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Biparatopic nanobodies targeting the receptor binding domain efficiently neutralize SARS-CoV-2.
Pymm, Phillip; Redmond, Samuel J; Dolezal, Olan; Mordant, Francesca; Lopez, Ester; Cooney, James P; Davidson, Kathryn C; Haycroft, Ebene R; Tan, Chee Wah; Seneviratna, Rebecca; Grimley, Samantha L; Purcell, Damian F J; Kent, Stephen J; Wheatley, Adam K; Wang, Lin-Fa; Leis, Andrew; Glukhova, Alisa; Pellegrini, Marc; Chung, Amy W; Subbarao, Kanta; Uldrich, Adam P; Tham, Wai-Hong; Godfrey, Dale I; Gherardin, Nicholas A.
  • Pymm P; The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia.
  • Redmond SJ; Department of Medical Biology, University of Melbourne, Melbourne, VIC 3010, Australia.
  • Dolezal O; Department of Microbiology & Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, VIC 3000, Australia.
  • Mordant F; Commonwealth Scientific and Industrial Research Organisation (CSIRO) Biomedical Program, Clayton, VIC 3168, Australia.
  • Lopez E; Department of Microbiology & Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, VIC 3000, Australia.
  • Cooney JP; Department of Microbiology & Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, VIC 3000, Australia.
  • Davidson KC; The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia.
  • Haycroft ER; Department of Medical Biology, University of Melbourne, Melbourne, VIC 3010, Australia.
  • Tan CW; The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia.
  • Seneviratna R; Department of Medical Biology, University of Melbourne, Melbourne, VIC 3010, Australia.
  • Grimley SL; Department of Microbiology & Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, VIC 3000, Australia.
  • Purcell DFJ; Programme in Emerging Infectious Diseases, Duke NUS Medical School, Singapore 169857, Singapore.
  • Kent SJ; Department of Microbiology & Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, VIC 3000, Australia.
  • Wheatley AK; Department of Microbiology & Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, VIC 3000, Australia.
  • Wang LF; Department of Microbiology & Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, VIC 3000, Australia.
  • Leis A; Department of Microbiology & Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, VIC 3000, Australia.
  • Glukhova A; Australian Research Council Centre for Excellence in Convergent Bio-Nano Science and Technology, University of Melbourne, Melbourne VIC 3010, Australia.
  • Pellegrini M; Department of Microbiology & Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, VIC 3000, Australia.
  • Chung AW; Programme in Emerging Infectious Diseases, Duke NUS Medical School, Singapore 169857, Singapore.
  • Subbarao K; Programme in Emerging Infectious Diseases, Duke NUS Medical School, Singapore 169857, Singapore.
  • Uldrich AP; The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia.
  • Tham WH; The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia.
  • Godfrey DI; Department of Medical Biology, University of Melbourne, Melbourne, VIC 3010, Australia.
  • Gherardin NA; Drug Discovery Biology, Monash Faculty of Pharmacy and Pharmaceutical Sciences, Monash University, Parkville 3052 VIC, Australia.
iScience ; 25(11): 105259, 2022 Nov 18.
Article in English | MEDLINE | ID: covidwho-2122546
ABSTRACT
The development of therapeutics to prevent or treat COVID-19 remains an area of intense focus. Protein biologics, including monoclonal antibodies and nanobodies that neutralize virus, have potential for the treatment of active disease. Here, we have used yeast display of a synthetic nanobody library to isolate nanobodies that bind the receptor-binding domain (RBD) of SARS-CoV-2 and neutralize the virus. We show that combining two clones with distinct binding epitopes within the RBD into a single protein construct to generate biparatopic reagents dramatically enhances their neutralizing capacity. Furthermore, the biparatopic nanobodies exhibit enhanced control over clinically relevant RBD variants that escaped recognition by the individual nanobodies. Structural analysis of biparatopic binding to spike (S) protein revealed a unique binding mode whereby the two nanobody paratopes bridge RBDs encoded by distinct S trimers. Accordingly, biparatopic nanobodies offer a way to rapidly generate powerful viral neutralizers with enhanced ability to control viral escape mutants.
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Full text: Available Collection: International databases Database: MEDLINE Type of study: Prognostic study Topics: Variants Language: English Journal: IScience Year: 2022 Document Type: Article Affiliation country: J.isci.2022.105259

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Full text: Available Collection: International databases Database: MEDLINE Type of study: Prognostic study Topics: Variants Language: English Journal: IScience Year: 2022 Document Type: Article Affiliation country: J.isci.2022.105259