A novel bispecific antibody dual-targeting approach for enhanced neutralization against fast-evolving SARS-CoV-2 variants
- 주제(키워드) bispecific antibody , fusion peptide , phage display , receptor-binding domain , SARS-CoV-2
- 주제(기타) Immunology
- 설명문(일반) [Kim, Ji Woong; Heo, Kyun; Cho, Yea Bin; Lee, Sukmook] Kookmin Univ, Dept Chem, Seoul, South Korea; [Kim, Hyun Jung; Heo, Kyun; Lee, Ji Hyun; Shin, Ha Gyeong; Yang, Ha Rim; Choi, Hye Lim; Lee, Sukmook] Kookmin Univ, Dept Biopharmaceut Chem, Seoul, South Korea; [Heo, Kyun; Lee, Sukmook] Kookmin Univ, Antibody Res Inst, Seoul, South Korea; [Lee, Yoonwoo; Jang, Hui Jeong; Lee, Ho-Young] Seoul Natl Univ, Bundang Hosp, Dept Nucl Med, Seoul, South Korea; [Park, Jun Won] Kangwon Natl Univ, Dept Biohlth Convergence, Chunchon, South Korea; [Shim, Hyun Bo] Ewha Womans Univ, Dept Life Sci, Seoul, South Korea
- 등재 SCIE, SCOPUS
- OA유형 Gold Open Access; Green Published
- 발행기관 FRONTIERS MEDIA SA
- 발행년도 2023
- 총서유형 Journal
- URI http://www.dcollection.net/handler/ewha/000000213494
- 본문언어 영어
- Published As https://doi.org/10.3389/fimmu.2023.1271508
- PubMed 37822941
초록/요약
IntroductionThe 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.MethodsUsing 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.ResultsOur 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.ConclusionThese 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.
more