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Abstract: TH-PO550

Urinary Extracellular Vesicles Reveal Distinct Biological Effects of Voclosporin in the Treatment of Lupus Nephritis

Session Information

Category: Glomerular Diseases

  • 1401 Glomerular Diseases: From Inflammation to Fibrosis

Authors

  • van Heugten, Martijn H., Erasmus MC Afdeling Inwendige Geneeskunde, Rotterdam, Zuid-Holland, Netherlands
  • Wei, Kuangyu, Erasmus MC Afdeling Inwendige Geneeskunde, Rotterdam, Netherlands
  • van Willigenburg, Hester, Erasmus MC Afdeling Inwendige Geneeskunde, Rotterdam, Zuid-Holland, Netherlands
  • Demir, Fatih, Aarhus Universitet, Aarhus, Midtjylland, Denmark
  • Rehaume, Linda M., Aurinia Pharmaceuticals Inc, Victoria, British Columbia, Canada
  • Viel, John, Aurinia Pharmaceuticals Inc, Victoria, British Columbia, Canada
  • Rinschen, Markus M., Aarhus Universitet, Aarhus, Midtjylland, Denmark
  • Hoorn, Ewout J., Erasmus MC Afdeling Inwendige Geneeskunde, Rotterdam, Zuid-Holland, Netherlands
Background

In the Phase 2 AURA-LV and Phase 3 AURORA 1 trials the novel calcineurin inhibitor voclosporin significantly increased complete renal response rates compared to placebo, both including mycophenolate mofetil and low-dose steroids. We further explore this treatment response by analyzing urinary extracellular vesicles (uEV), which are secreted by kidney cells and have the potential to provide a non-invasive read-out of cellular processes.

Methods

We isolated uEV from biobanked spot urine samples collected from patients with active lupus nephritis (LN) treated with voclosporin or placebo in AURORA 1 (n=60 per arm). uEVs were isolated at baseline and at the end of treatment using a differential ultracentrifugation protocol. Proteomes were quantified by tandem mass spectrometry on a Thermo Exploris480 with a data-independent acquisition strategy. Data was analyzed with Spectronaut and proteins with a log2-fold change >1 and q-value <0.05 considered significant. Pathway analysis was performed using the Reactome database.

Results

We identified 3708 proteins in uEV. At baseline 545 proteins were different in patients who responded to voclosporin. Pathway analysis linked these proteins to neutrophil degranulation, selenoamino acid metabolism, and Robo-receptors. Previous work on Robo-signaling showed it controls leukocyte infiltration and podocyte function in kidney injury and is increased in LN, while selenoamino acids are key to cellular antioxidant defenses and control Akt signaling through calcineurin. 732 proteins significantly changed in the patients who responded to voclosporin. Pathway analysis for voclosporin-altered proteins showed enrichment of the complement C2 and C4 pathways, while Fc-gamma receptor phagocytosis and tyrosine kinase signaling changed in patients responding to placebo. Neutrophil degranulation was changed by both voclosporin (61 proteins) and placebo (52 proteins), but involved different proteins (15 shared).

Conclusion

Using mass spectrometry of uEV we identified potential non-invasive biomarkers for treatment response to voclosporin in patients with LN. In addition, we were able to characterize the altered processes in the patients responding to voclosporin, which included complement and a specific change in neutrophil-associated proteins.

Funding

  • Commercial Support – Aurinia Pharmaceuticals