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Kidney Week

Abstract: SA-PO1006

Integrin α3β1 as a Potential Target for Diabetic Kidney Disease (DKD)

Session Information

Category: Glomerular Diseases

  • 1403 Podocyte Biology

Authors

  • Bukanov, Nikolay O., Janssen Research and Development LLC, Raritan, New Jersey, United States
  • Natoli, Thomas A., Janssen Research and Development LLC, Raritan, New Jersey, United States
  • Chipashvili, Vaja, Janssen Research and Development LLC, Raritan, New Jersey, United States
  • Zhou, Wen, Janssen Research and Development LLC, Raritan, New Jersey, United States
  • Rana, Rajashree, Janssen Research and Development LLC, Raritan, New Jersey, United States
  • Pissios, Pavlos, Janssen Research and Development LLC, Raritan, New Jersey, United States
  • Zheng, Gang, Janssen Research and Development LLC, Raritan, New Jersey, United States
  • Nchaw, Gladys A., Janssen Research and Development LLC, Raritan, New Jersey, United States
  • Lutnick, Brendon R., Janssen Research and Development LLC, Raritan, New Jersey, United States
  • Yip, Stephen SF, Janssen Research and Development LLC, Raritan, New Jersey, United States
  • Lin, Fu-Yang, Morphic Therapeutic Inc, Waltham, Massachusetts, United States
  • Moy, Terence, Morphic Therapeutic Inc, Waltham, Massachusetts, United States
  • Leloup, Nadia, Morphic Therapeutic Inc, Waltham, Massachusetts, United States
  • Habte, Habtom, Janssen Research and Development LLC, Raritan, New Jersey, United States
  • Tobin, James F., Janssen Research and Development LLC, Raritan, New Jersey, United States
  • Magnone, Maria Chiara, Janssen Research and Development LLC, Raritan, New Jersey, United States
Background

Integrin α3β1 is highly expressed in kidney and is critical for maintaining the glomerular filtration barrier integrity by mediating adhesion of podocytes to laminin on the glomerular basement membrane. In human, loss-of-function mutations of α3 or its ligand laminin cause congenital nephrotic syndrome. We hypothesized that α3β1 activity in DKD is reduced and that activating α3β1 should preserve podocyte adhesion and kidney function. Here, we tested this hypothesis in a proof of mechanism (POM) experiment using the integrin β1-agonistic antibody 9EG7 in translational mouse model of severe DKD.

Methods

Integrin α3β1 loss in DKD was measured by α3 expression in kidney tissues from DKD patients with increasing disease severity by immunofluorescence staining. Antibody 9EG7 was characterized in vitro using adhesion assay in cells overexpressing α3β1, as well as adhesion, binding and cell morphology in human and mouse podocytes. The in vivo POM experiment with 9EG7 was performed in hypertensive diabetic ReninAAV Unix db/db mice. End points were kidney function (albuminuria), biomarkers (podocytes markers in urinary shed cells (uSC) and exosomes-like vesicles (ELV)), AI-based assessment of podocytes counts and the analysis of podocyte foot process effacement (measured by super-resolution microscopy).

Results

We confirmed that in DKD there is a progressive loss and mis-localization of α3 with disease progression, supporting the notion of a potential beneficial effect of an agonistic mAb. In vivo efficacy studies with integrin β1-agonistic monoclonal antibody 9EG7 (2 weeks treatment) showed a dose dependent decrease in uACR ratio and reduction of podocyte markers in whole urine and isolated urinary ELV and uSC. AI-enabled quantification of podocyte marker WT1 showed increased podocytes counts per glomerulus. Quantitative analysis of podocyte foot process formation by super-resolution microscopy showed improved podocyte structure.

Conclusion

Integrin β1-activation with the monoclonal antibody 9EG7 ameliorated hypertension-and diabetes-induced albuminuria, increased podocyte counts in glomerulus and decreased urinary podocyte markers in a preclinical model of DKD. These findings suggest that α3β1 could be a potential target for DKD.

Funding

  • Commercial Support – Janssen Pharmaceuticals, Morphic Therapeutic