Abstract: TH-PO0685
Dual TLR7/8 Inhibition with ST-303 Attenuates Lupus Pathogenesis and Extends Survival in Murine Models of Systemic Lupus Erythematosus
Session Information
- Glomerular Diseases: Immunopathogenesis and Targeted Therapeutics
November 06, 2025 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Glomerular Diseases
- 1401 Glomerular Diseases: Mechanisms, including Podocyte Biology
Author
- Yu, Michael Z., Renalvo Institute, Houston, Texas, United States
Background
Toll-like receptors 7 and 8 (TLR 7/8) are endosomal innate viral RNA sensors, primarily expressed in plasmacytoid dendritic cells and B cells. Much evidence supports enhanced TLR7/8 signaling as a mechanism of human systemic autoimmune disease.
ST-303 is a potent dual selective TLR 7/8 inhibitor and has similar human and mouse potency. ST-303 was used to investigate the role of TLR7/9 signaling in murine lupus models
Methods
MRL/lpr and NZB/W mice were treated with a vehicle or a selected dose of ST-303, prednisolone, ST-303 plus prednisone. MRL/lpr mice were treated for 6 weeks on the early-stage disease with positive anti-dsDNA antibodies but negative proteinuria. NZB/W mice were treated for 20 weeks on the early-stage disease with positive anti-dsDNA antibodies but negative proteinuria, twelve weeks on established disease, and 8 weeks on advanced disease (proteinuria >100 mg/dL).
Results
In MRL/lpr mice with early-stage disease, six weeks of ST-303 treatment significantly delayed proteinuria onset (p<0.01), reduced anti-dsDNA antibody titers, and decreased glomerular IgG deposition.
In NZB/W mice with early disease, ST-303 delayed the onset of lupus nephritis, reduced proteinuria incidence, and significant attenuation of renal IgG deposition. In NZB/W mice established disease model, ST-303 reduced proteinuria, decreased glomerular IgG deposition, and ameliorated interstitial fibrosis. In the advanced disease phase, ST-303 showed a significant reduction in proteinuria and less renal IgG deposition. Notably, ST-303 consistently suppressed serum autoantibody reduction across all disease stages vs baseline and showed a significant survival benefit with a prolonged lifespan (p<0.05).
Conclusion
The dual TLR7/8 inhibitor ST-303 demonstrated significant therapeutic efficacy in MRL/lpr and NZB/W murine lupus models, delaying lupus nephritis onset (p<0.01), attenuating disease progression, and improving survival (HR=0.35–0.45, p<0.01). Treatment reduced proteinuria, autoantibody production, and renal IgG deposition, while markedly ameliorating interstitial fibrosis in established/advanced disease ( p<0.01). These multi-faceted effects and end-organ protection—strongly implicate TLR7/8 inhibition as a promising disease-modifying strategy for SLE.
Funding
- Private Foundation Support