Abstract: FR-PO477

Blockade of the Chemokine Receptor CX3CR1 with a Single Chain Antibody Reduces the Progression of Atherosclerosis and Glomerulosclerosis in Mice

Session Information

Category: Chronic Kidney Disease (Non-Dialysis)

  • 303 CKD: Epidemiology, Outcomes - Cardiovascular

Authors

  • Kerr, Steven W., Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, Connecticut, United States
  • Nie, Xingtie, Boehringer-ingelheim company, Danbury, Connecticut, United States
  • Qian, Hu Sheng, Boehringer Ingelheim Pharmaceuticals, Inc, Ridgefield, Connecticut, United States
  • Broadwater, John, Boehringer Ingelheim, Ridgefield, Connecticut, United States
  • Berger, Valentina, Boehringe-Ingelheim Pharm, Ridgefield, Connecticut, United States
  • Villalona, Jorge L., Boehringer Ingelheim Pharmaceuticals , Ridgefield, Connecticut, United States
  • Dave, Rajvee, Boehringer Ingelheim Pharmaceuticals , Ridgefield, Connecticut, United States
  • Wang, Hong, Boehringer Ingelheim Pharmaceuticals , Ridgefield, Connecticut, United States
  • O'Neill, Margaret M., Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Alabama, United States
  • Toth, Joshuaine, Boehringer Ingelheim, Ridgefield, Connecticut, United States
  • Mcfarland, Mary, Beoheringer Ingelheim Pharmaceuticals, Ridgefield, Connecticut, United States
  • Pantages, Lynn, Boehringer Ingelheim Pharmaceuticals, Inc, Ridgefield, Connecticut, United States
Background

The fractalkine receptor CX3CR1 regulates leukocyte trafficking during inflammation and is associated with cardiovascular disease risk. We developed a high-affinity, selective, single chain antibody that targets human CX3CR1, designated BI655088. Since cardiovascular disease is the major cause of morbidity and mortality in patients with chronic kidney disease, we used a cardiorenal model to evaluate atherosclerosis and renal parameters.

Methods

Therefore, BI655088 was administered at 30mg/kg i.p. 2x/wk for 12 weeks to hyperlipidemic ApoE-/- mice expressing the human CX3CR1 gene and induced renal insufficiency by performing a uninephrectomy.

Results

BI655088 significantly reduced atherosclerotic plaque area by 28% compared to vehicle-treated mice with no change in total cholesterol or triglycerides. In addition, BI655088 significantly reduced glomerulosclerosis incidence by 43% and severity in the remnant kidney. This effect was accompanied by a significant decrease in macrophage infiltration consistent with the mechanism of action. Plasma levels of fractalkine, used as a biomarker for antibody blockade of CX3CR1, were significantly increased in treated animals. In order to evaluate the potential effect of BI655088 for treating diabetic nephropathy, BI655088 was tested in streptozotocin-treated C57BL/6 mice transgenic for the human CX3CR1 gene. BI655088 dosed at 30, 3, and 0.3mg/kg i.p. 2x/wk for 12 weeks showed dose dependent decreases in both glomerulosclerosis, (-46%, -27%, and -15%), and interstitial lesions (-56%, -33%, and -16%), respectively, compared to vehicle-treated mice with no effect on glucose levels.

Conclusion


These results demonstrate that treatment with the CX3CR1 antagonist BI655088 can mitigate both renal and vascular injury induced in diabetic and hyperlipidemic mouse models.