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Development of A Novel Highly Selective TLR8 Agonist for Cancer Immunotherapy

By Yuxun Wang, Heping Yang, Huanping Li, Shuda Zhao, Yikun Zeng, Panpan Zhang, Xiaoqin Lin, Xiaoxiang Sun, Longsheng Wang, Guangliang Fu, Yaqiao Gao, Pei Wang, Daxin Gao

Posted 15 Mar 2020
bioRxiv DOI: 10.1101/2020.03.14.991760

Toll-like receptors (TLRs) are a family of proteins that recognize pathogen associated molecular patterns (PAMPs). Their primary function is to activate innate immune responses while also involved in facilitating adaptive immune responses. Different TLRs exert distinct functions by activating varied immune cascades. Several TLRs are being pursued as cancer drug targets. We discovered a novel, highly potent and selective small molecule TLR8 agonist DN052. DN052 exhibited strong in vitro cellular activity with EC50 at 6.7 nM and was highly selective for TLR8 over other TLRs including TLR4, 7 and 9. The selectivity profile distinguished DN052 from all other TLR agonists currently in clinical development. DN052 displayed excellent in vitro ADMET and in vivo PK profiles. DN052 potently inhibited tumor growth as a single agent. Moreover, combination of DN052 with the immune checkpoint inhibitor, selected targeted therapeutics or chemotherapeutic drugs further enhanced efficacy of single agents. Mechanistically, treatment with DN052 resulted in strong induction of pro-inflammatory cytokines in ex vivo human PBMC assay and in vivo monkey study. GLP toxicity studies in rats and monkeys demonstrated favorable safety profile. This led to the advancement of DN052 into phase I clinical trials.

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