From Functional Group and Metabolite Analysis to Rational Design: Discovery of BXY-14 as a Highly Potent TLR2 Agonist with Enhanced Vaccine Adjuvants and Cancer Immunotherapy - PubMed
4 hours ago
- #TLR2 agonist
- #vaccine adjuvant
- #cancer immunotherapy
- TLR2 agonists bridge innate and adaptive immunity, showing promise in vaccines and cancer therapy.
- Natural product CaLGL-1 acts as a 'quiescent agonist' of TLR2, with its immunostimulatory potential masked by a labile acetal group.
- In oxidative environments, CaLGL-1 converts into a potent TLR2 agonist.
- BXY-14, a rationally designed derivative, exhibits cross-species TLR2 agonist activity with exceptional potency (EC50 = 2.2 nM in THP-1 cells, 1.8 nM in mBMDCs).
- BXY-14 functions as a superior vaccine adjuvant, eliciting stronger antibody responses than Diprovocim.
- In murine models, BXY-14 downregulated intratumoral PD-L1 expression and showed synergistic efficacy with anti-PD-L1 monoclonal antibody atezolizumab, prolonging overall survival.
- This work establishes metabolically gated immunity and delivers a translational TLR2 agonist linking bacterial metabolite chemistry with immunotherapy.