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.
N1 - Funding Information:
This work was supported by the following NIH grant R35HL139930 (JK) and R21OD024931. (XQ) as well as a grant from Emergent Ventures and the Paul Bechtner Foundation (JK). This work was also partly supported by CRIP (Center for Research for Influenza Pathogenesis), a NIAID supported Center of Excellence for Influenza Research and Surveillance (CEIRS, contract #HHSN272201400008C) and CRIPT (Center for Research on Influenza Pathogenesis and Transmission), a NIAID funded Center of Excellence for Influenza Research and Response (CEIRR, contract #75N93021C00014), by DARPA grant HR0011-19-2-0020, and by the generous support of the JPB Foundation, the Open Philanthropy Project (research grant 2020-215611 (5384)), and anonymous donors to AG-S. The following reagent was produced under HHSN272201400008C and obtained through BEI Resources, NIAID, NIH: Spike Glycoprotein Receptor-Binding Domain (RBD) from SARS-Related Coronavirus 2, Wuhan-Hu-1, Recombinant from HEK293 Cells, NR-52306.The S-Tag of SARS, S-Tag of SARS2 containing plasmids were kindly provided by Dr.Thomas Gallagher (Loyola University Chicago). We are grateful for technical help from Cecily C Midkiff in the histological core of Tulane National Primate Research Center and Christopher J Monjure and Tammy Bavaret in the Tulane ABSL3 core. We appreciate Dr. Florian Krammer (Professor of Vaccinology, Icahn School of Medicine at Mount Sinai in New York) for providing us the spike proteins including variants of concern. We thank Randy Albrecht for support with the BSL3 facility and procedures at the ISMMS. Conceptualization, N.I. and J.K.; Methodology, N.I. L.C. N.M. Z.Q. J.C. R.B. S.J. M.S. C.S. A.S. and J.K.; Validation, N.I. L.R. N.M. R.T. R.B. A.S. J.R. X.Q. and J.K.; Investigation, N.I. L.C. B.B. Z.Q. J.C. H.Y. R.B. S.J. M.S. C.S. A.S. and F.R.; Writing, N.I. and J.K.; Funding acquisition and Supervision, J.K. NI and JKK are named inventor on a patent application owned by Tulane University on MDR504. The A.G.-S. laboratory has received research support from Pfizer, Senhwa Biosciences, Kenall Manufacturing, Avimex, Johnson & Johnson, Dynavax, 7Hills Pharma, Pharmamar, ImmunityBio, Accurius, Nanocomposix, Hexamer, N-fold LLC, Model Medicines, Atea Pharma, and Merck, outside of the reported work. A.G.-S. has consulting agreements for the following companies involving cash and/or stock: Vivaldi Biosciences, Contrafect, 7Hills Pharma, Avimex, Vaxalto, Pagoda, Accurius, Esperovax, Farmak, Applied Biological Laboratories, Pharmamar, Paratus, and Pfizer, outside of the reported work. A.G.-S. is inventor on patents and patent applications on the use of antivirals and vaccines for the treatment and prevention of virus infections, owned by the Icahn School of Medicine at Mount Sinai, New York, outside of the reported work.
Funding Information:
This work was supported by the following NIH grant R35HL139930 (JK) and R21OD024931 . (XQ) as well as a grant from Emergent Ventures and the Paul Bechtner Foundation (JK). This work was also partly supported by CRIP (Center for Research for Influenza Pathogenesis), a NIAID supported Center of Excellence for Influenza Research and Surveillance (CEIRS, contract #HHSN272201400008C ) and CRIPT (Center for Research on Influenza Pathogenesis and Transmission), a NIAID funded Center of Excellence for Influenza Research and Response (CEIRR, contract #75N93021C00014 ), by DARPA grant HR0011-19-2-0020 , and by the generous support of the JPB Foundation , the Open Philanthropy Project (research grant 2020-215611 (5384) ), and anonymous donors to AG-S. The following reagent was produced under HHSN272201400008C and obtained through BEI Resources, NIAID, NIH: Spike Glycoprotein Receptor-Binding Domain (RBD) from SARS-Related Coronavirus 2, Wuhan-Hu-1, Recombinant from HEK293 Cells, NR-52306.The S-Tag of SARS, S-Tag of SARS2 containing plasmids were kindly provided by Dr.Thomas Gallagher (Loyola University Chicago). We are grateful for technical help from Cecily C Midkiff in the histological core of Tulane National Primate Research Center and Christopher J Monjure and Tammy Bavaret in the Tulane ABSL3 core. We appreciate Dr. Florian Krammer (Professor of Vaccinology, Icahn School of Medicine at Mount Sinai in New York) for providing us the spike proteins including variants of concern. We thank Randy Albrecht for support with the BSL3 facility and procedures at the ISMMS .
Publisher Copyright:
© 2021 The Author(s)
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
UR - http://www.scopus.com/inward/record.url?scp=85122199176&partnerID=8YFLogxK
U2 - 10.1016/j.isci.2021.103670
DO - 10.1016/j.isci.2021.103670
M3 - Article
AN - SCOPUS:85122199176
VL - 25
JO - iScience
JF - iScience
SN - 2589-0042
IS - 1
M1 - 103670
ER -