A novel soluble ACE2 protein totally protects from lethal disease caused by SARS-CoV-2 infection
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Abstract
Severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) uses full-length angiotensin converting enzyme 2 (ACE2), which is membrane bound, as its initial cell contact receptor preceding viral entry. Here we report a human soluble ACE2 variant fused with a 5kD albumin binding domain (ABD) and bridged via a dimerization motif hinge-like 4-cysteine dodecapeptide, which we term ACE2 1-618-DDC-ABD. This protein is enzymatically active, has increased duration of action in vivo conferred by the ABD-tag, and displays 20-30-fold higher binding affinity to the SARS-CoV-2 receptor binding domain than its des-DDC monomeric form (ACE2 1-618-ABD) due to DDC-linked dimerization. ACE2 1-618-DDC-ABD was administered for 3 consecutive days to transgenic k18-hACE2 mice, a model that develops lethal SARS-CoV-2 infection, to evaluate the preclinical preventative/ therapeutic value for COVID-19. Mice treated with ACE2 1-618-DDC-ABD developed a mild to moderate disease for the first few days assessed by a clinical score and modest weight loss. The untreated control animals, by contrast, became severely ill and had to be sacrificed by day 6/7 and lung histology revealed extensive pulmonary alveolar hemorrhage and mononuclear infiltrates. At 6 days, mortality was totally prevented in the treated group, lung histopathology was improved and viral titers markedly reduced. This demonstrates for the first time in vivo the preventative/ therapeutic potential of a novel soluble ACE2 protein in a preclinical animal model.
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SciScore for 10.1101/2021.03.12.435191: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement IACUC: In vivo infectivity studies: All work with live SARS-CoV-2 was performed in the BSL-3 facility of the Ricketts Regional Biocontainment Laboratory, operated by The University of Chicago following a protocol approved by the Institutional Animal Care and Use Committees of Northwestern University and University of Chicago. Randomization not detected. Blinding One blinded lung pathologist evaluated the severity and presence of lung injury using a scoring system recently described in k18-hACE2 mice infected with SARS-CoV-2 (26). Power Analysis not detected. Sex as a biological variable Plasma ACE2 activity after injection of ACE2 1-618-ABD-DDC: Pharmacokinetics of ACE2 … SciScore for 10.1101/2021.03.12.435191: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement IACUC: In vivo infectivity studies: All work with live SARS-CoV-2 was performed in the BSL-3 facility of the Ricketts Regional Biocontainment Laboratory, operated by The University of Chicago following a protocol approved by the Institutional Animal Care and Use Committees of Northwestern University and University of Chicago. Randomization not detected. Blinding One blinded lung pathologist evaluated the severity and presence of lung injury using a scoring system recently described in k18-hACE2 mice infected with SARS-CoV-2 (26). Power Analysis not detected. Sex as a biological variable Plasma ACE2 activity after injection of ACE2 1-618-ABD-DDC: Pharmacokinetics of ACE2 1-618-DDC-ABD were examined in male wild-type mice (C57/B6), as previously described (16). Cell Line Authentication not detected. Table 2: Resources
Antibodies Sentences Resources For staining studies, an ACE2 antibody AF933 (R&D Systems) was used (16) and staining performed as previously described (32). ACE2suggested: NoneExperimental Models: Cell Lines Sentences Resources Samples were then centrifuged at 1000g for 5 minutes and the supernatant was serially diluted 10-fold and used to infect VeroE6 cells for 1 hour. VeroE6suggested: JCRB Cat# JCRB1819, RRID:CVCL_YQ49)Experimental Models: Organisms/Strains Sentences Resources Plasma ACE2 activity after injection of ACE2 1-618-ABD-DDC: Pharmacokinetics of ACE2 1-618-DDC-ABD were examined in male wild-type mice (C57/B6), as previously described (16). C57/B6suggested: NoneK18-hACE2 mice (8 weeks old) were purchased from Jackson. K18-hACE2suggested: RRID:IMSR_GPT:T037657)Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.Results from TrialIdentifier: We found the following clinical trial numbers in your paper:
Identifier Status Title NCT00886353 Completed Safety and Tolerability Study of APN01 (Recombinant Human An… Results from Barzooka: We did not find any issues relating to the usage of bar graphs.
Results from JetFighter: We did not find any issues relating to colormaps.
Results from rtransparent:- Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
- Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
- No protocol registration statement was detected.
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