Development of A Novel Highly Selective TLR8 Agonist for Cancer Immunotherapy

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. 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.

Bioinformatic Identification of Neuroblastoma Microenvironment-Associated Biomarkers with Prognostic Value

“…TLR8 has been identified as a natural receptor for single-stranded RNA and is thought to act as an effective activator of the innate immune response after viral infection [ 41 – 43 ]. TLR8 is the only TLR that has been shown to be necessary and sufficient to reverse the suppressive function of Treg cells, resulting in strong tumor-suppressive effects [ 44 ]. Numerous reports have described the Toll-like receptor (TLR) expression in the tumor microenvironment as it relates to cancer progression, as well as their involvement in inflammation [ 45 ].…”

Immunotherapy in Ovarian Cancer: Thinking Beyond PD-1/PD-L1

“…Unfortunately, the addition of VTX-2337 to pegylated lyposomal doxorubicin did not improve clinical outcomes compared with placebo. Another potent TLR8 agonist, DN052 inhibited tumor growth and enhanced efficacy of ICIs in vitro ( 87 ) and is currently advancing in phase 1 trials in patients with advanced solid tumors (NCT03934359).…”