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

Abstract 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...

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Autores principales:	Vidhi Khanna, Hyunjoon Kim, Wenqiu Zhang, Peter Larson, Manan Shah, Thomas S. Griffith, David Ferguson, Jayanth Panyam
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/27dcaeb327f34221a5a50d887ce3dbbf
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spelling	oai:doaj.org-article:27dcaeb327f34221a5a50d887ce3dbbf2021-12-02T14:11:29ZNovel TLR 7/8 agonists for improving NK cell mediated antibody-dependent cellular cytotoxicity (ADCC)10.1038/s41598-021-83005-62045-2322https://doaj.org/article/27dcaeb327f34221a5a50d887ce3dbbf2021-02-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-83005-6https://doaj.org/toc/2045-2322Abstract 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.Vidhi KhannaHyunjoon KimWenqiu ZhangPeter LarsonManan ShahThomas S. GriffithDavid FergusonJayanth PanyamNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-13 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Vidhi Khanna Hyunjoon Kim Wenqiu Zhang Peter Larson Manan Shah Thomas S. Griffith David Ferguson Jayanth Panyam Novel TLR 7/8 agonists for improving NK cell mediated antibody-dependent cellular cytotoxicity (ADCC)
description	Abstract 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.
format	article
author	Vidhi Khanna Hyunjoon Kim Wenqiu Zhang Peter Larson Manan Shah Thomas S. Griffith David Ferguson Jayanth Panyam
author_facet	Vidhi Khanna Hyunjoon Kim Wenqiu Zhang Peter Larson Manan Shah Thomas S. Griffith David Ferguson Jayanth Panyam
author_sort	Vidhi Khanna
title	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_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_sort	novel tlr 7/8 agonists for improving nk cell mediated antibody-dependent cellular cytotoxicity (adcc)
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/27dcaeb327f34221a5a50d887ce3dbbf
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Novel TLR 7/8 agonists for improving NK cell mediated antibody-dependent cellular cytotoxicity (ADCC)

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