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Development of Clinical-Stage Human Monoclonal Antibodies That Treat Advanced Ebola Virus Disease in Nonhuman Primates
BACKGROUND: For most classes of drugs, rapid development of therapeutics to treat emerging infections is challenged by the timelines needed to identify compounds with the desired efficacy, safety, and pharmacokinetic profiles. Fully human monoclonal antibodies (mAbs) provide an attractive method to...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6249601/ https://www.ncbi.nlm.nih.gov/pubmed/29860496 http://dx.doi.org/10.1093/infdis/jiy285 |
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author | Pascal, Kristen E Dudgeon, Drew Trefry, John C Anantpadma, Manu Sakurai, Yasuteru Murin, Charles D Turner, Hannah L Fairhurst, Jeanette Torres, Marcela Rafique, Ashique Yan, Ying Badithe, Ashok Yu, Kevin Potocky, Terra Bixler, Sandra L Chance, Taylor B Pratt, William D Rossi, Franco D Shamblin, Joshua D Wollen, Suzanne E Zelko, Justine M Carrion, Ricardo Worwa, Gabriella Staples, Hilary M Burakov, Darya Babb, Robert Chen, Gang Martin, Joel Huang, Tammy T Erlandson, Karl Willis, Melissa S Armstrong, Kimberly Dreier, Thomas M Ward, Andrew B Davey, Robert A Pitt, Margaret L M Lipsich, Leah Mason, Peter Olson, William Stahl, Neil Kyratsous, Christos A |
author_facet | Pascal, Kristen E Dudgeon, Drew Trefry, John C Anantpadma, Manu Sakurai, Yasuteru Murin, Charles D Turner, Hannah L Fairhurst, Jeanette Torres, Marcela Rafique, Ashique Yan, Ying Badithe, Ashok Yu, Kevin Potocky, Terra Bixler, Sandra L Chance, Taylor B Pratt, William D Rossi, Franco D Shamblin, Joshua D Wollen, Suzanne E Zelko, Justine M Carrion, Ricardo Worwa, Gabriella Staples, Hilary M Burakov, Darya Babb, Robert Chen, Gang Martin, Joel Huang, Tammy T Erlandson, Karl Willis, Melissa S Armstrong, Kimberly Dreier, Thomas M Ward, Andrew B Davey, Robert A Pitt, Margaret L M Lipsich, Leah Mason, Peter Olson, William Stahl, Neil Kyratsous, Christos A |
author_sort | Pascal, Kristen E |
collection | PubMed |
description | BACKGROUND: For most classes of drugs, rapid development of therapeutics to treat emerging infections is challenged by the timelines needed to identify compounds with the desired efficacy, safety, and pharmacokinetic profiles. Fully human monoclonal antibodies (mAbs) provide an attractive method to overcome many of these hurdles to rapidly produce therapeutics for emerging diseases. METHODS: In this study, we deployed a platform to generate, test, and develop fully human antibodies to Zaire ebolavirus. We obtained specific anti-Ebola virus (EBOV) antibodies by immunizing VelocImmune mice that use human immunoglobulin variable regions in their humoral responses. RESULTS: Of the antibody clones isolated, 3 were selected as best at neutralizing EBOV and triggering FcγRIIIa. Binding studies and negative-stain electron microscopy revealed that the 3 selected antibodies bind to non-overlapping epitopes, including a potentially new protective epitope not targeted by other antibody-based treatments. When combined, a single dose of a cocktail of the 3 antibodies protected nonhuman primates (NHPs) from EBOV disease even after disease symptoms were apparent. CONCLUSIONS: This antibody cocktail provides complementary mechanisms of actions, incorporates novel specificities, and demonstrates high-level postexposure protection from lethal EBOV disease in NHPs. It is now undergoing testing in normal healthy volunteers in preparation for potential use in future Ebola epidemics. |
format | Online Article Text |
