Antiviral Res . Novel bispecific human antibody platform specifically targeting a fully open spike conformation potently neutralizes multiple SARS-CoV-2 variants

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Antiviral Res


. 2023 Mar 2;105576.
doi: 10.1016/j.antiviral.2023.105576. Online ahead of print.
Novel bispecific human antibody platform specifically targeting a fully open spike conformation potently neutralizes multiple SARS-CoV-2 variants


Ji Woong Kim ¹ , Kyun Heo ² , Hyun Jung Kim ³ , Youngki Yoo ⁴ , Hyun-Soo Cho ⁴ , Hui Jeong Jang ⁵ , Ho-Young Lee ⁵ , In Young Ko ⁶ , Ju Rang Woo ⁶ , Yea Bin Cho ¹ , Ji Hyun Lee ³ , Ha Rim Yang ³ , Ha Gyeong Shin ³ , Hye Lim Choi ³ , Kyusang Hwang ³ , Sokho Kim ⁷ , Hanseong Kim ⁸ , Kwangrok Chun ⁹ , Sukmook Lee ¹⁰



Affiliations

• PMID: 36870394
• DOI: 10.1016/j.antiviral.2023.105576

Abstract

Rapid emergence of new variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has prompted an urgent need for the development of broadly applicable and potently neutralizing antibody platform against the SARS-CoV-2, which can be used for combatting the coronavirus disease 2019 (COVID-19). In this study, based on a noncompeting pair of phage display-derived human monoclonal antibodies (mAbs) specific to the receptor-binding domain (RBD) of SARS-CoV-2 isolated from human synthetic antibody library, we generated K202.B, a novel engineered bispecific antibody with an immunoglobulin G4-single-chain variable fragment design, with sub- or low nanomolar antigen-binding avidity. Compared with the parental mAbs or mAb cocktail, the K202.B antibody showed superior neutralizing potential against a variety of SARS-CoV-2 variants in vitro. Furthermore, structural analysis of bispecific antibody-antigen complexes using cryo-electron microscopy revealed the mode of action of K202.B complexed with a fully open three-RBD-up conformation of SARS-CoV-2 trimeric spike proteins by simultaneously interconnecting two independent epitopes of the SARS-CoV-2 RBD via inter-protomer interactions. Intravenous monotherapy using K202.B exhibited potent neutralizing activity in SARS-CoV-2 wild-type- and B.1.617.2 variant-infected mouse models, without significant toxicity in vivo. The results indicate that this novel approach of development of immunoglobulin G4-based bispecific antibody from an established human recombinant antibody library is likely to be an effective strategy for the rapid development of bispecific antibodies, and timely management against fast-evolving SARS-CoV-2 variants.

Keywords: Bispecific antibody; Cryo-EM; Immunoglobulin G4; Phage display; SARS-CoV-2 variants; Structural analysis.