Development of a novel TLR8 agonist for cancer immunotherapy
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Molecular Biomedicine
RESEARCH
Open Access
Development of a novel TLR8 agonist for cancer immunotherapy Yuxun Wang*, Heping Yang, Huanping Li, Shuda Zhao, Yikun Zeng, Panpan Zhang, Xiaoqin Lin, Xiaoxiang Sun, Longsheng Wang, Guangliang Fu, Yaqiao Gao, Pei Wang and Daxin Gao
Abstract 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. 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 1 clinical trials. Keywords: TLR8, Innate immunity, Cancer, Immunotherapy
Introduction Human immune defense system comprises both innate and adaptive immune pathways [1]. Most of the targets drugged by the recently approved cancer immunotherapeutic agents including the immune checkpoint proteins PD-1, PD-L1 and CTLA-4 function in adaptive immune pathways [2, 3]. In contrast, targets involved in the innate immune pathway had been under-developed [4, 5]. Innate immunity acts as the body’s first line of immune defense. Drugs targeting innate immunity hold potential for more rapid and broader spectrum anti-cancer effect than adaptive immunity. Furthermore, combinations of drugs targeting innate and adaptive immunity are expected to produce strong synergistic efficacy owing to their complementary nature as body’s immune defense [6]. Toll-like receptors (TLRs) are a family of proteins * Correspondence: [email protected] Shanghai Denovo Pharmatech Co., Ltd., 576 Libing Road, Shanghai Zhangjiang High-Tech Park, Pudong New District, Shanghai 201203, China
that recognize pathogen associated molecular patterns (PAMPs). Their primary function is to activate innate immune responses while they are also involved in facilitating adaptive immune responses [7]. Different TLRs differ in their expression in various target cells and exert distinct functions by activating varied immune cascades [7–9]. In the TLR family, several TLRs have been studied as cancer drug targets such as TLR2, 4, 7, 8 and 9 [7, 10–14]. Some of them are being drugged by conventional small molecule modality while others a
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