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

Area of Science:

• Virology
• Immunology
• Protein Engineering

Background:

• Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) rapidly evolves, diminishing the effectiveness of current monoclonal antibody treatments.
• Immunocompromised individuals are particularly vulnerable to severe COVID-19 due to compromised immune responses.

Purpose of the Study:

• To engineer optimized angiotensin-converting enzyme 2 (ACE2)-Fc fusion proteins with enhanced neutralizing activity against SARS-CoV-2 variants.
• To evaluate the efficacy of these novel ACE2-Fc fusion proteins against a broad range of SARS-CoV-2 variants, including Omicron sublineages.

Main Methods:

• In silico mutagenesis of the S protein binding interface to increase affinity.
• Incorporation of a flexible linker for improved protein stability and S protein accessibility.
• Generation of tetrameric ACE2-Fc molecules to enhance binding avidity.

Main Results:

• Optimized ACE2-Fc fusion proteins demonstrated potent neutralizing activity in the picomolar range against all tested SARS-CoV-2 variants, including JN.1 and KP.2.
• The engineered molecules exhibited comparable potency and superior resilience compared to the monoclonal antibody Sipavibart.
• Neutralizing activity was confirmed against both pseudoviruses and authentic SARS-CoV-2 strains.

Conclusions:

• Engineered ACE2-Fc fusion proteins represent a promising strategy for next-generation COVID-19 interventions.
• These molecules offer a robust alternative for treating infections caused by evolving SARS-CoV-2 strains, especially in immunocompromised patients.
• The optimized ACE2-Fc platform provides a versatile approach to combatting viral evolution and maintaining therapeutic efficacy.