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Potential of conventional & bispecific broadly neutralizing antibodies for prevention of HIV-1 subtype A, C & D infections
There is great interest in passive transfer of broadly neutralizing antibodies (bnAbs) and engineered bispecific antibodies (Abs) for prevention of HIV-1 infections due to their in vitro neutralization breadth and potency against global isolates and long in vivo half-lives. We compared the potential...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5854441/ https://www.ncbi.nlm.nih.gov/pubmed/29505593 http://dx.doi.org/10.1371/journal.ppat.1006860 |
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author | Wagh, Kshitij Seaman, Michael S. Zingg, Marshall Fitzsimons, Tomas Barouch, Dan H. Burton, Dennis R. Connors, Mark Ho, David D. Mascola, John R. Nussenzweig, Michel C. Ravetch, Jeffrey Gautam, Rajeev Martin, Malcolm A. Montefiori, David C. Korber, Bette |
author_facet | Wagh, Kshitij Seaman, Michael S. Zingg, Marshall Fitzsimons, Tomas Barouch, Dan H. Burton, Dennis R. Connors, Mark Ho, David D. Mascola, John R. Nussenzweig, Michel C. Ravetch, Jeffrey Gautam, Rajeev Martin, Malcolm A. Montefiori, David C. Korber, Bette |
author_sort | Wagh, Kshitij |
collection | PubMed |
description | There is great interest in passive transfer of broadly neutralizing antibodies (bnAbs) and engineered bispecific antibodies (Abs) for prevention of HIV-1 infections due to their in vitro neutralization breadth and potency against global isolates and long in vivo half-lives. We compared the potential of eight bnAbs and two bispecific Abs currently under clinical development, and their 2 Ab combinations, to prevent infection by dominant HIV-1 subtypes in sub-Saharan Africa. Using in vitro neutralization data for Abs against 25 subtype A, 100 C, and 20 D pseudoviruses, we modeled neutralization by single Abs and 2 Ab combinations assuming realistic target concentrations of 10μg/ml total for bnAbs and combinations, and 5μg/ml for bispecifics. We used IC(80) breadth-potency, completeness of neutralization, and simultaneous coverage by both Abs in the combination as metrics to characterize prevention potential. Additionally, we predicted in vivo protection by Abs and combinations by modeling protection as a function of in vitro neutralization based on data from a macaque simian-human immunodeficiency virus (SHIV) challenge study. Our model suggests that nearly complete neutralization of a given virus is needed for in vivo protection (~98% neutralization for 50% relative protection). Using the above metrics, we found that bnAb combinations should outperform single bnAbs, as expected; however, different combinations are optimal for different subtypes. Remarkably, a single bispecific 10E8-iMAb, which targets HIV Env and host-cell CD4, outperformed all combinations of two conventional bnAbs, with 95–97% predicted relative protection across subtypes. Combinations that included 10E8-iMAb substantially improved protection over use of 10E8-iMAb alone. Our results highlight the promise of 10E8-iMAb and its combinations to prevent HIV-1 infections in sub-Saharan Africa. |
format | Online Article Text |
id | pubmed-5854441 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-58544412018-03-28 Potential of conventional & bispecific broadly neutralizing antibodies for prevention of HIV-1 subtype A, C & D infections Wagh, Kshitij Seaman, Michael S. Zingg, Marshall Fitzsimons, Tomas Barouch, Dan H. Burton, Dennis R. Connors, Mark Ho, David D. Mascola, John R. Nussenzweig, Michel C. Ravetch, Jeffrey Gautam, Rajeev Martin, Malcolm A. Montefiori, David C. Korber, Bette PLoS Pathog Research Article There is great interest in passive transfer of broadly neutralizing antibodies (bnAbs) and engineered bispecific antibodies (Abs) for prevention of HIV-1 infections due to their in vitro neutralization breadth and potency against global isolates and long in vivo half-lives. We compared the potential of eight bnAbs and two bispecific Abs currently under clinical development, and their 2 Ab combinations, to prevent infection by dominant HIV-1 subtypes in sub-Saharan Africa. Using in vitro neutralization data for Abs against 25 subtype A, 100 C, and 20 D pseudoviruses, we modeled neutralization by single Abs and 2 Ab combinations assuming realistic target concentrations of 10μg/ml total for bnAbs and combinations, and 5μg/ml for bispecifics. We used IC(80) breadth-potency, completeness of neutralization, and simultaneous coverage by both Abs in the combination as metrics to characterize prevention potential. Additionally, we predicted in vivo protection by Abs and combinations by modeling protection as a function of in vitro neutralization based on data from a macaque simian-human immunodeficiency virus (SHIV) challenge study. Our model suggests that nearly complete neutralization of a given virus is needed for in vivo protection (~98% neutralization for 50% relative protection). Using the above metrics, we found that bnAb combinations should outperform single bnAbs, as expected; however, different combinations are optimal for different subtypes. Remarkably, a single bispecific 10E8-iMAb, which targets HIV Env and host-cell CD4, outperformed all combinations of two conventional bnAbs, with 95–97% predicted relative protection across subtypes. Combinations that included 10E8-iMAb substantially improved protection over use of 10E8-iMAb alone. Our results highlight the promise of 10E8-iMAb and its combinations to prevent HIV-1 infections in sub-Saharan Africa. Public Library of Science 2018-03-05 /pmc/articles/PMC5854441/ /pubmed/29505593 http://dx.doi.org/10.1371/journal.ppat.1006860 Text en https://creativecommons.org/publicdomain/zero/1.0/ This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 (https://creativecommons.org/publicdomain/zero/1.0/) public domain dedication. |
spellingShingle | Research Article Wagh, Kshitij Seaman, Michael S. Zingg, Marshall Fitzsimons, Tomas Barouch, Dan H. Burton, Dennis R. Connors, Mark Ho, David D. Mascola, John R. Nussenzweig, Michel C. Ravetch, Jeffrey Gautam, Rajeev Martin, Malcolm A. Montefiori, David C. Korber, Bette Potential of conventional & bispecific broadly neutralizing antibodies for prevention of HIV-1 subtype A, C & D infections |
title | Potential of conventional & bispecific broadly neutralizing antibodies for prevention of HIV-1 subtype A, C & D infections |
title_full | Potential of conventional & bispecific broadly neutralizing antibodies for prevention of HIV-1 subtype A, C & D infections |
title_fullStr | Potential of conventional & bispecific broadly neutralizing antibodies for prevention of HIV-1 subtype A, C & D infections |
title_full_unstemmed | Potential of conventional & bispecific broadly neutralizing antibodies for prevention of HIV-1 subtype A, C & D infections |
title_short | Potential of conventional & bispecific broadly neutralizing antibodies for prevention of HIV-1 subtype A, C & D infections |
title_sort | potential of conventional & bispecific broadly neutralizing antibodies for prevention of hiv-1 subtype a, c & d infections |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5854441/ https://www.ncbi.nlm.nih.gov/pubmed/29505593 http://dx.doi.org/10.1371/journal.ppat.1006860 |
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