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Kidney Week

Abstract: PO0645

IL-33 as a Novel Target for the Treatment of Diabetic Kidney Disease

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic

Authors

  • Musial, Barbara, Bioscience Renal, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Cambridge, United Kingdom
  • Seth, Asha, Bioscience Renal, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Cambridge, United Kingdom
  • Baker, David J., Bioscience Metabolism, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Cambridge, United Kingdom
  • Heasman, Stephanie C., Imaging and Data Analytics, Clinical Pharmacology & Safety Sciences, R&D, AstraZeneca, Cambridge, United Kingdom
  • Conway, James, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, Maryland, United States
  • Slidel, Tim, BioPharmaceuticals R&D, AstraZeneca, Cambridge, United Kingdom
  • Wang, Xiaozhen J., Translational Science & Experimental Medicine, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, Maryland, United States
  • Ryden-Bergsten, Tina, Projects, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
  • Laerkegaard Hansen, Pernille B., Bioscience Renal, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
  • Woollard, Kevin, Bioscience Renal, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Cambridge, United Kingdom
  • Liarte Marin, Elena, Bioscience Renal, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Cambridge, United Kingdom
Background

Diabetic kidney disease (DKD) has classically been thought as a microvascular disorder, although inflammation has emerged as a key pathophysiological mechanism involved in the development of diabetic kidney injury. Consequently, inflammatory mediators have aroused as promising therapeutic targets.

Methods

IL-33 is a broad acting cytokine, expressed in endothelial and epithelial barriers, that mediates local tissue inflammation. It exerts its function by binding to a heterodimer formed by its specific receptor ST2 and co-receptor IL-1RAcP. Due to the evidence of the role of IL-33 in kidney injury, we generated MEDI3506, a potent IL-33 blocking mAb for the treatment of DKD.

Results

Transcriptomic analysis showed that expression of IL-33 RNA is upregulated in both the glomeruli and tubulointerstitium of DKD patients in two independent cohorts. Assessment of expression in both human and experimental DKD demonstrated that IL-33 is among the most regulated inflammatory genes. Preliminary data on IL-33 protein levels in human kidney biopsies indicates that IL-33 is increased in DKD versus controls.
Preclinically, the db/db uninephrectomy model of DKD showed IL-33 protein levels in kidney lysates positively correlated with histological glomerular damage from week 7 to 21. More importantly, blockade of ST2 signalling by using a mAb, prevented the progression of albuminuria. In vitro mechanistic studies using primary human glomerular endothelial cells (GECs) and mesangial cells (MCs) showed that both cell types expressed ST2 and upregulated IL-33 in response to TNFα and IFNγ, commonly upregulated in diabetic kidney microenvironment. Moreover, GECs and to a lesser extent MCs, displayed a significant IL-33 induced proinflammatory cytokine release (e.g. IL-8, IL-6...) mediated by MAP kinase activation and NF-kB translocation. All these effects were inhibited by MEDI3506.

Conclusion

Upregulation of IL-33 in diabetic kidney, generates localised chronic kidney inflammation through autocrine signalling in GECs and MCs. This data suggest that targeting IL-33 with MEDI3506 arises as a promising therapeutic intervention for DKD, currently in Ph2b trial.

Funding

  • Commercial Support