A single injection of crystallizable fragment domain–modified antibodies elicits durable protection from SHIV infection

In the absence of an effective and safe vaccine against HIV-1, the administration of broadly neutralizing antibodies (bNAbs) represents a logical alternative approach to prevent virus transmission. Here, we introduced two mutations encoding amino acid substitutions (M428L and N434S, collectively ref...

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Autores principales: Gautam, Rajeev, Nishimura, Yoshiaki, Gaughan, Natalie, Gazumyan, Anna, Schoofs, Till, Buckler-White, Alicia, Seaman, Michael S., Swihart, Bruce J., Follmann, Dean A., Nussenzweig, Michel C., Martin, Malcolm A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group US 2018
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Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5989326/
https://www.ncbi.nlm.nih.gov/pubmed/29662199
http://dx.doi.org/10.1038/s41591-018-0001-2
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author Gautam, Rajeev
Nishimura, Yoshiaki
Gaughan, Natalie
Gazumyan, Anna
Schoofs, Till
Buckler-White, Alicia
Seaman, Michael S.
Swihart, Bruce J.
Follmann, Dean A.
Nussenzweig, Michel C.
Martin, Malcolm A.
author_facet Gautam, Rajeev
Nishimura, Yoshiaki
Gaughan, Natalie
Gazumyan, Anna
Schoofs, Till
Buckler-White, Alicia
Seaman, Michael S.
Swihart, Bruce J.
Follmann, Dean A.
Nussenzweig, Michel C.
Martin, Malcolm A.
author_sort Gautam, Rajeev
collection PubMed
description In the absence of an effective and safe vaccine against HIV-1, the administration of broadly neutralizing antibodies (bNAbs) represents a logical alternative approach to prevent virus transmission. Here, we introduced two mutations encoding amino acid substitutions (M428L and N434S, collectively referred to as ‘LS’) into the genes encoding the crystallizable fragment domains of the highly potent HIV-specific 3BNC117 and 10-1074 bNAbs to increase their half-lives and evaluated their efficacy in blocking infection following repeated low-dose mucosal challenges of rhesus macaques (Macaca mulatta) with the tier 2 SHIV(AD8-EO). A single intravenous infusion of 10-1074-LS monoclonal antibodies markedly delayed virus acquisition for 18 to 37 weeks (median, 27 weeks), whereas the protective effect of the 3BNC117-LS bNAb was more modest (provided protection for 11–23 weeks; median, 17 weeks). Serum concentrations of the 10-1074-LS monoclonal antibody gradually declined and became undetectable in all recipients between weeks 26 and 41, whereas the 3BNC117-LS bNAb exhibited a shorter half-life. To model immunoprophylaxis against genetically diverse and/or neutralization-resistant HIV-1 strains, a combination of the 3BNC117-LS plus 10-1074-LS monoclonal antibodies was injected into macaques via the more clinically relevant subcutaneous route. Even though the administered mixture contained an amount of each bNAb that was nearly threefold less than the quantity of the single monoclonal antibody in the intravenous injections, the monoclonal antibody combination still protected macaques for a median of 20 weeks. The extended period of protection observed in macaques for the 3BNC117-LS plus 10-1074-LS combination could translate into an effective semiannual or annual immunoprophylaxis regimen for preventing HIV-1 infections in humans.
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spelling pubmed-59893262018-06-06 A single injection of crystallizable fragment domain–modified antibodies elicits durable protection from SHIV infection Gautam, Rajeev Nishimura, Yoshiaki Gaughan, Natalie Gazumyan, Anna Schoofs, Till Buckler-White, Alicia Seaman, Michael S. Swihart, Bruce J. Follmann, Dean A. Nussenzweig, Michel C. Martin, Malcolm A. Nat Med Article In the absence of an effective and safe vaccine against HIV-1, the administration of broadly neutralizing antibodies (bNAbs) represents a logical alternative approach to prevent virus transmission. Here, we introduced two mutations encoding amino acid substitutions (M428L and N434S, collectively referred to as ‘LS’) into the genes encoding the crystallizable fragment domains of the highly potent HIV-specific 3BNC117 and 10-1074 bNAbs to increase their half-lives and evaluated their efficacy in blocking infection following repeated low-dose mucosal challenges of rhesus macaques (Macaca mulatta) with the tier 2 SHIV(AD8-EO). A single intravenous infusion of 10-1074-LS monoclonal antibodies markedly delayed virus acquisition for 18 to 37 weeks (median, 27 weeks), whereas the protective effect of the 3BNC117-LS bNAb was more modest (provided protection for 11–23 weeks; median, 17 weeks). Serum concentrations of the 10-1074-LS monoclonal antibody gradually declined and became undetectable in all recipients between weeks 26 and 41, whereas the 3BNC117-LS bNAb exhibited a shorter half-life. To model immunoprophylaxis against genetically diverse and/or neutralization-resistant HIV-1 strains, a combination of the 3BNC117-LS plus 10-1074-LS monoclonal antibodies was injected into macaques via the more clinically relevant subcutaneous route. Even though the administered mixture contained an amount of each bNAb that was nearly threefold less than the quantity of the single monoclonal antibody in the intravenous injections, the monoclonal antibody combination still protected macaques for a median of 20 weeks. The extended period of protection observed in macaques for the 3BNC117-LS plus 10-1074-LS combination could translate into an effective semiannual or annual immunoprophylaxis regimen for preventing HIV-1 infections in humans. Nature Publishing Group US 2018-04-16 2018 /pmc/articles/PMC5989326/ /pubmed/29662199 http://dx.doi.org/10.1038/s41591-018-0001-2 Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Gautam, Rajeev
Nishimura, Yoshiaki
Gaughan, Natalie
Gazumyan, Anna
Schoofs, Till
Buckler-White, Alicia
Seaman, Michael S.
Swihart, Bruce J.
Follmann, Dean A.
Nussenzweig, Michel C.
Martin, Malcolm A.
A single injection of crystallizable fragment domain–modified antibodies elicits durable protection from SHIV infection
title A single injection of crystallizable fragment domain–modified antibodies elicits durable protection from SHIV infection
title_full A single injection of crystallizable fragment domain–modified antibodies elicits durable protection from SHIV infection
title_fullStr A single injection of crystallizable fragment domain–modified antibodies elicits durable protection from SHIV infection
title_full_unstemmed A single injection of crystallizable fragment domain–modified antibodies elicits durable protection from SHIV infection
title_short A single injection of crystallizable fragment domain–modified antibodies elicits durable protection from SHIV infection
title_sort single injection of crystallizable fragment domain–modified antibodies elicits durable protection from shiv infection
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5989326/
https://www.ncbi.nlm.nih.gov/pubmed/29662199
http://dx.doi.org/10.1038/s41591-018-0001-2
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