Development of multi-specific humanized llama antibodies blocking SARS-CoV-2/ACE2 interaction with high affinity and...

Area of Science:

• Immunology
• Virology
• Biotechnology

Background:

• Coronaviruses, including SARS-CoV-2, cause severe respiratory illnesses like COVID-19.
• The SARS-CoV-2 virus uses its spike (S) protein to bind the ACE2 receptor, enabling cell entry.
• Effective therapeutics against SARS-CoV-2 are urgently needed.

Discussion:

• This study explores humanized llama variable heavy-heavy (VHH) chains as potential therapeutic agents against SARS-CoV-2.
• VHHs were identified from llama libraries that effectively bind the SARS-CoV-2 spike protein and inhibit S/ACE2 interaction.
• Pairwise combinations of VHHs demonstrated synergistic blocking activity, suggesting enhanced therapeutic potential.

Key Insights:

• Novel humanized VHHs targeting the SARS-CoV-2 spike protein and blocking S/ACE2 interaction were successfully identified.
• Combinations of VHHs exhibit synergistic effects, improving the blockade of viral entry.
• A bispecific antibody demonstrated potent S/ACE2 blocking with high affinity (KD = 0.25 nM) and efficacy (IC50 = 1 nM).

Outlook:

• Further development involves creating multi-specific antibodies using an in-silico approach, fusing VHHs to Fc domains for enhanced properties.
• These engineered VHH-based antibodies aim to provide multiple mechanisms of action against SARS-CoV-2.
• The research contributes to developing advanced therapeutic antibodies and diagnostics for combating COVID-19.