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Dromedary camel nanobodies broadly neutralize SARS-CoV-2 variants.
Hong, Jessica; Kwon, Hyung Joon; Cachau, Raul; Chen, Catherine Z; Butay, Kevin John; Duan, Zhijian; Li, Dan; Ren, Hua; Liang, Tianyuzhou; Zhu, Jianghai; Dandey, Venkata P; Martin, Negin P; Esposito, Dominic; Ortega-Rodriguez, Uriel; Xu, Miao; Borgnia, Mario J; Xie, Hang; Ho, Mitchell.
  • Hong J; Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20891.
  • Kwon HJ; Division of Viral Products, Office of Vaccines Research and Review, Center for Biologics Evaluation and Research, United States Food and Drug Administration, Silver Spring, MD 20993.
  • Cachau R; Data Science and Information Technology Program, Leidos Biomedical Research, Inc., Frederick, MD 21702.
  • Chen CZ; National Center for Advancing Translational Sciences, NIH, Rockville, MD 20850.
  • Butay KJ; Molecular Microscopy Group, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709.
  • Duan Z; Antibody Engineering Program, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20891.
  • Li D; Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20891.
  • Ren H; Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20891.
  • Liang T; Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20891.
  • Zhu J; Data Science and Information Technology Program, Leidos Biomedical Research, Inc., Frederick, MD 21702.
  • Dandey VP; Molecular Microscopy Group, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709.
  • Martin NP; Viral Vector Core, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709.
  • Esposito D; Protein Expression Laboratory, NCI RAS Initiative, Frederick National Laboratory for Cancer Research, Frederick, MD 21702.
  • Ortega-Rodriguez U; Division of Viral Products, Office of Vaccines Research and Review, Center for Biologics Evaluation and Research, United States Food and Drug Administration, Silver Spring, MD 20993.
  • Xu M; National Center for Advancing Translational Sciences, NIH, Rockville, MD 20850.
  • Borgnia MJ; Molecular Microscopy Group, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709.
  • Xie H; Division of Viral Products, Office of Vaccines Research and Review, Center for Biologics Evaluation and Research, United States Food and Drug Administration, Silver Spring, MD 20993.
  • Ho M; Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20891.
Proc Natl Acad Sci U S A ; 119(18): e2201433119, 2022 05 03.
Article in English | MEDLINE | ID: covidwho-1815698
ABSTRACT
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike is a trimer of S1/S2 heterodimers with three receptor-binding domains (RBDs) at the S1 subunit for human angiotensin-converting enzyme 2 (hACE2). Due to their small size, nanobodies can recognize protein cavities that are not accessible to conventional antibodies. To isolate high-affinity nanobodies, large libraries with great diversity are highly desirable. Dromedary camels (Camelus dromedarius) are natural reservoirs of coronaviruses like Middle East respiratory syndrome CoV (MERS-CoV) that are transmitted to humans. Here, we built large dromedary camel VHH phage libraries to isolate nanobodies that broadly neutralize SARS-CoV-2 variants. We isolated two VHH nanobodies, NCI-CoV-7A3 (7A3) and NCI-CoV-8A2 (8A2), which have a high affinity for the RBD via targeting nonoverlapping epitopes and show broad neutralization activity against SARS-CoV-2 and its emerging variants of concern. Cryoelectron microscopy (cryo-EM) complex structures revealed that 8A2 binds the RBD in its up mode with a long CDR3 loop directly involved in the ACE2 binding residues and that 7A3 targets a deeply buried region that uniquely extends from the S1 subunit to the apex of the S2 subunit regardless of the conformational state of the RBD. At a dose of ≥5 mg/kg, 7A3 efficiently protected transgenic mice expressing hACE2 from the lethal challenge of variants B.1.351 or B.1.617.2, suggesting its therapeutic use against COVID-19 variants. The dromedary camel VHH phage libraries could be helpful as a unique platform ready for quickly isolating potent nanobodies against future emerging viruses.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Single-Domain Antibodies / COVID-19 Topics: Variants Limits: Animals / Humans Language: English Journal: Proc Natl Acad Sci U S A Year: 2022 Document Type: Article

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Single-Domain Antibodies / COVID-19 Topics: Variants Limits: Animals / Humans Language: English Journal: Proc Natl Acad Sci U S A Year: 2022 Document Type: Article