Anti-Ebola virus mAb 3A6 protects highly viremic animals from fatal outcome via binding GP(1,2) in a position elevated from the virion membrane
Abstract Monoclonal antibodies (mAbs) against Ebola virus (EBOV) glycoprotein (GP1,2) are the standard of care for Ebola virus disease (EVD). Anti-GP1,2 mAbs targeting the stalk and membrane proximal external region (MPER) potently neutralize EBOV in vitro and are protective in a mouse model of EVD....
Saved in:
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2025-02-01
|
| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-56452-2 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1823861804224217088 |
|---|---|
| author | Kathryn M. Hastie Zhe Li Salie Zunlong Ke Peter J. Halfmann Lisa Evans DeWald Sara McArdle Ariadna Grinyó Edgar Davidson Sharon L. Schendel Chitra Hariharan Michael J. Norris Xiaoying Yu Chakravarthy Chennareddy Xiaoli Xiong Megan Heinrich Michael R. Holbrook Benjamin Doranz Ian Crozier Yoshihiro Kawaoka Luis M. Branco Jens H. Kuhn John A. G. Briggs Gabriella Worwa Carl W. Davis Rafi Ahmed Erica Ollmann Saphire |
| author_facet | Kathryn M. Hastie Zhe Li Salie Zunlong Ke Peter J. Halfmann Lisa Evans DeWald Sara McArdle Ariadna Grinyó Edgar Davidson Sharon L. Schendel Chitra Hariharan Michael J. Norris Xiaoying Yu Chakravarthy Chennareddy Xiaoli Xiong Megan Heinrich Michael R. Holbrook Benjamin Doranz Ian Crozier Yoshihiro Kawaoka Luis M. Branco Jens H. Kuhn John A. G. Briggs Gabriella Worwa Carl W. Davis Rafi Ahmed Erica Ollmann Saphire |
| author_sort | Kathryn M. Hastie |
| collection | DOAJ |
| description | Abstract Monoclonal antibodies (mAbs) against Ebola virus (EBOV) glycoprotein (GP1,2) are the standard of care for Ebola virus disease (EVD). Anti-GP1,2 mAbs targeting the stalk and membrane proximal external region (MPER) potently neutralize EBOV in vitro and are protective in a mouse model of EVD. However, their neutralization mechanism is poorly understood because they target a GP1,2 epitope that has evaded structural characterization. Using X-ray crystallography and cryo-electron tomography of mAb 3A6 complexed with its stalk–MPER epitope, we reveal a previously undescribed mechanism in which 3A6 binds to a conformation of GP1,2 that is lifted from the virion membrane. We further show that in both domestic guinea pig and rhesus monkey EVD models, 3A6 provides therapeutic benefit at high-viremia advanced disease stages and at the lowest dose yet demonstrated for any anti-EBOV mAb-based monotherapy. The findings reported here can guide design of next-generation highly potent anti-EBOV therapeutics and vaccines. |
| format | Article |
| id | doaj-art-58205650c67d45e4be0b6469c386bdcf |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-58205650c67d45e4be0b6469c386bdcf2025-02-09T12:44:16ZengNature PortfolioNature Communications2041-17232025-02-0116111210.1038/s41467-025-56452-2Anti-Ebola virus mAb 3A6 protects highly viremic animals from fatal outcome via binding GP(1,2) in a position elevated from the virion membraneKathryn M. Hastie0Zhe Li Salie1Zunlong Ke2Peter J. Halfmann3Lisa Evans DeWald4Sara McArdle5Ariadna Grinyó6Edgar Davidson7Sharon L. Schendel8Chitra Hariharan9Michael J. Norris10Xiaoying Yu11Chakravarthy Chennareddy12Xiaoli Xiong13Megan Heinrich14Michael R. Holbrook15Benjamin Doranz16Ian Crozier17Yoshihiro Kawaoka18Luis M. Branco19Jens H. Kuhn20John A. G. Briggs21Gabriella Worwa22Carl W. Davis23Rafi Ahmed24Erica Ollmann Saphire25Center for Vaccine Innovation, La Jolla Institute for ImmunologyCenter for Vaccine Innovation, La Jolla Institute for ImmunologyDivision of Structural Studies, Medical Research Council Laboratory of Molecular BiologyInfluenza Research Institute, Department of Pathobiological Sciences, School of Veterinary Medicine, University of WisconsinIntegrated Research Facility at Fort