Structural basis for SARS-CoV-2 neutralizing antibodies with novel binding epitopes.

Area of Science:

• Immunology
• Virology
• Structural Biology

Background:

• The COVID-19 pandemic necessitates rapid development of medical interventions.
• Understanding neutralizing antibodies (NAbs) is crucial for advancing monoclonal antibody (mAb) therapies and vaccine design.

Purpose of the Study:

• To isolate and characterize novel neutralizing antibodies against SARS-CoV-2.
• To elucidate the structural basis of antibody-virus interactions for therapeutic development.

Main Methods:

• Utilized H2L2 transgenic mice and an advanced antibody discovery platform for NAb isolation.
• Employed X-ray crystallography to determine the structures of NAbs bound to the SARS-CoV-2 spike protein.
• Evaluated NAb efficacy in an Ad5-hACE2 transduction mouse model of COVID-19.

Main Results:

• Identified 25 potent NAbs with sub-nanomolar neutralizing activity against the spike receptor-binding domain (RBD).
• Determined high-resolution structures revealing novel epitopes for NAbs PR1077 and PR953 that block hACE2 binding.
• Characterized NAb PR961 with a novel non-blocking epitope near the RBD.
• Demonstrated potent prophylactic and therapeutic protection against SARS-CoV-2 infection with a single dose of PR1077 in a mouse model.

Conclusions:

• The identified NAbs, particularly PR1077, represent promising candidates for COVID-19 therapeutic interventions.
• Structural insights into novel epitopes advance the design of next-generation vaccines and antibody therapies.
• This study provides a foundation for developing effective mAb treatments against SARS-CoV-2.