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Development of a novel TLR8 agonist for cancer immunotherapy
Yuxun Wang1, Heping Yang2, Huanping Li2
1Shanghai Denovo Pharmatech Co., Ltd., 576 Libing Road, Shanghai Zhangjiang High-Tech Park, Pudong New District, Shanghai, 201203, China. yuxun_wang@yahoo.com.
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.
Insights
A novel Toll-like receptor 8 (TLR8) agonist, DN052, shows potent anti-tumor activity and favorable safety. This small molecule effectively inhibits tumor growth and enhances combination therapies, advancing to clinical trials.
Area of Science:
- Immunology
- Pharmacology
- Oncology
Background:
- Toll-like receptors (TLRs) are crucial for innate and adaptive immunity.
- Dysregulated TLR signaling is implicated in various diseases, including cancer.
- Targeting specific TLRs presents a therapeutic opportunity for cancer treatment.
Purpose of the Study:
- To discover and characterize a novel, potent, and selective small molecule agonist for Toll-like receptor 8 (TLR8).
- To evaluate the anti-tumor efficacy and safety profile of the TLR8 agonist DN052.
- To explore the potential of DN052 in combination therapies for cancer treatment.
Main Methods:
- In vitro assays to determine cellular activity, selectivity, and ADMET properties of DN052.
- In vivo studies to assess tumor growth inhibition and pharmacokinetic profiles.
- Ex vivo and in vivo studies to analyze cytokine induction and safety in preclinical models.
Main Results:
- DN052 demonstrated high potency (EC50 6.7 nM) and selectivity for TLR8.
- DN052 exhibited favorable in vitro ADMET and in vivo PK profiles.
- DN052 potently inhibited tumor growth as a single agent and enhanced combination therapies.
- DN052 induced pro-inflammatory cytokines and showed a favorable safety profile in GLP toxicity studies.
Conclusions:
- DN052 is a potent and selective small molecule TLR8 agonist with significant anti-tumor activity.
- DN052 shows promise as a single agent and in combination therapies for cancer.
- The favorable safety profile supports the advancement of DN052 into phase 1 clinical trials.
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