Detrick, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Fort DetrickMicroscopy Core, La Jolla Institute for Immunology, La JollaIntegral MolecularIntegral MolecularCenter for Vaccine Innovation, La Jolla Institute for ImmunologyCenter for Vaccine Innovation, La Jolla Institute for ImmunologyCenter for Vaccine Innovation, La Jolla Institute for ImmunologyCenter for Vaccine Innovation, La Jolla Institute for ImmunologyDepartment of Microbiology and Immunology, Emory Vaccine CenterDivision of Structural Studies, Medical Research Council Laboratory of Molecular BiologyZalgen Labs LLCIntegrated Research Facility at Fort Detrick, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Fort DetrickIntegral MolecularClinical Monitoring Research Program Directorate, Frederick National Laboratory for Cancer ResearchInfluenza Research Institute, Department of Pathobiological Sciences, School of Veterinary Medicine, University of WisconsinZalgen Labs LLCIntegrated Research Facility at Fort Detrick, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Fort DetrickDivision of Structural Studies, Medical Research Council Laboratory of Molecular BiologyIntegrated Research Facility at Fort Detrick, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Fort DetrickDepartment of Microbiology and Immunology, Emory Vaccine CenterDepartment of Microbiology and Immunology, Emory Vaccine CenterCenter for Vaccine Innovation, La Jolla Institute for ImmunologyAbstract Monoclonal antibodies (mAbs) against Ebola virus (EBOV) glycoprotein (GP1,2) are the standard of care for Ebola virus disease (EVD). Anti-GP1,2 mAbs targeting the stalk and membrane proximal external region (MPER) potently neutralize EBOV in vitro and are protective in a mouse model of EVD. However, their neutralization mechanism is poorly understood because they target a GP1,2 epitope that has evaded structural characterization. Using X-ray crystallography and cryo-electron tomography of mAb 3A6 complexed with its stalk–MPER epitope, we reveal a previously undescribed mechanism in which 3A6 binds to a conformation of GP1,2 that is lifted from the virion membrane. We further show that in both domestic guinea pig and rhesus monkey EVD models, 3A6 provides therapeutic benefit at high-viremia advanced disease stages and at the lowest dose yet demonstrated for any anti-EBOV mAb-based monotherapy. The findings reported here can guide design of next-generation highly potent anti-EBOV therapeutics and vaccines.https://doi.org/10.1038/s41467-025-56452-2 |
| spellingShingle | Kathryn M. Hastie Zhe Li Salie Zunlong Ke Peter J. Halfmann Lisa Evans DeWald Sara McArdle Ariadna Grinyó Edgar Davidson Sharon L. Schendel Chitra Hariharan Michael J. Norris Xiaoying Yu Chakravarthy Chennareddy Xiaoli Xiong Megan Heinrich Michael R. Holbrook Benjamin Doranz Ian Crozier Yoshihiro Kawaoka Luis M. Branco Jens H. Kuhn John A. G. Briggs Gabriella Worwa Carl W. Davis Rafi Ahmed Erica Ollmann Saphire Anti-Ebola virus mAb 3A6 protects highly viremic animals from fatal outcome via binding GP(1,2) in a position elevated from the virion membrane Nature Communications |
| title | Anti-Ebola virus mAb 3A6 protects highly viremic animals from fatal outcome via binding GP(1,2) in a position elevated from the virion membrane |
| title_full | Anti-Ebola virus mAb 3A6 protects highly viremic animals from fatal outcome via binding GP(1,2) in a position elevated from the virion membrane |
| title_fullStr | Anti-Ebola virus mAb 3A6 protects highly viremic animals from fatal outcome via binding GP(1,2) in a position elevated from the virion membrane |
| title_full_unstemmed | Anti-Ebola virus mAb 3A6 protects highly viremic animals from fatal outcome via binding GP(1,2) in a position elevated from the virion membrane |
