The evolution and determinants of neutralization of potent head-binding antibodies against Ebola virus

Monoclonal antibodies against the Ebola virus (EBOV) surface glycoprotein are effective treatments for EBOV disease. Antibodies targeting the EBOV glycoprotein (GP) head epitope have potent neutralization and Fc effector function activity and thus are of high interest as therapeutics and for vaccine...

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Published in:Cell reports (Cambridge) 2023-11, Vol.42 (11), p.113366-113366, Article 113366
Main Authors: Yu, Xiaoying, Hastie, Kathryn M., Davis, Carl W., Avalos, Ruben Diaz, Williams, Dewight, Parekh, Diptiben, Hui, Sean, Mann, Colin, Hariharan, Chitra, Takada, Ayato, Ahmed, Rafi, Saphire, Erica Ollmann
Format: Article
Language:English
Subjects:
Antibodies, Neutralizing
Antibodies, Viral
antibody evolution
antibody therapeutic
CP: Immunology
Cryoelectron Microscopy
Ebola virus glycoprotein
Ebolavirus
head epitope
Hemorrhagic Fever, Ebola
Humans
Longitudinal Studies
monoclonal antibody
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Summary:Monoclonal antibodies against the Ebola virus (EBOV) surface glycoprotein are effective treatments for EBOV disease. Antibodies targeting the EBOV glycoprotein (GP) head epitope have potent neutralization and Fc effector function activity and thus are of high interest as therapeutics and for vaccine design. Here we focus on the head-binding antibodies 1A2 and 1D5, which have been identified previously in a longitudinal study of survivors of EBOV infection. 1A2 and 1D5 have the same heavy- and light-chain germlines despite being isolated from different individuals and at different time points after recovery from infection. Cryoelectron microscopy analysis of each antibody in complex with the EBOV surface GP reveals key amino acid substitutions in 1A2 that contribute to greater affinity, improved neutralization potency, and enhanced breadth as well as two strategies for antibody evolution from a common site. [Display omitted] •Structures of two EBOV survivor antibodies reveal disparate paths of maturation•Each antibody shows an unusually strong paratope contribution by CDRL3•Germline-encoded and invariably mutated residues prevent pan-ebolavirus neutralization Yu et al. present the structures of two survivor-derived antibodies with a common heavy and light chain, each in complex with Ebola virus GP. Biochemical and structural analyses reveal germline restriction of pan-ebolavirus reactivity and suggest that these two antibodies may have divergent paths of evolution.
ISSN:2211-1247
2211-1247
DOI:10.1016/j.celrep.2023.113366