Kidney Week

Abstract: FR-PO334

Effects of a Vascular Endothelial Protein Tyrosine Phosphatase (VE-PTP) Blocking Antibody in a Mouse Model of Severe Diabetic Kidney Disease

Session Information

• Diabetic Kidney Disease: Basic - I
  November 03, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Diabetic Kidney Disease

• 701 Diabetic Kidney Disease: Basic

Authors

• Rana, Rajashree, Janssen Research and Development LLC, Boston, Massachusetts, United States

Rajashree Rana,

• Natoli, Thomas A., Janssen Research and Development LLC, Cambridge, Massachusetts, United States

Thomas A. Natoli,

• Khandelwal, Puneet, Janssen Research and Development LLC, Spring House, Pennsylvania, United States

Puneet Khandelwal,

• Pissios, Pavlos, Janssen Research and Development LLC, Boston, Massachusetts, United States

Pavlos Pissios,

• Muhammad, Abdul Bari, Janssen Research and Development LLC, Cambridge, Massachusetts, United States

Abdul Bari Muhammad,

• Chipashvili, Vaja, Janssen Research and Development LLC, Cambridge, Massachusetts, United States

Vaja Chipashvili,

• Farrington, Krista P., Janssen Research and Development LLC, Cambridge, Massachusetts, United States

Krista P. Farrington,

• Zhou, Wen, Janssen Research and Development LLC, Cambridge, Massachusetts, United States

Wen Zhou,

• Zheng, Gang, Janssen Research and Development LLC, Boston, Massachusetts, United States

Gang Zheng,

• Bukanov, Nikolay O., Janssen Research and Development LLC, Boston, Massachusetts, United States

Nikolay O. Bukanov,

• Magnone, Maria Chiara, Janssen Research and Development LLC, Boston, Massachusetts, United States

Maria Chiara Magnone,

Background

Diabetic Kidney Disease (DKD) is a disease with complex pathophysiology wherein endothelial dysfunction plays a central role in disease formation and progression. Emerging evidence emphasizes the critical role of the Tie-2 receptor and Angiopoietin 1 and 2 ligands in DKD. Tie-2 signaling is negatively regulated by the endothelial specific transmembrane Vascular Endothelial Protein Tyrosine Phosphatase (VE-PTP). Recently, it has been reported that the genetic deletion of VE-PTP provided protection from hypertension and diabetes induced renal injury in a mouse model of DKD. In the current study we investigated the efficacy of VE-PTP inhibition in a mouse model of severe DKD with an extracellular domain (ECD) targeting VE-PTP blocking antibody.

Methods

VE-PTP blocking antibody was characterized in vitro, in vivo in dermal vascular permeability assays, and in pharmacokinetic experiments. The in vivo proof-of-concept experiment with the VE-PTP blocking antibody and standard of care lisinopril were performed in hypertensive diabetic mice. Renin overexpression (AAV) was used to induce hypertension in db/db mice following uninephrectomy (Unx). Treatment was initiated 4-weeks after renin AAV administration and continued for another 4 weeks.

Results

Our results showed that VE-PTP inhibition with an ECD targeting VE-PTP antibody induced Tie2-phosphorylation and provided protection against VEGF-A induced vascular permeability both in vitro and in vivo. Furthermore, treatment with the VE-PTP antibody resulted in decreased kidney gene expression of endothelial activation markers (Angpt2, Edn1, Icam1 and Vcam1). However, the VE-PTP blocking antibody treatment did not alter urinary albumin-to-creatinine ratio (uACR) in a severe mouse model of DKD.

Conclusion

VE-PTP inhibition with an ECD targeting antibody did not ameliorate hypertension- and diabetes-induced albuminuria in a preclinical mouse model of DKD.

Funding

• Commercial Support – Janssen Pharmaceuticals, Johnson & Johnson