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Publications

Journal Article Ppublish

PubMed: 41603290 DOI: 10.1002/pro.70489

Optimized ACE2-Fc fusion proteins with picomolar neutralization activity against highly evolved SARS-CoV-2 variants.

Protein Sci 35(2):e70489

Authors: Ferran Abancó, Ferran Tarrés-Freixas, Rosalba Lepore, Elisa Molina-Molina, Eloi Franco, Rytis Boreika, Edwards Pradenas, Dàlia Raïch-Regué, Itziar Erkizia, Bonaventura Clotet, Alfonso Valencia, Júlia Vergara-Alert, Joaquim Segalés, Jorge Carrillo, Nuria Izquierdo-Useros, Julià Blanco, Benjamin Trinité

Affiliations

  • IrsiCaixa, Badalona, Spain. Medicine and Biomedical Sciences Program, University of Vic-Central University of Catalonia (UVic-UCC), Vic, Spain.
  • IrsiCaixa, Badalona, Spain.
  • Medicine and Biomedical Sciences Program, University of Vic-Central University of Catalonia (UVic-UCC), Vic, Spain.
  • Unitat Mixta d'Investigació IRTA-UAB en Sanitat Animal, Centre de Recerca en Sanitat Animal (CReSA), Campus de la Universitat Autònoma de Barcelona (UAB), Bellaterra, Spain.
  • Programa de Sanitat Animal, IRTA, Centre de Recerca en Sanitat Animal (CReSA), Universitat Autònoma de Barcelona (UAB), Campus UAB, Bellaterra, Spain.
  • Life Sciences Department, Barcelona Supercomputing Center (BSC), Barcelona, Spain.
  • CIBER Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, Madrid, Spain.
  • Department de Sanitat i Anatomia Animals, Facultat de Veterinària, Campus de la UAB, Bellaterra, Spain.
  • Germans Trias i Pujol Research Institute (IGTP), Badalona, Spain.

Abstract

The rapid evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has compromised the efficacy of many authorized monoclonal antibody products. This highlights the need for alternative strategies, especially for vulnerable populations such as immunocompromised individuals. Here, we optimized angiotensin-converting enzyme 2 (ACE2)-Fc fusion proteins by combining three engineering steps: in silico mutagenesis of the S protein binding interface to increase affinity, insertion of a flexible linker to improve protein stability and S protein accessibility, and generation of a tetrameric molecule to maximize avidity. Neutralizing activity was tested against a large panel of pre-Omicron and Omicron pseudoviruses and authentic viruses, including JN.1 and KP.2 variants. Optimized ACE2-Fc molecules demonstrated potent neutralizing activity, in the picomolar range, against all SARS-CoV-2 variants. Our molecules displayed similar potency but better resilience when compared to the monoclonal antibody Sipavibart. These findings support ACE2-Fc proteins as robust candidates for next-generation interventions against infection by an evolving SARS-CoV-2.

MeSH

Coronavirus, Sars-Cov-2, Viruses, Antibodies, Monoclonal, Severe Acute Respiratory Syndrome-Related Coronavirus