Pan-ebolavirus protective therapy by two multifunctional human antibodies.
Amino Acid Sequence
Animals
Antibodies, Monoclonal
/ immunology
Antibodies, Neutralizing
/ immunology
Antibodies, Viral
/ immunology
Binding Sites
Cell Line
Cryoelectron Microscopy
Ebolavirus
/ immunology
Epitopes
/ immunology
Female
Glycoproteins
/ chemistry
Hemorrhagic Fever, Ebola
/ immunology
Humans
Hydrogen-Ion Concentration
Mice, Inbred BALB C
Models, Molecular
Primates
Receptors, Fc
/ metabolism
Recombinant Proteins
/ immunology
Viremia
/ immunology
Ebolavirus
antibody therapeutics
ebolavirus infection
epitope mapping
glycoprotein
neutralizing antibodies
viral antibodies
Journal
Cell
ISSN: 1097-4172
Titre abrégé: Cell
Pays: United States
ID NLM: 0413066
Informations de publication
Date de publication:
28 10 2021
28 10 2021
Historique:
received:
06
04
2021
revised:
27
07
2021
accepted:
27
09
2021
entrez:
29
10
2021
pubmed:
30
10
2021
medline:
7
1
2022
Statut:
ppublish
Résumé
Ebolaviruses cause a severe and often fatal illness with the potential for global spread. Monoclonal antibody-based treatments that have become available recently have a narrow therapeutic spectrum and are ineffective against ebolaviruses other than Ebola virus (EBOV), including medically important Bundibugyo (BDBV) and Sudan (SUDV) viruses. Here, we report the development of a therapeutic cocktail comprising two broadly neutralizing human antibodies, rEBOV-515 and rEBOV-442, that recognize non-overlapping sites on the ebolavirus glycoprotein (GP). Antibodies in the cocktail exhibited synergistic neutralizing activity, resisted viral escape, and possessed differing requirements for their Fc-regions for optimal in vivo activities. The cocktail protected non-human primates from ebolavirus disease caused by EBOV, BDBV, or SUDV with high therapeutic effectiveness. High-resolution structures of the cocktail antibodies in complex with GP revealed the molecular determinants for neutralization breadth and potency. This study provides advanced preclinical data to support clinical development of this cocktail for pan-ebolavirus therapy.
Identifiants
pubmed: 34715022
pii: S0092-8674(21)01165-X
doi: 10.1016/j.cell.2021.09.035
pmc: PMC8716180
mid: NIHMS1745395
pii:
doi:
Substances chimiques
Antibodies, Monoclonal
0
Antibodies, Neutralizing
0
Antibodies, Viral
0
Epitopes
0
Glycoproteins
0
Receptors, Fc
0
Recombinant Proteins
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
5593-5607.e18Subventions
Organisme : NIAID NIH HHS
ID : U19 AI109711
Pays : United States
Organisme : NIAID NIH HHS
ID : UC7 AI094660
Pays : United States
Organisme : NIAID NIH HHS
ID : U19 AI109762
Pays : United States
Organisme : NIAID NIH HHS
ID : HHSN272201400058C
Pays : United States
Organisme : NCATS NIH HHS
ID : UL1 TR002243
Pays : United States
Organisme : NIAID NIH HHS
ID : U19 AI142785
Pays : United States
Informations de copyright
Copyright © 2021 Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests J.E.C. has served as a consultant for Eli Lilly, GlaxoSmithKline and Luna Biologics, is a member of the Scientific Advisory Boards of CompuVax and Meissa Vaccines, and is Founder of IDBiologics. The Crowe laboratory at Vanderbilt University Medical Center has received unrelated sponsored research agreements from Takeda Vaccines, IDBiologics, and AstraZeneca. Vanderbilt University has applied for patents concerning ebolavirus antibodies that are related to this work. All other authors declare no competing interests.
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