Protective neutralizing antibodies from human survivors of Crimean-Congo hemorrhagic fever.
Amino Acid Sequence
Animals
Antibodies, Monoclonal
/ immunology
Antibodies, Neutralizing
/ immunology
Antigens, Viral
/ metabolism
Biophysical Phenomena
Chlorocebus aethiops
Epitope Mapping
Epitopes
/ metabolism
Female
Hemorrhagic Fever Virus, Crimean-Congo
/ immunology
Hemorrhagic Fever, Crimean
/ immunology
Humans
Immunoglobulin G
/ metabolism
Male
Mice
Neutralization Tests
Protein Binding
Protein Engineering
Recombinant Proteins
/ immunology
Survivors
Vero Cells
Viral Proteins
/ chemistry
CCHFV
Crimean-Congo hemorrhagic fever virus
antibody therapeutic
bunyavirus
emerging virus
human monoclonal antibody
monoclonal antibody
nairovirus
tickborne
viral glycoprotein
Journal
Cell
ISSN: 1097-4172
Titre abrégé: Cell
Pays: United States
ID NLM: 0413066
Informations de publication
Date de publication:
24 06 2021
24 06 2021
Historique:
received:
25
11
2020
revised:
19
03
2021
accepted:
29
04
2021
pubmed:
3
6
2021
medline:
6
1
2022
entrez:
2
6
2021
Statut:
ppublish
Résumé
Crimean-Congo hemorrhagic fever virus (CCHFV) is a World Health Organization priority pathogen. CCHFV infections cause a highly lethal hemorrhagic fever for which specific treatments and vaccines are urgently needed. Here, we characterize the human immune response to natural CCHFV infection to identify potent neutralizing monoclonal antibodies (nAbs) targeting the viral glycoprotein. Competition experiments showed that these nAbs bind six distinct antigenic sites in the Gc subunit. These sites were further delineated through mutagenesis and mapped onto a prefusion model of Gc. Pairwise screening identified combinations of non-competing nAbs that afford synergistic neutralization. Further enhancements in neutralization breadth and potency were attained by physically linking variable domains of synergistic nAb pairs through bispecific antibody (bsAb) engineering. Although multiple nAbs protected mice from lethal CCHFV challenge in pre- or post-exposure prophylactic settings, only a single bsAb, DVD-121-801, afforded therapeutic protection. DVD-121-801 is a promising candidate suitable for clinical development as a CCHFV therapeutic.
Identifiants
pubmed: 34077751
pii: S0092-8674(21)00584-5
doi: 10.1016/j.cell.2021.05.001
pmc: PMC8559771
mid: NIHMS1702235
pii:
doi:
Substances chimiques
Antibodies, Monoclonal
0
Antibodies, Neutralizing
0
Antigens, Viral
0
Epitopes
0
Immunoglobulin G
0
Recombinant Proteins
0
Viral Proteins
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3486-3501.e21Subventions
Organisme : NIAID NIH HHS
ID : R01 AI132246
Pays : United States
Organisme : NIAID NIH HHS
ID : T32 AI070117
Pays : United States
Organisme : NIAID NIH HHS
ID : U19 AI142777
Pays : United States
Informations de copyright
Copyright © 2021 Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests K.C. is a scientific advisory board member of Integrum Scientific and Biovaxys Technology Corporation. K.C., J.S.M., and J.R.L. are scientific advisory board members of the Pandemic Security Initiative of Celdara Medical. N.T.P. and L.M.W. are employees and shareholders of Adimab. D.P.M. is a shareholder of Adimab. Z.A.B., D.M.A., C.L.M., and L.Z. are shareholders and employees of Mapp Biopharmaceutical. Mapp Biopharmaceutical has filed a patent application related to this work.
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