Rational strategies for enhancing mAb binding to SARS-CoV-2 variants through CDR diversification and antibody-escape prediction

Front Immunol. 2023 Mar 31:14:1113175. doi: 10.3389/fimmu.2023.1113175. eCollection 2023.

Abstract

Since the emergence of SARS-CoV-2, dozens of variants of interest and half a dozen variants of concern (VOCs) have been documented by the World Health Organization. The emergence of these VOCs due to the continuous evolution of the virus is a major concern for COVID-19 therapeutic antibodies and vaccines because they are designed to target prototype/previous strains and lose effectiveness against new VOCs. Therefore, there is a need for time- and cost-effective strategies to estimate the immune escape and redirect therapeutic antibodies against newly emerging variants. Here, we computationally predicted the neutralization escape of the SARS-CoV-2 Delta and Omicron variants against the mutational space of RBD-mAbs interfaces. Leveraging knowledge of the existing RBD-mAb interfaces and mutational space, we fine-tuned and redirected CT-p59 (Regdanvimab) and Etesevimab against the escaped variants through complementarity-determining regions (CDRs) diversification. We identified antibodies against the Omicron lineage BA.1 and BA.2 and Delta variants with comparable or better binding affinities to that of prototype Spike. This suggests that CDRs diversification by hotspot grafting, given an existing insight into the Ag-Abs interface, is an exquisite strategy to redirect antibodies against preselected epitopes and combat the neutralization escape of emerging SARS-CoV-2 variants.

Keywords: CDR diversification; Omicron (B.1.1.529); SARS-CoV-2; antibody; immune escape; omicron.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antibodies, Monoclonal / therapeutic use
  • COVID-19*
  • Complementarity Determining Regions / genetics
  • Humans
  • SARS-CoV-2* / genetics

Substances

  • Antibodies, Monoclonal
  • Complementarity Determining Regions

Supplementary concepts

  • SARS-CoV-2 variants

Grants and funding

This research was supported by grants from the National Research Foundation of Korea (NRF) funded by the Ministry of Science and ICT (MSIT) (NRF-2019R1A5A2026045) and the grant from the Korea Health Industry Development Institute (KHIDI) funded by the Ministry of Health & Welfare, Republic of Korea (HI21C1003 and HV22C0164). This study was also supported by KREONET (Korea Research Environment Open NETwork), which is managed and operated by KISTI (Korea Institute of Science and Technology Information).