1 research outputs found
Discovery of Novel TLR7 Agonists as Systemic Agent for Combination With aPD1 for Use in Immuno-oncology
We have designed and developed novel and selective TLR7
agonists
that exhibited potent receptor activity in a cell-based reporter assay. In vitro, these agonists significantly induced secretion
of cytokines IL-6, IL-1β, IL-10, TNFa, IFNa, and IP-10 in human
and mouse whole blood. Pharmacokinetic and pharmacodynamic studies
in mice showed a significant secretion of IFNα and TNFα
cytokines. When combined with aPD1 in a CT-26 tumor model, the lead
compound showed strong synergistic antitumor activity with complete
tumor regression in 8/10 mice dosed using the intravenous route. Structure–activity
relationship studies enabled by structure-based designs of TLR7 agonists
are disclosed