Fc-binding nanodisc restores antiviral efficacy of antibodies with reduced neutralizing effects against evolving SARS-CoV-2 variants.

Summary

An Fc-binding nanodisc co-delivered intranasally with antibodies extended local airway persistence and enhanced neutralization, restoring efficacy of Sotrovimab across Omicron variants and boosting sACE2-Fc activity. In ACE2 transgenic mice, nanodisc complexes reduced lung viral titers by ≥2 logs beyond sACE2-Fc alone.

Key Findings

• Fc-binding nanodisc extended antibody residence in larynx/trachea and enhanced neutralization in the upper airway.
• Sotrovimab nanodisc complexes restored robust antiviral activity across tested Omicron variants in vitro.
• In ACE2 transgenic mice, nanodisc with sACE2-Fc achieved ≥2 log additional lung viral titer reduction versus sACE2-Fc alone.

Clinical Implications

Supports development of intranasal antibody formulations (including repurposing previously deauthorized mAbs) and sACE2-Fc for pre- or post-exposure prophylaxis in high-risk populations, pending human pharmacokinetic and efficacy data.

Limitations

• Preclinical study; human pharmacokinetics, safety, and efficacy are not yet established
• Long-term mucosal retention and immunogenicity of nanodisc complexes require evaluation

Future Directions

First-in-human studies of intranasal nanodisc–antibody and nanodisc–sACE2-Fc complexes; comparative trials versus parenteral mAbs for pre-exposure prophylaxis; manufacturability and stability assessments.