Variant-proof high affinity ACE2 antagonist limits SARS-CoV-2 replication in upper and lower airways

Area of Science:

• Virology
• Immunology
• Biomedical Engineering

Background:

• Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) evolves rapidly, developing mutations that confer resistance to vaccines, prior infection immunity, and antiviral medications.
• The emergence of new SARS-CoV-2 variants necessitates the development of variant-agnostic therapeutic agents that can maintain efficacy against diverse viral strains and avoid exerting selective pressure.
• A therapeutic agent that prevents severe disease without promoting viral resistance would be a significant advancement in managing the ongoing pandemic.

Purpose of the Study:

• To evaluate the efficacy of aerosolized RBD-62, a protein engineered for enhanced binding to the SARS-CoV-2 receptor-binding domain (RBD), in preventing severe disease caused by the Delta variant.
• To assess whether RBD-62 treatment impacts the development of virus-specific T- and B-cell responses or elicits anti-drug immunity.
• To demonstrate proof-of-concept for RBD-62 as a potential therapeutic intervention against highly virulent SARS-CoV-2 variants.

Main Methods:

• Male rhesus macaques were challenged with the SARS-CoV-2 Delta variant, a highly pathogenic strain.
• At the time of challenge, macaques were treated with aerosolized RBD-62, a protein with a 1000-fold enhanced ACE2 binding affinity compared to the wild-type RBD.
• Virus replication was assessed in both upper and lower airways, and virus-specific T- and B-cell responses were monitored. Anti-drug immunity was also evaluated.

Main Results:

• Aerosolized RBD-62 treatment effectively suppressed SARS-CoV-2 Delta variant replication in both the upper and lower airways of macaques.
• This suppression of viral replication was observed to be equivalent across both airway compartments, a finding not previously documented with clinically approved vaccines.
• Importantly, RBD-62 treatment did not impede the development of virus-specific T- and B-cell responses and did not induce anti-drug immunity in the treated animals.

Conclusions:

• RBD-62 demonstrates significant potential as a variant-agnostic therapeutic agent against SARS-CoV-2.
• The ability of RBD-62 to suppress replication without compromising host immune responses or inducing drug resistance is a key advantage.
• These findings provide strong preclinical evidence supporting the development of RBD-62 for preventing severe COVID-19, even in the face of emerging viral variants.