IgA class switching enhances neutralizing potency against SARS-CoV-2 by increased antibody hinge flexibility

Area of Science:

• Immunology
• Virology
• Structural Biology

Background:

• Mucosal immunity relies on Immunoglobulin A (IgA) for defense against viral pathogens.
• SARS-CoV-2 infection elicits neutralizing antibodies, but their isotype-dependent efficacy requires further investigation.

Purpose of the Study:

• To compare the neutralization efficacy of IgA1 and IgG1 isotypes with identical variable regions against SARS-CoV-2.
• To investigate the structural basis for enhanced neutralization by IgA1.
• To evaluate the in vivo prophylactic efficacy of an IgA1-based therapeutic candidate.

Main Methods:

• Engineering recombinant IgA1 and IgG1 antibodies from SARS-CoV-2 convalescent plasma.
• Assessing neutralization potency using in vitro assays.
• Determining antibody-Spike protein interaction via structural analysis.
• Evaluating prophylactic efficacy in a mouse model of SARS-CoV-2 infection.

Main Results:

• Switching from IgG1 to IgA1 monomeric antibody (CAV-C65) resulted in a ten-fold increase in neutralization potency.
• Structural analysis revealed CAV-C65 binds to two adjacent receptor-binding domains on the SARS-CoV-2 spike protein.
• Enhanced IgA1 neutralization is linked to increased affinity, hinge region properties, and viral particle cross-linking.
• Inhaled CAV-C65 IgA1 provided prophylactic protection against lethal SARS-CoV-2 challenge in hACE2 mice.

Conclusions:

• IgA1 demonstrates superior neutralization efficacy compared to IgG1 against SARS-CoV-2.
• The structural features and multivalent binding of IgA1 contribute to its enhanced antiviral activity.
• IgA-based antibodies hold significant promise as therapeutics for viral infections, including SARS-CoV-2.