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Nanobody cocktails potently neutralize SARS-CoV-2 D614G N501Y variant and protect mice.
Pymm, Phillip; Adair, Amy; Chan, Li-Jin; Cooney, James P; Mordant, Francesca L; Allison, Cody C; Lopez, Ester; Haycroft, Ebene R; O'Neill, Matthew T; Tan, Li Lynn; Dietrich, Melanie H; Drew, Damien; Doerflinger, Marcel; Dengler, Michael A; Scott, Nichollas E; Wheatley, Adam K; Gherardin, Nicholas A; Venugopal, Hariprasad; Cromer, Deborah; Davenport, Miles P; Pickering, Raelene; Godfrey, Dale I; Purcell, Damian F J; Kent, Stephen J; Chung, Amy W; Subbarao, Kanta; Pellegrini, Marc; Glukhova, Alisa; Tham, Wai-Hong.
  • Pymm P; Infectious Diseases and Immune Defences Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia.
  • Adair A; Department of Medical Biology, University of Melbourne, Melbourne, VIC 3010, Australia.
  • Chan LJ; Infectious Diseases and Immune Defences Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia.
  • Cooney JP; Infectious Diseases and Immune Defences Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia.
  • Mordant FL; Department of Medical Biology, University of Melbourne, Melbourne, VIC 3010, Australia.
  • Allison CC; Infectious Diseases and Immune Defences Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia.
  • Lopez E; Department of Medical Biology, University of Melbourne, Melbourne, VIC 3010, Australia.
  • Haycroft ER; Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC 3000, Australia.
  • O'Neill MT; Infectious Diseases and Immune Defences Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia.
  • Tan LL; Department of Medical Biology, University of Melbourne, Melbourne, VIC 3010, Australia.
  • Dietrich MH; Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC 3000, Australia.
  • Drew D; Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC 3000, Australia.
  • Doerflinger M; Infectious Diseases and Immune Defences Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia.
  • Dengler MA; Infectious Diseases and Immune Defences Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia.
  • Scott NE; Infectious Diseases and Immune Defences Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia.
  • Wheatley AK; Department of Medical Biology, University of Melbourne, Melbourne, VIC 3010, Australia.
  • Gherardin NA; Infectious Diseases and Immune Defences Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia.
  • Venugopal H; Infectious Diseases and Immune Defences Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia.
  • Cromer D; Department of Medical Biology, University of Melbourne, Melbourne, VIC 3010, Australia.
  • Davenport MP; Infectious Diseases and Immune Defences Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia.
  • Pickering R; Department of Medical Biology, University of Melbourne, Melbourne, VIC 3010, Australia.
  • Godfrey DI; Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC 3000, Australia.
  • Purcell DFJ; Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC 3000, Australia.
  • Kent SJ; Australian Research Council Centre for Excellence in Convergent Bio-Nano Science and Technology, University of Melbourne, Melbourne, VIC 3010, Australia.
  • Chung AW; Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC 3000, Australia.
  • Subbarao K; Australian Research Council Centre of Excellence in Advanced Molecular Imaging, University of Melbourne, Melbourne, VIC 3010, Australia.
  • Pellegrini M; Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC 3800, Australia.
  • Glukhova A; Kirby Institute, University of New South Wales, Sydney, NSW 2052, Australia.
  • Tham WH; Department of Mathematics and Statistics, University of New South Wales, Sydney, NSW 2052, Australia.
Proc Natl Acad Sci U S A ; 118(19)2021 05 11.
Article in English | MEDLINE | ID: covidwho-1203483
ABSTRACT
Neutralizing antibodies are important for immunity against SARS-CoV-2 and as therapeutics for the prevention and treatment of COVID-19. Here, we identified high-affinity nanobodies from alpacas immunized with coronavirus spike and receptor-binding domains (RBD) that disrupted RBD engagement with the human receptor angiotensin-converting enzyme 2 (ACE2) and potently neutralized SARS-CoV-2. Epitope mapping, X-ray crystallography, and cryo-electron microscopy revealed two distinct antigenic sites and showed two neutralizing nanobodies from different epitope classes bound simultaneously to the spike trimer. Nanobody-Fc fusions of the four most potent nanobodies blocked ACE2 engagement with RBD variants present in human populations and potently neutralized both wild-type SARS-CoV-2 and the N501Y D614G variant at concentrations as low as 0.1 nM. Prophylactic administration of either single nanobody-Fc or as mixtures reduced viral loads by up to 104-fold in mice infected with the N501Y D614G SARS-CoV-2 virus. These results suggest a role for nanobody-Fc fusions as prophylactic agents against SARS-CoV-2.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Antibodies, Neutralizing / Single-Domain Antibodies / SARS-CoV-2 / COVID-19 / COVID-19 Drug Treatment / Antibodies, Viral Topics: Variants Limits: Animals / Humans Language: English Year: 2021 Document Type: Article Affiliation country: Pnas.2101918118

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Antibodies, Neutralizing / Single-Domain Antibodies / SARS-CoV-2 / COVID-19 / COVID-19 Drug Treatment / Antibodies, Viral Topics: Variants Limits: Animals / Humans Language: English Year: 2021 Document Type: Article Affiliation country: Pnas.2101918118