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Khanna V , Kim H , Zhang W , Larson P , Shah M , Griffith TS , Ferguson D , Panyam J
Novel TLR 7/8 agonists for improving NK cell mediated antibody-dependent cellular cytotoxicity (ADCC)
Sci Rep. 2021 Feb 8;11(1) :3346
PMID: 33558639   
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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.
2045-2322 Khanna, Vidhi Kim, Hyunjoon Zhang, Wenqiu Larson, Peter Shah, Manan Griffith, Thomas S Ferguson, David Panyam, Jayanth Orcid: 0000-0002-8656-2244 Journal Article Sci Rep. 2021 Feb 8;11(1):3346. doi: 10.1038/s41598-021-83005-6.