PMID- 35476528
OWN - NLM
STAT- MEDLINE
DCOM- 20220429
LR  - 20240214
IS  - 1091-6490 (Electronic)
IS  - 0027-8424 (Print)
IS  - 0027-8424 (Linking)
VI  - 119
IP  - 18
DP  - 2022 May 3
TI  - Dromedary camel nanobodies broadly neutralize SARS-CoV-2 variants.
PG  - e2201433119
LID - 10.1073/pnas.2201433119 [doi]
LID - e2201433119
AB  - 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.
FAU - Hong, Jessica
AU  - Hong J
AD  - Laboratory of Molecular Biology, Center for Cancer Research, National Cancer 
      Institute, NIH, Bethesda, MD 20891.
FAU - Kwon, Hyung Joon
AU  - Kwon HJ
AUID- ORCID: 0000-0001-7846-8779
AD  - 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.
FAU - Cachau, Raul
AU  - Cachau R
AD  - Data Science and Information Technology Program, Leidos Biomedical Research, 
      Inc., Frederick, MD 21702.
FAU - Chen, Catherine Z
AU  - Chen CZ
AUID- ORCID: 0000-0002-6900-6553
AD  - National Center for Advancing Translational Sciences, NIH, Rockville, MD 20850.
FAU - Butay, Kevin John
AU  - Butay KJ
AD  - Molecular Microscopy Group, National Institute of Environmental Health Sciences, 
      Research Triangle Park, NC 27709.
FAU - Duan, Zhijian
AU  - Duan Z
AD  - Antibody Engineering Program, Center for Cancer Research, National Cancer 
      Institute, NIH, Bethesda, MD 20891.
FAU - Li, Dan
AU  - Li D
AD  - Laboratory of Molecular Biology, Center for Cancer Research, National Cancer 
      Institute, NIH, Bethesda, MD 20891.
FAU - Ren, Hua
AU  - Ren H
AD  - Laboratory of Molecular Biology, Center for Cancer Research, National Cancer 
      Institute, NIH, Bethesda, MD 20891.
FAU - Liang, Tianyuzhou
AU  - Liang T
AD  - Laboratory of Molecular Biology, Center for Cancer Research, National Cancer 
      Institute, NIH, Bethesda, MD 20891.
FAU - Zhu, Jianghai
AU  - Zhu J
AD  - Data Science and Information Technology Program, Leidos Biomedical Research, 
      Inc., Frederick, MD 21702.
FAU - Dandey, Venkata P
AU  - Dandey VP
AD  - Molecular Microscopy Group, National Institute of Environmental Health Sciences, 
      Research Triangle Park, NC 27709.
FAU - Martin, Negin P
AU  - Martin NP
AUID- ORCID: 0000-0003-3166-8989
AD  - Viral Vector Core, National Institute of Environmental Health Sciences, Research 
      Triangle Park, NC 27709.
FAU - Esposito, Dominic
AU  - Esposito D
AUID- ORCID: 0000-0002-9987-1687
AD  - Protein Expression Laboratory, NCI RAS Initiative, Frederick National Laboratory 
      for Cancer Research, Frederick, MD 21702.
FAU - Ortega-Rodriguez, Uriel
AU  - Ortega-Rodriguez U
AD  - 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.
FAU - Xu, Miao
AU  - Xu M
AD  - National Center for Advancing Translational Sciences, NIH, Rockville, MD 20850.
FAU - Borgnia, Mario J
AU  - Borgnia MJ
AUID- ORCID: 0000-0001-9159-1413
AD  - Molecular Microscopy Group, National Institute of Environmental Health Sciences, 
      Research Triangle Park, NC 27709.
FAU - Xie, Hang
AU  - Xie H
AUID- ORCID: 0000-0001-8318-5554
AD  - 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.
FAU - Ho, Mitchell
AU  - Ho M
AUID- ORCID: 0000-0002-9152-5405
AD  - Laboratory of Molecular Biology, Center for Cancer Research, National Cancer 
      Institute, NIH, Bethesda, MD 20891.
AD  - Antibody Engineering Program, Center for Cancer Research, National Cancer 
      Institute, NIH, Bethesda, MD 20891.
LA  - eng
GR  - ZIA ES103341/ImNIH/Intramural NIH HHS/United States
GR  - 75N91019D00024/CA/NCI NIH HHS/United States
GR  - ZIA BC011943/ImNIH/Intramural NIH HHS/United States
GR  - ZIC BC011891/ImNIH/Intramural NIH HHS/United States
GR  - ZIA BC010891/ImNIH/Intramural NIH HHS/United States
GR  - Z01 BC010891/ImNIH/Intramural NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, N.I.H., Intramural
DEP - 20220427
PL  - United States
TA  - Proc Natl Acad Sci U S A
JT  - Proceedings of the National Academy of Sciences of the United States of America
JID - 7505876
RN  - 0 (Single-Domain Antibodies)
RN  - SARS-CoV-2 variants
SB  - IM
UOF - bioRxiv. 2021 Oct 29;:. PMID: 34751270
MH  - Animals
MH  - *COVID-19
MH  - Camelus
MH  - Humans
MH  - Mice
MH  - SARS-CoV-2/genetics
MH  - *Single-Domain Antibodies/genetics
PMC - PMC9170159
OTO - NOTNLM
OT  - SARS-CoV-2
OT  - cryo-EM
OT  - dromedary camel nanobody VHH
OT  - neutralizing antibody
OT  - single-domain antibody
COIS- Competing interest statement: M.H. and J.H. are inventors on provisional patent 
      application no. US 63/105,769 assigned to the NIH, "Single domain antibodies 
      targeting SARS coronavirus spike protein and uses thereof."
EDAT- 2022/04/28 06:00
MHDA- 2022/04/30 06:00
PMCR- 2022/04/27
CRDT- 2022/04/27 17:04
PHST- 2022/04/27 17:04 [entrez]
PHST- 2022/04/28 06:00 [pubmed]
PHST- 2022/04/30 06:00 [medline]
PHST- 2022/04/27 00:00 [pmc-release]
AID - 202201433 [pii]
AID - 10.1073/pnas.2201433119 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 2022 May 3;119(18):e2201433119. doi: 
      10.1073/pnas.2201433119. Epub 2022 Apr 27.