A novel bispecific antibody dual-targeting approach for enhanced neutralization against fast-evolving SARS-CoV-2 variants

Ji Woong Kim, Hyun Jung Kim, Kyun Heo, Yoonwoo Lee, Hui Jeong Jang, Ho Young Lee, Jun Won Park, Yea Bin Cho, Ji Hyun Lee, Ha Gyeong Shin, Ha Rim Yang, Hye Lim Choi, Hyun Bo Shim, Sukmook Lee

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

Introduction: The emergence of new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants has caused unprecedented health and socioeconomic crises, necessitating the immediate development of highly effective neutralizing antibodies. Despite recent advancements in anti-SARS-CoV-2 receptor-binding domain (RBD)-specific monoclonal antibodies (mAbs) derived from convalescent patient samples, their efficacy against emerging variants has been limited. In this study, we present a novel dual-targeting strategy using bispecific antibodies (bsAbs) that specifically recognize both the SARS-CoV-2 RBD and fusion peptide (FP), crucial domains for viral attachment to the host cell membrane and fusion in SARS-CoV-2 infection. Methods: Using phage display technology, we rapidly isolated FP-specific mAbs from an established human recombinant antibody library, identifying K107.1 with a nanomolar affinity for SARS-CoV-2 FP. Furthermore, we generated K203.A, a new bsAb built in immunoglobulin G4-(single-chain variable fragment)2 forms and demonstrating a high manufacturing yield and nanomolar affinity to both the RBD and FP, by fusing K102.1, our previously reported RBD-specific mAb, with K107.1. Results: Our comprehensive in vitro functional analyses revealed that the K203.A bsAb significantly outperformed the parental RBD-specific mAb in terms of neutralization efficacy against SARS-CoV-2 variants. Furthermore, intravenous monotherapy with K203.A demonstrated potent in vivo neutralizing activity without significant in vivo toxicity in a mouse model infected with a SARS-CoV-2 variant. Conclusion: These findings present a novel bsAb dual-targeting strategy, directed at SARS-CoV-2 RBD and FP, as an effective approach for rapid development and management against continuously evolving SARS-CoV-2 variants.

Original languageEnglish
Article number1271508
JournalFrontiers in Immunology
Volume14
DOIs
StatePublished - 2023

Bibliographical note

Publisher Copyright:
Copyright © 2023 Kim, Kim, Heo, Lee, Jang, Lee, Park, Cho, Lee, Shin, Yang, Choi, Shim and Lee.

Keywords

  • SARS-CoV-2
  • bispecific antibody
  • fusion peptide
  • phage display
  • receptor-binding domain

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