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