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

Vidhi Devendra Khanna, Hyunjoon Kim, Wenqiu Zhang, Peter Larson, Manan Shah, Thomas S. Griffith, David Ferguson, Jayanth Panyam

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Article number3346
JournalScientific reports
Volume11
Issue number1
DOIs
StatePublished - Dec 2021

Bibliographical note

Funding Information:
This research was funded by the grant in aid program, University of Minnesota (JP), GAP award (JP), Masonic Cancer Center, University of Minnesota (TG), the Prostate and Urological Cancer Translational Working Group (TG), and the Randy Shaver Cancer Research & Community Fund (TG, DF).

Publisher Copyright:
© 2021, The Author(s).

PubMed: MeSH publication types

  • Journal Article

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