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Discovery of Novel TLR7 Agonists as Systemic Agent for Combination With aPD1 for Use in Immuno-oncology
Yam B Poudel1, Liqi He1, Matthew Cox1
1Bristol-Myers Squibb Research & Development, 700 Bay Road, Redwood City, California 94063, United States.
Abstract:
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.
Insights
Novel Toll-like receptor 7 (TLR7) agonists show potent activity, inducing cytokine secretion and synergistic antitumor effects when combined with aPD1 therapy. These findings highlight potential new cancer treatment strategies.
Area of Science:
- Immunology
- Medicinal Chemistry
- Pharmacology
Background:
- Toll-like receptor 7 (TLR7) agonists are investigated for their immunomodulatory properties.
- Developing selective TLR7 agonists is crucial for therapeutic applications.
Purpose of the Study:
- To design and develop novel, selective TLR7 agonists.
- To evaluate the in vitro and in vivo efficacy of these agonists, including their combination with anti-PD1 therapy.
Main Methods:
- Cell-based reporter assays to assess receptor activity.
- Cytokine secretion analysis in human and mouse whole blood.
- Pharmacokinetic and pharmacodynamic studies in mice.
- Antitumor activity evaluation in a CT-26 tumor model in combination with aPD1.
Main Results:
- Novel TLR7 agonists demonstrated potent receptor activity.
- Significant induction of cytokines (IL-6, IL-1β, IL-10, TNFα, IFNα, IP-10) in vitro.
- In vivo studies confirmed IFNα and TNFα secretion.
- The lead compound combined with aPD1 achieved complete tumor regression in 8/10 mice.
Conclusions:
- Novel selective TLR7 agonists exhibit potent immune-stimulating and antitumor activities.
- Combination therapy with aPD1 shows significant synergistic effects.
- Structure-activity relationship studies provide insights for further drug development.
