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Novel TLR 7/8 agonists for improving NK cell mediated antibody-dependent cellular cytotoxicity (ADCC)

There is a significant interest in designing therapeutic agents that can enhance ADCC and thereby improve clinical responses with approved antibodies. We recently reported the combination of an imidazoquinoline-based TLR7/8 agonist (522) with a monoclonal antibody improved ADCC in vitro and in vivo....

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Autores principales: Khanna, Vidhi, Kim, Hyunjoon, Zhang, Wenqiu, Larson, Peter, Shah, Manan, Griffith, Thomas S., Ferguson, David, Panyam, Jayanth
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7870826/
https://www.ncbi.nlm.nih.gov/pubmed/33558639
http://dx.doi.org/10.1038/s41598-021-83005-6
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author Khanna, Vidhi
Kim, Hyunjoon
Zhang, Wenqiu
Larson, Peter
Shah, Manan
Griffith, Thomas S.
Ferguson, David
Panyam, Jayanth
author_facet Khanna, Vidhi
Kim, Hyunjoon
Zhang, Wenqiu
Larson, Peter
Shah, Manan
Griffith, Thomas S.
Ferguson, David
Panyam, Jayanth
author_sort Khanna, Vidhi
collection PubMed
description There is a significant interest in designing therapeutic agents that can enhance ADCC and thereby improve clinical responses with approved antibodies. We recently reported the combination of an imidazoquinoline-based TLR7/8 agonist (522) with a monoclonal antibody improved ADCC in vitro and in vivo. In the present study, we tested several new small molecule TLR7/8 agonists that induce significantly higher cytokines compared to both the FDA-approved TLR7 agonist, imiquimod, and 522. We evaluated these agonists in combination with monoclonal antibody therapy, with the main goal of enhancing ADCC. Our studies show these TLR7/8 agonists induce robust pro-inflammatory cytokine secretion and activate NK cells. Specifically, we found the agonists 574 and 558 significantly enhanced NK cell-mediated ADCC in vitro as well as enhanced the anti-cancer efficacy of monoclonal antibodies in two different in vivo mouse models. Additionally, we found the agonists were able to stimulate CD8 T cells, likely indicative of an early adaptive immune response.
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spelling pubmed-78708262021-02-10 Novel TLR 7/8 agonists for improving NK cell mediated antibody-dependent cellular cytotoxicity (ADCC) Khanna, Vidhi Kim, Hyunjoon Zhang, Wenqiu Larson, Peter Shah, Manan Griffith, Thomas S. Ferguson, David Panyam, Jayanth Sci Rep Article There is a significant interest in designing therapeutic agents that can enhance ADCC and thereby improve clinical responses with approved antibodies. We recently reported the combination of an imidazoquinoline-based TLR7/8 agonist (522) with a monoclonal antibody improved ADCC in vitro and in vivo. In the present study, we tested several new small molecule TLR7/8 agonists that induce significantly higher cytokines compared to both the FDA-approved TLR7 agonist, imiquimod, and 522. We evaluated these agonists in combination with monoclonal antibody therapy, with the main goal of enhancing ADCC. Our studies show these TLR7/8 agonists induce robust pro-inflammatory cytokine secretion and activate NK cells. Specifically, we found the agonists 574 and 558 significantly enhanced NK cell-mediated ADCC in vitro as well as enhanced the anti-cancer efficacy of monoclonal antibodies in two different in vivo mouse models. Additionally, we found the agonists were able to stimulate CD8 T cells, likely indicative of an early adaptive immune response. Nature Publishing Group UK 2021-02-08 /pmc/articles/PMC7870826/ /pubmed/33558639 http://dx.doi.org/10.1038/s41598-021-83005-6 Text en © The Author(s) 2021 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 licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence 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 licence, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Khanna, Vidhi
Kim, Hyunjoon
Zhang, Wenqiu
Larson, Peter
Shah, Manan
Griffith, Thomas S.
Ferguson, David
Panyam, Jayanth
Novel TLR 7/8 agonists for improving NK cell mediated antibody-dependent cellular cytotoxicity (ADCC)
title Novel TLR 7/8 agonists for improving NK cell mediated antibody-dependent cellular cytotoxicity (ADCC)
title_full Novel TLR 7/8 agonists for improving NK cell mediated antibody-dependent cellular cytotoxicity (ADCC)
title_fullStr Novel TLR 7/8 agonists for improving NK cell mediated antibody-dependent cellular cytotoxicity (ADCC)
title_full_unstemmed Novel TLR 7/8 agonists for improving NK cell mediated antibody-dependent cellular cytotoxicity (ADCC)
title_short Novel TLR 7/8 agonists for improving NK cell mediated antibody-dependent cellular cytotoxicity (ADCC)
title_sort novel tlr 7/8 agonists for improving nk cell mediated antibody-dependent cellular cytotoxicity (adcc)
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7870826/
https://www.ncbi.nlm.nih.gov/pubmed/33558639
http://dx.doi.org/10.1038/s41598-021-83005-6
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