Abstract: SA-PO756
Immune Profiling-Based Targeting of Pathogenic T Cells with Ustekinumab in ANCA-Associated Glomerulonephritis
Session Information
- ANCA-Associated Vasculitis, Anti-GBM Disease, and Other RPGN
October 26, 2024 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Glomerular Diseases
- 1402 Glomerular Diseases: Clinical, Outcomes, and Therapeutics
Authors
- Engesser, Jonas, Universitatsklinikum Hamburg-Eppendorf, Hamburg, Hamburg, Germany
- Khatri, Robin, Universitatsklinikum Hamburg-Eppendorf, Hamburg, Hamburg, Germany
- Schaub, Darius P., Universitatsklinikum Hamburg-Eppendorf, Hamburg, Hamburg, Germany
- Paust, Hans-Joachim, Universitatsklinikum Hamburg-Eppendorf, Hamburg, Hamburg, Germany
- Sultana, Zeba, Universitatsklinikum Hamburg-Eppendorf, Hamburg, Hamburg, Germany
- Asada, Nariaki, Universitatsklinikum Hamburg-Eppendorf, Hamburg, Hamburg, Germany
- Sivayoganathan, Varshi, Universitatsklinikum Hamburg-Eppendorf, Hamburg, Hamburg, Germany
- Puelles, Victor G., Universitatsklinikum Hamburg-Eppendorf, Hamburg, Hamburg, Germany
- Wenzel, Ulrich O., Universitatsklinikum Hamburg-Eppendorf, Hamburg, Hamburg, Germany
- Steinmetz, Oliver M., Universitatsklinikum Hamburg-Eppendorf, Hamburg, Hamburg, Germany
- Hoxha, Elion, Universitatsklinikum Hamburg-Eppendorf, Hamburg, Hamburg, Germany
- Mittrücker, Hans-willi, Universitatsklinikum Hamburg-Eppendorf, Hamburg, Hamburg, Germany
- Wiech, Thorsten, Universitatsklinikum Hamburg-Eppendorf, Hamburg, Hamburg, Germany
- Huber, Tobias B., Universitatsklinikum Hamburg-Eppendorf, Hamburg, Hamburg, Germany
- Bonn, Stefan, Universitatsklinikum Hamburg-Eppendorf, Hamburg, Hamburg, Germany
- Krebs, Christian F., Universitatsklinikum Hamburg-Eppendorf, Hamburg, Hamburg, Germany
- Panzer, Ulf, Universitatsklinikum Hamburg-Eppendorf, Hamburg, Hamburg, Germany
Background
Antineutrophil cytoplasmatic antibody (ANCA)-associated vasculitis is a life-threatening autoimmune disease that often results in kidney failure caused by crescentic glomerulonephritis (ANCA-GN). To date, treatment of most patients with ANCA-GN relies on unspecific immunosuppressive drugs that are often only partially effective and harbor serious adverse effects. This underscores the unmet need for the development of pathogenesis-based and safer therapies.
Methods
Here, we performed combined spatial and single cell transcriptome analysis to characterize the inflammatory niches in the kidneys of 34 patients with ANCA-GN. Digital pharmacology was used to predict the most promising drugs for treatment of kidney inflammation. Subsequently, we treated four relapsing ANCA-GN patients in a proof-of-concept study with ustekinumab (90 mg s.c. at weeks 0, 4, 12 and 24) in combination with low dose cyclophosphamide and steroids. Patients were followed up for 26 weeks.
Results
Spatial transcriptome analysis revealed distinct inflammatory niches in both glomerular and tubulointerstitial regions, each associated with T cell activation. By using unsupervised single-cell transcriptomics and epitome mapping of renal T cells, we identified a predominance of proinflammatory, cytokine-producing Th1/Tc1 and Th17/Tc17-like effector T cells. Ensuing digital pharmacology pinpointed ustekinumab, a human monoclonal antibody binding the common p40-subunit shared by lL-12/IL-23, thus blocking Th1 as well as Th17 responses, as the most promising drug to target these pathogenic T cells in a pathogenesis-based treatment approach. The treatment of four ANCA-GN patients with relapsing disease using ustekinumab led to a rapid clinical response in all four patients, including improved kidney function and lower Birmingham Vasculitis Activity Scores. No treatment related adverse effects were observed during the follow up period.
Conclusion
Our findings suggest that immune profiling-based targeting of pathogenic T cells in ANCA-GN patients with ustekinumab is a promising approach and warrants further investigation in clinical trials.
Funding
- Government Support – Non-U.S.