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...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2021-02-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-021-83005-6 |
| _version_ | 1818431852906545152 |
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| 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 |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-12-14T15:55:54Z |
| format | Article |
| id | doaj.art-27dcaeb327f34221a5a50d887ce3dbbf |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-12-14T15:55:54Z |
| publishDate | 2021-02-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-27dcaeb327f34221a5a50d887ce3dbbf2022-12-21T22:55:16ZengNature PortfolioScientific Reports2045-23222021-02-0111111310.1038/s41598-021-83005-6Novel TLR 7/8 agonists for improving NK cell mediated antibody-dependent cellular cytotoxicity (ADCC)Vidhi Khanna0Hyunjoon Kim1Wenqiu Zhang2Peter Larson3Manan Shah4Thomas S. Griffith5David Ferguson6Jayanth Panyam7Department of Pharmaceutics, University of MinnesotaDepartment of Pharmaceutics, University of MinnesotaDepartment of Pharmaceutics, University of MinnesotaDepartment of Medicinal Chemistry, University of MinnesotaDepartment of Pharmaceutics, University of MinnesotaMasonic Cancer Center, University of MinnesotaDepartment of Medicinal Chemistry, University of MinnesotaDepartment of Pharmaceutics, University of MinnesotaAbstract 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.https://doi.org/10.1038/s41598-021-83005-6 |
| spellingShingle | 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) Scientific Reports |
| 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 |
| url | https://doi.org/10.1038/s41598-021-83005-6 |
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