Engineering a “muco-trapping” ACE2-immunoglobulin hybrid with picomolar affinity as an inhaled, pan-variant immunotherapy for COVID-19

Karthik Tiruthani, Carlos Cruz-Teran, Jasper F.W. Chan, Alice Ma, Morgan McSweeney, Whitney Wolf, Shoufeng Yuan, Vincent K.M. Poon, Chris C.S. Chan, Lakshmi Botta, Brian Farrer, Ian Stewart, Alison Schaefer, Jasmine Edelstein, Priya Kumar, Harendra Arora, Jeff T. Hutchins, Anthony J. Hickey, Kwok Yung Yuen, Samuel K. Lai

Research output: Contribution to journalArticlepeer-review

3 Citations (Scopus)

Abstract

Soluble angiotensin-converting enzyme 2 (ACE2) can act as a decoy molecule that neutralizes severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by blocking spike (S) proteins on virions from binding ACE2 on host cells. Based on structural insights of ACE2 and S proteins, we designed a “muco-trapping” ACE2-Fc conjugate, termed ACE2-(G4S)6-Fc, comprised of the extracellular segment of ACE2 (lacking the C-terminal collectrin domain) that is linked to mucin-binding IgG1-Fc via an extended glycine-serine flexible linker. ACE2-(G4S)6-Fc exhibits substantially greater binding affinity and neutralization potency than conventional full length ACE2-Fc decoys or similar truncated ACE2-Fc decoys without flexible linkers, possessing picomolar binding affinity and strong neutralization potency against pseudovirus and live virus. ACE2-(G4S)6-Fc effectively trapped fluorescent SARS-CoV-2 virus like particles in fresh human airway mucus and was stably nebulized using a commercial vibrating mesh nebulizer. Intranasal dosing of ACE2-(G4S)6-Fc in hamsters as late as 2 days postinfection provided a 10-fold reduction in viral load in the nasal turbinate tissues by Day 4. These results strongly support further development of ACE2-(G4S)6-Fc as an inhaled immunotherapy for COVID-19, as well as other emerging viruses that bind ACE2 for cellular entry.

Original languageEnglish
Article numbere10650
JournalBioengineering and Translational Medicine
Volume9
Issue number4
DOIs
Publication statusPublished - Jul 2024
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2024 The Authors. Bioengineering & Translational Medicine published by Wiley Periodicals LLC on behalf of American Institute of Chemical Engineers.

ASJC Scopus Subject Areas

  • Biotechnology
  • Biomedical Engineering
  • Pharmaceutical Science

Keywords

  • ACE2
  • antibody
  • COVID-19
  • drug delivery
  • immunodecoy
  • inhaled delivery
  • monoclonal antibody
  • SARS-CoV-2

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