id | pubmed-6249601 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-62496012018-11-27 Development of Clinical-Stage Human Monoclonal Antibodies That Treat Advanced Ebola Virus Disease in Nonhuman Primates Pascal, Kristen E Dudgeon, Drew Trefry, John C Anantpadma, Manu Sakurai, Yasuteru Murin, Charles D Turner, Hannah L Fairhurst, Jeanette Torres, Marcela Rafique, Ashique Yan, Ying Badithe, Ashok Yu, Kevin Potocky, Terra Bixler, Sandra L Chance, Taylor B Pratt, William D Rossi, Franco D Shamblin, Joshua D Wollen, Suzanne E Zelko, Justine M Carrion, Ricardo Worwa, Gabriella Staples, Hilary M Burakov, Darya Babb, Robert Chen, Gang Martin, Joel Huang, Tammy T Erlandson, Karl Willis, Melissa S Armstrong, Kimberly Dreier, Thomas M Ward, Andrew B Davey, Robert A Pitt, Margaret L M Lipsich, Leah Mason, Peter Olson, William Stahl, Neil Kyratsous, Christos A J Infect Dis Supplement Articles BACKGROUND: For most classes of drugs, rapid development of therapeutics to treat emerging infections is challenged by the timelines needed to identify compounds with the desired efficacy, safety, and pharmacokinetic profiles. Fully human monoclonal antibodies (mAbs) provide an attractive method to overcome many of these hurdles to rapidly produce therapeutics for emerging diseases. METHODS: In this study, we deployed a platform to generate, test, and develop fully human antibodies to Zaire ebolavirus. We obtained specific anti-Ebola virus (EBOV) antibodies by immunizing VelocImmune mice that use human immunoglobulin variable regions in their humoral responses. RESULTS: Of the antibody clones isolated, 3 were selected as best at neutralizing EBOV and triggering FcγRIIIa. Binding studies and negative-stain electron microscopy revealed that the 3 selected antibodies bind to non-overlapping epitopes, including a potentially new protective epitope not targeted by other antibody-based treatments. When combined, a single dose of a cocktail of the 3 antibodies protected nonhuman primates (NHPs) from EBOV disease even after disease symptoms were apparent. CONCLUSIONS: This antibody cocktail provides complementary mechanisms of actions, incorporates novel specificities, and demonstrates high-level postexposure protection from lethal EBOV disease in NHPs. It is now undergoing testing in normal healthy volunteers in preparation for potential use in future Ebola epidemics. Oxford University Press 2018-12-15 2018-05-31 /pmc/articles/PMC6249601/ /pubmed/29860496 http://dx.doi.org/10.1093/infdis/jiy285 Text en © The Author(s) 2018. Published by Oxford University Press for the Infectious Diseases Society of America. http://creativecommons.org/licenses/by/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Supplement Articles Pascal, Kristen E Dudgeon, Drew Trefry, John C Anantpadma, Manu Sakurai, Yasuteru Murin, Charles D Turner, Hannah L Fairhurst, Jeanette Torres, Marcela Rafique, Ashique Yan, Ying Badithe, Ashok Yu, Kevin Potocky, Terra Bixler, Sandra L Chance, Taylor B Pratt, William D Rossi, Franco D Shamblin, Joshua D Wollen, Suzanne E Zelko, Justine M Carrion, Ricardo Worwa, Gabriella Staples, Hilary M Burakov, Darya Babb, Robert Chen, Gang Martin, Joel Huang, Tammy T Erlandson, Karl Willis, Melissa S Armstrong, Kimberly Dreier, Thomas M Ward, Andrew B Davey, Robert A Pitt, Margaret L M Lipsich, Leah Mason, Peter Olson, William Stahl, Neil Kyratsous, Christos A Development of Clinical-Stage Human Monoclonal Antibodies That Treat Advanced Ebola Virus Disease in Nonhuman Primates |
title | Development of Clinical-Stage Human Monoclonal Antibodies That Treat Advanced Ebola Virus Disease in Nonhuman Primates |
title_full | Development of Clinical-Stage Human Monoclonal Antibodies That Treat Advanced Ebola Virus Disease in Nonhuman Primates |
title_fullStr | Development of Clinical-Stage Human Monoclonal Antibodies That Treat Advanced Ebola Virus Disease in Nonhuman Primates |
title_full_unstemmed | Development of Clinical-Stage Human Monoclonal Antibodies That Treat Advanced Ebola Virus Disease in Nonhuman Primates |
title_short | Development of Clinical-Stage Human Monoclonal Antibodies That Treat Advanced Ebola Virus Disease in Nonhuman Primates |
title_sort | development of clinical-stage human monoclonal antibodies that treat advanced ebola virus disease in nonhuman primates |
topic | Supplement Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6249601/ https://www.ncbi.nlm.nih.gov/pubmed/29860496 http://dx.doi.org/10.1093/infdis/jiy285 |
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