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Evaluating mAbs binding abilities to Omicron subvariant RBDs: implications for selecting effective mAb therapies
Song Luo1, Danyang Xiong1, Bolin Tang1
1School of Physics and Electronics, Shandong Normal University, Jinan, 250014, China. duanll@sdnu.edu.cn.
Physical Chemistry Chemical Physics : PCCP
|April 9, 2024
Summary
Certain monoclonal antibodies (mAbs) maintain binding against Omicron subvariants, offering resilience against immune escape. This study analyzed SARS-CoV-2 receptor-binding domains and mAbs to understand escape mechanisms and guide therapeutic antibody development.
Area of Science:
- Virology and Immunology
- Structural Biology
- Computational Biophysics
Background:
- The Omicron lineage of SARS-CoV-2 continuously evolves, producing subvariants that challenge existing antibody neutralization capabilities.
- Understanding the binding interactions between the spike receptor-binding domain (RBD) of SARS-CoV-2 variants and monoclonal antibodies (mAbs) is crucial for addressing immune escape.
- This knowledge is vital for developing effective therapeutic antibodies against current and future coronavirus threats.
Purpose of the Study:
- To investigate the binding dynamics between the RBDs of Omicron subvariants (BA.2, BA.5, BF.7, XBB.1.5) and a panel of six mAbs.
- To elucidate the mechanisms of immune escape by analyzing energetic and structural factors influencing RBD-mAb interactions.
- To identify potential therapeutic antibody candidates and key residues involved in binding and immune evasion.
Main Methods:
- Molecular dynamics simulations were employed to model the binding interactions between SARS-CoV-2 RBDs and mAbs.
- Energetic and structural analyses were performed to understand the origins of immune escape.
- Key residues facilitating or hindering protein-protein interactions were identified.
Main Results:
- The antibody LY-COV1404 demonstrated consistent binding affinities across all Omicron subvariants studied, indicating resilience to immune escape.
- The novel mAb 002-S21F2 showed comparable efficacy to LY-COV1404, with a slight reduction in binding to the BF.7 subvariant.
- mAb REGN-10933 emerged as a promising candidate against BF.7 and XBB.1.5, highlighting the importance of variant-specific antibody interactions. Key binding residues (e.g., T345, L441) and hindering residues (e.g., D420, L455) were identified, with V445 and R509 showing inhibited binding in the presence of mAb 002-S21F2, potentially via reduced V445 hydrophobicity.
Conclusions:
- The study enhances the understanding of mAb-RBD binding interactions and mechanisms of viral immune escape.
- Findings provide a basis for designing and optimizing antiviral drugs targeting SARS-CoV-2.
- The research has significant implications for developing effective treatments against existing and emerging coronavirus variants.
