tetano
Editor, Senior Moderator
Front Immunol
. 2023 Sep 26:14:1271508.
doi: 10.3389/fimmu.2023.1271508. eCollection 2023. A novel bispecific antibody dual-targeting approach for enhanced neutralization against fast-evolving SARS-CoV-2 variants
Ji Woong Kim[SUP] 1 [/SUP], Hyun Jung Kim[SUP] 2 [/SUP], Kyun Heo[SUP] 1 2 3 [/SUP], Yoonwoo Lee[SUP] 4 [/SUP], Hui Jeong Jang[SUP] 4 [/SUP], Ho-Young Lee[SUP] 4 [/SUP], Jun Won Park[SUP] 5 [/SUP], Yea Bin Cho[SUP] 1 [/SUP], Ji Hyun Lee[SUP] 2 [/SUP], Ha Gyeong Shin[SUP] 2 [/SUP], Ha Rim Yang[SUP] 2 [/SUP], Hye Lim Choi[SUP] 2 [/SUP], Hyun Bo Shim[SUP] 6 [/SUP], Sukmook Lee[SUP] 1 2 3 [/SUP]
Affiliations
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)[SUB]2[/SUB] 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.
Keywords: SARS-CoV-2; bispecific antibody; fusion peptide; phage display; receptor-binding domain.
. 2023 Sep 26:14:1271508.
doi: 10.3389/fimmu.2023.1271508. eCollection 2023. A novel bispecific antibody dual-targeting approach for enhanced neutralization against fast-evolving SARS-CoV-2 variants
Ji Woong Kim[SUP] 1 [/SUP], Hyun Jung Kim[SUP] 2 [/SUP], Kyun Heo[SUP] 1 2 3 [/SUP], Yoonwoo Lee[SUP] 4 [/SUP], Hui Jeong Jang[SUP] 4 [/SUP], Ho-Young Lee[SUP] 4 [/SUP], Jun Won Park[SUP] 5 [/SUP], Yea Bin Cho[SUP] 1 [/SUP], Ji Hyun Lee[SUP] 2 [/SUP], Ha Gyeong Shin[SUP] 2 [/SUP], Ha Rim Yang[SUP] 2 [/SUP], Hye Lim Choi[SUP] 2 [/SUP], Hyun Bo Shim[SUP] 6 [/SUP], Sukmook Lee[SUP] 1 2 3 [/SUP]
Affiliations
- PMID: 37822941
- PMCID: PMC10562541
- DOI: 10.3389/fimmu.2023.1271508
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)[SUB]2[/SUB] 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.
Keywords: SARS-CoV-2; bispecific antibody; fusion peptide; phage display; receptor-binding domain.