Potent TLR7 agonist small molecules can turn cold tumors hot in combination with immune check-point blockade agents such as Opdivo. 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, IL1B, IL-10, TNFa, INFa, IP-10 in human and mouse whole blood. Pharmacokinetic and pharmacodymic studies in mice showed significant secretion of IFNa and TLFa cytokines. When combined with aPD1 in the CT-26 tumor model, an optimized molecule showed strong synergistic antitumor activity with complete tumor regression in 8/10 mice when dosed IV. Structure-activity relationship studies enabled by structure-based designs of TLR7 agonists will be disclosed.

Turning cold tumors hot: Discovery of novel TLR7 agonists as systemic agent for combination with aPD1 for use in immuno-oncology

ACS Spring 2022

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.