Molecular mechanism and structure-guided humanization of a broadly neutralizing antibody against SFTSV
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Le résumé fourni par la source
Severe fever with thrombocytopenia syndrome virus (SFTSV) is a novel tick-borne bunyavirus that causes severe fever with thrombocytopenia syndrome (SFTS), with a high mortality rate of up to 30%. The envelope glycoproteins of SFTSV, glycoprotein N (Gn) and glycoprotein C (Gc), facilitate the recognition of host receptors and the process of membrane fusion, allowing the virus to enter host cells. We previously reported a monoclonal antibody, mAb 40C10, capable of neutralizing different genotypes of SFTSV and SFTSV-related viruses. However, the specific neutralization mechanism is poorly understood. In this study, we elucidated the high-resolution structure of the SFTSV Gn head domain in complex with mAb 40C10, confirming that the binding epitope in the domain I region of SFTSV Gn, and it represented that a novel binding epitope of SFTSV Gn was identified. Through in-depth structural and sequence analyses, we found that the binding sites of mAb 40C10 are relatively conserved among different genotypes of SFTSV and SFTSV-related Heartland virus and Guertu virus, elucidating the molecular mechanism underlying the broad-spectrum neutralizing activity of mAb 40C10. Furthermore, we humanized of mAb 40C10, which is originally of murine origin, to reduce its immunogenicity. The resulting nine humanized antibodies maintained potent affinity and neutralizing activity. One of the humanized antibodies exhibited neutralizing activity at picomolar IC50 values and demonstrated effective therapeutic and protective effects in a mouse infection model. These findings provide a novel target for the future development of SFTSV vaccines or drugs and establish a foundation for the research and development of antibody therapeutics for clinical applications.
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Le contrôle bibliographique ouvert
DOI retrouvé dans Crossref DOI retrouvé ; titre concordant.
- Titre Crossref
- Molecular mechanism and structure-guided humanization of a broadly neutralizing antibody against SFTSV
- Date Crossref
- 25/09/2024
- Éditeur
- Public Library of Science (PLoS)
- Type
- journal-article
Ce recoupement confirme des métadonnées liées au DOI. Il ne confirme ni la méthode ni les conclusions de l’étude, et il ne compte pas comme une seconde source scientifique indépendante.
Où se fait cette recherche
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Nankai University pays non établi dans la noticeUniversité ou école supérieure
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Chinese Academy of Sciences pays non établi dans la noticeOrganisme public
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Wuhan Institute of Virology pays non établi dans la noticeStructure de recherche
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Zhejiang Zanyu Technology (China) pays non établi dans la noticeEntreprise
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State Key Laboratory of Medicinal Chemical Biology and College of Life Sciences pays non établi dans la noticeUniversité ou école supérieure
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Key Laboratory of Virology and Biosafety and National Virus Resource Center pays non établi dans la noticeStructure de recherche
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Guangzhou National Laboratory pays non établi dans la noticeStructure de recherche
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Ltd. Hangzhou Medimscience Biomedical Technology Co. pays non établi dans la noticeEntreprise
Nankai University, Chinese Academy of Sciences et Wuhan Institute of Virology, avec 5 autres affiliations.
Une affiliation ne permet pas de déduire la nationalité d’un auteur.