| title_short | Anti-Ebola virus mAb 3A6 protects highly viremic animals from fatal outcome via binding GP(1,2) in a position elevated from the virion membrane |
| title_sort | anti ebola virus mab 3a6 protects highly viremic animals from fatal outcome via binding gp 1 2 in a position elevated from the virion membrane |
| url | https://doi.org/10.1038/s41467-025-56452-2 |
| work_keys_str_mv | AT kathrynmhastie antiebolavirusmab3a6protectshighlyviremicanimalsfromfataloutcomeviabindinggp12inapositionelevatedfromthevirionmembrane AT zhelisalie antiebolavirusmab3a6protectshighlyviremicanimalsfromfataloutcomeviabindinggp12inapositionelevatedfromthevirionmembrane AT zunlongke antiebolavirusmab3a6protectshighlyviremicanimalsfromfataloutcomeviabindinggp12inapositionelevatedfromthevirionmembrane AT peterjhalfmann antiebolavirusmab3a6protectshighlyviremicanimalsfromfataloutcomeviabindinggp12inapositionelevatedfromthevirionmembrane AT lisaevansdewald antiebolavirusmab3a6protectshighlyviremicanimalsfromfataloutcomeviabindinggp12inapositionelevatedfromthevirionmembrane AT saramcardle antiebolavirusmab3a6protectshighlyviremicanimalsfromfataloutcomeviabindinggp12inapositionelevatedfromthevirionmembrane AT ariadnagrinyo antiebolavirusmab3a6protectshighlyviremicanimalsfromfataloutcomeviabindinggp12inapositionelevatedfromthevirionmembrane AT edgardavidson antiebolavirusmab3a6protectshighlyviremicanimalsfromfataloutcomeviabindinggp12inapositionelevatedfromthevirionmembrane AT sharonlschendel antiebolavirusmab3a6protectshighlyviremicanimalsfromfataloutcomeviabindinggp12inapositionelevatedfromthevirionmembrane AT chitrahariharan antiebolavirusmab3a6protectshighlyviremicanimalsfromfataloutcomeviabindinggp12inapositionelevatedfromthevirionmembrane AT michaeljnorris antiebolavirusmab3a6protectshighlyviremicanimalsfromfataloutcomeviabindinggp12inapositionelevatedfromthevirionmembrane AT xiaoyingyu antiebolavirusmab3a6protectshighlyviremicanimalsfromfataloutcomeviabindinggp12inapositionelevatedfromthevirionmembrane AT chakravarthychennareddy antiebolavirusmab3a6protectshighlyviremicanimalsfromfataloutcomeviabindinggp12inapositionelevatedfromthevirionmembrane AT xiaolixiong antiebolavirusmab3a6protectshighlyviremicanimalsfromfataloutcomeviabindinggp12inapositionelevatedfromthevirionmembrane AT meganheinrich antiebolavirusmab3a6protectshighlyviremicanimalsfromfataloutcomeviabindinggp12inapositionelevatedfromthevirionmembrane AT michaelrholbrook antiebolavirusmab3a6protectshighlyviremicanimalsfromfataloutcomeviabindinggp12inapositionelevatedfromthevirionmembrane AT benjamindoranz antiebolavirusmab3a6protectshighlyviremicanimalsfromfataloutcomeviabindinggp12inapositionelevatedfromthevirionmembrane AT iancrozier antiebolavirusmab3a6protectshighlyviremicanimalsfromfataloutcomeviabindinggp12inapositionelevatedfromthevirionmembrane AT yoshihirokawaoka antiebolavirusmab3a6protectshighlyviremicanimalsfromfataloutcomeviabindinggp12inapositionelevatedfromthevirionmembrane AT luismbranco antiebolavirusmab3a6protectshighlyviremicanimalsfromfataloutcomeviabindinggp12inapositionelevatedfromthevirionmembrane AT jenshkuhn antiebolavirusmab3a6protectshighlyviremicanimalsfromfataloutcomeviabindinggp12inapositionelevatedfromthevirionmembrane AT johnagbriggs antiebolavirusmab3a6protectshighlyviremicanimalsfromfataloutcomeviabindinggp12inapositionelevatedfromthevirionmembrane AT gabriellaworwa antiebolavirusmab3a6protectshighlyviremicanimalsfromfataloutcomeviabindinggp12inapositionelevatedfromthevirionmembrane AT carlwdavis antiebolavirusmab3a6protectshighlyviremicanimalsfromfataloutcomeviabindinggp12inapositionelevatedfromthevirionmembrane AT rafiahmed antiebolavirusmab3a6protectshighlyviremicanimalsfromfataloutcomeviabindinggp12inapositionelevatedfromthevirionmembrane AT ericaollmannsaphire antiebolavirusmab3a6protectshighlyviremicanimalsfromfataloutcomeviabindinggp12inapositionelevatedfromthevirionmembrane |