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Kidney Week

Abstract: PO0894

Targeting αvβ8 Integrin Improves Renal Function Through Local Inhibition of TGF-β Activation

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic

Authors

  • Liarte Marin, Elena, Renal Bioscience, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Cambridge, United Kingdom
  • Liang, Lihuan, Renal Bioscience, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Cambridge, United Kingdom
  • Seth, Asha, Renal Bioscience, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Cambridge, United Kingdom
  • Heasman, Stephanie C., Imaging & Artificial Intelligence, Clinical Pharmacology & Safety Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, United Kingdom
  • Selvarajah, Viknesh, Clinical Development, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Cambridge, United Kingdom
  • MacPhee, Iain, Clinical Development, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Cambridge, United Kingdom
  • Wang, Xiaozhen, Translational Science and Experimental Medicine, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, Maryland, United States
  • Hartleib-Geschwindner, Judith, Projects, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
  • Moreno Quinn, Carol Patricia, Renal Bioscience, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Cambridge, United Kingdom
  • Baker, David J., Metabolism Bioscience, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Cambridge, United Kingdom
  • Feliers, Denis, Renal Bioscience, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Cambridge, United Kingdom
Background

TGFβ signalling plays a central role in the development and progression of renal interstitial fibrosis in chronic kidney disease (CKD), which predicts time to dialysis. Systemic blockade of TGFβ has shown serious adverse effects (progression of premalignant lesions) and limited efficacy at doses that were safe for patients, highlighting the need for a targeted inhibition of TGFβ in the kidney. αvβ integrins have a unique ability to activate latent TGFβ through the binding of latency-associated peptide (LAP) to release active TGFβ and therefore can modulate fibrotic processes. Consequently, they have emerged as promising therapeutic targets.

Methods

We generated MEDI8367, an antibody that specifically binds human integrin β8 and works allosterically reducing its affinity for the LAP domain, hence preventing β8-mediated TGFβ activation but not its cell adhesion function. We confirmed its neutralising activity using a reporter cell in vitro assay that detects TGFβ bioactivity.

Results

To assess its therapeutic effect ITGB8 humanized mice were subjected to unilateral ureteral obstruction to induce fibrosis. Obstructed kidneys showed strong up-regulation of integrin β8 in the tubular compartment and MEDI8367 significantly improved fibrosis without affecting integrin β8 expression. This was accompanied by inhibition of TGFβ activation, which mimicked the effect of a pan-TGFβ neutralizing antibody, suggesting that MEDI8367 reduces renal fibrosis by blocking local TGFβ activation.

We next tested the effect of targeting integrin β8 in a mouse model of diabetic nephropathy, the db/db-uninephrectomy model. Mice underwent uni-nephrectomy at 8 weeks of age and were randomized to receive either an anti integrin β6/β8 or an anti integrin β6 antibody at 12 weeks of age for 3 weeks. Blocking integrin β6 did not affect albuminuria in these mice while blocking integrins β6/β8 stopped the progression of albuminuria in all the mice tested (n=9). These data suggest that it is the blockade of integrin β8 that has a beneficial effect on albuminuria.

Conclusion

We conclude that targeting integrin β8 in CKD ameliorates kidney dysfunction and reduces fibrosis, an effect that is mediated by inhibition of local TGFβ activation.