qin and Jackelyn Crabtree and Tripp, {Ralph A.} and Haoran Yang and Robert Blair and Sonia Jangra and Adolfo Garc{\'i}a-Sastre and Michael Schotsaert and Sruti Chandra and Robinson, {James E.} and Akhilesh Srivastava and Felix Rabito and Xuebin Qin and Kolls, {Jay K.}",

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year = "2022",

month = jan,

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doi = "10.1016/j.isci.2021.103670",

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Iwanaga, N, Cooper, L, Rong, L, Maness, NJ, Beddingfield, B, Qin, Z, Crabtree, J, Tripp, RA, Yang, H, Blair, R, Jangra, S, García-Sastre, A , Schotsaert, M, Chandra, S, Robinson, JE, Srivastava, A, Rabito, F, Qin, X & Kolls, JK 2022, 'ACE2-IgG1 fusions with improved in vitro and in vivo activity against SARS-CoV-2', iScience, vol. 25, no. 1, 103670. https://doi.org/10.1016/j.isci.2021.103670

TY - JOUR

T1 - ACE2-IgG1 fusions with improved in vitro and in vivo activity against SARS-CoV-2

AU - Iwanaga, Naoki

AU - Cooper, Laura

AU - Rong, Lijun

AU - Maness, Nicholas J.

AU - Beddingfield, Brandon

AU - Qin, Zhongnan

AU - Crabtree, Jackelyn

AU - Tripp, Ralph A.

AU - Yang, Haoran

AU - Blair, Robert

AU - Jangra, Sonia

AU - García-Sastre, Adolfo

AU - Schotsaert, Michael

AU - Chandra, Sruti

AU - Robinson, James E.

AU - Srivastava, Akhilesh

AU - Rabito, Felix

AU - Qin, Xuebin

AU - Kolls, Jay K.

PY - 2022/1/21

Y1 - 2022/1/21

N2 - 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.

AB - 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.

KW - Drugs

KW - Virology

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DO - 10.1016/j.isci.2021.103670

M3 - Article

AN - SCOPUS:85122199176

SN - 2589-0042

VL - 25

JO - iScience

JF - iScience

IS - 1

M1 - 103670

ER -

ACE2-IgG1 fusions with improved in vitro and in vivo activity against SARS-CoV-2

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Keywords

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