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A therapeutic neutralizing antibody targeting receptor binding domain of SARS-CoV-2 spike protein.

ABSTRACT: Vaccines and therapeutics are urgently needed for the pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Here, we screen human monoclonal antibodies (mAb) targeting the receptor binding domain (RBD) of the viral spike protein via antibody library constructed from peripheral blood mononuclear cells of a convalescent patient. The CT-P59 mAb potently neutralizes SARS-CoV-2 isolates including the D614G variant without antibody-dependent enhancement effect. Complex crystal structure of CT-P59 Fab/RBD shows that CT-P59 blocks interaction regions of RBD for angiotensin converting enzyme 2 (ACE2) receptor with an orientation that is notably different from previously reported RBD-targeting mAbs. Furthermore, therapeutic effects of CT-P59 are evaluated in three animal models (ferret, hamster, and rhesus monkey), demonstrating a substantial reduction in viral titer along with alleviation of clinical symptoms. Therefore, CT-P59 may be a promising therapeutic candidate for COVID-19.

SUBMITTER: Kim C

PROVIDER: S-EPMC7803729 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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A therapeutic neutralizing antibody targeting receptor binding domain of SARS-CoV-2 spike protein.

Kim Cheolmin C Ryu Dong-Kyun DK Lee Jihun J Kim Young-Il YI Seo Ji-Min JM Kim Yeon-Gil YG Jeong Jae-Hee JH Kim Minsoo M Kim Jong-In JI Kim Pankyeom P Bae Jin Soo JS Shim Eun Yeong EY Lee Min Seob MS Kim Man Su MS Noh Hanmi H Park Geun-Soo GS Park Jae Sang JS Son Dain D An Yongjin Y Lee Jeong No JN Kwon Ki-Sung KS Lee Joo-Yeon JY Lee Hansaem H Yang Jeong-Sun JS Kim Kyung-Chang KC Kim Sung Soon SS Woo Hye-Min HM Kim Jun-Won JW Park Man-Seong MS Yu Kwang-Min KM Kim Se-Mi SM Kim Eun-Ha EH Park Su-Jin SJ Jeong Seong Tae ST Yu Chi Ho CH Song Youngjo Y Gu Se Hun SH Oh Hanseul H Koo Bon-Sang BS Hong Jung Joo JJ Ryu Choong-Min CM Park Wan Beom WB Oh Myoung-Don MD Choi Young Ki YK Lee Soo-Young SY

Nature communications 20210112 1

Vaccines and therapeutics are urgently needed for the pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Here, we screen human monoclonal antibodies (mAb) targeting the receptor binding domain (RBD) of the viral spike protein via antibody library constructed from peripheral blood mononuclear cells of a convalescent patient. The CT-P59 mAb potently neutralizes SARS-CoV-2 isolates including the D614G variant without antibody-dependent enhancement effect. Complex cryst ...[more]

PMID: 33436577

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Project description:The emerging new lineages of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) have marked a new phase of coronavirus disease 2019 (COVID-19). Understanding the recognition mechanisms of potent neutralizing monoclonal antibodies (NAbs) against the spike protein is pivotal for developing new vaccines and antibody drugs. Here, we isolated several monoclonal antibodies (MAbs) against the SARS-CoV-2 spike protein receptor-binding domain (S-RBD) from the B cell receptor repertoires of a SARS-CoV-2 convalescent. Among these MAbs, the antibody nCoV617 demonstrates the most potent neutralizing activity against authentic SARS-CoV-2 infection, as well as prophylactic and therapeutic efficacies against the human angiotensin-converting enzyme 2 (ACE2) transgenic mouse model in vivo. The crystal structure of S-RBD in complex with nCoV617 reveals that nCoV617 mainly binds to the back of the "ridge" of RBD and shares limited binding residues with ACE2. Under the background of the S-trimer model, it potentially binds to both "up" and "down" conformations of S-RBD. In vitro mutagenesis assays show that mutant residues found in the emerging new lineage B.1.1.7 of SARS-CoV-2 do not affect nCoV617 binding to the S-RBD. These results provide a new human-sourced neutralizing antibody against the S-RBD and assist vaccine development. IMPORTANCE COVID-19 is a respiratory disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The COVID-19 pandemic has posed a serious threat to global health and the economy, so it is necessary to find safe and effective antibody drugs and treatments. The receptor-binding domain (RBD) in the SARS-CoV-2 spike protein is responsible for binding to the angiotensin-converting enzyme 2 (ACE2) receptor. It contains a variety of dominant neutralizing epitopes and is an important antigen for the development of new coronavirus antibodies. The significance of our research lies in the determination of new epitopes, the discovery of antibodies against RBD, and the evaluation of the antibodies' neutralizing effect. The identified antibodies here may be drug candidates for the development of clinical interventions for SARS-CoV-2.

Dataset Information

A therapeutic neutralizing antibody targeting receptor binding domain of SARS-CoV-2 spike protein.

Publications

A therapeutic neutralizing antibody targeting receptor binding domain of SARS-CoV-2 spike protein.

Similar Datasets

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