Abstract: FR-OR060

CCR2 Inhibitor Improves Renal Function and Structure in Murine Models of Focal Segmental Glomerulosclerosis (FSGS)

Session Information

Category: Glomerular

  • 1001 Glomerular: Basic/Experimental Immunology and Inflammation

Authors

  • Miao, Zhenhua, ChemoCentryx, Mt View, California, United States
  • Singh, Rajinder, ChemoCentryx, Mt View, California, United States
  • Ertl, Linda, ChemoCentryx, Mt View, California, United States
  • Mcmahon, Jeffrey P., ChemoCentryx, Mt View, California, United States
  • Zhao, Bin N., ChemoCentryx, Mt View, California, United States
  • Campbell, James J., ChemoCentryx, Mt View, California, United States
  • Liu, Xiaoli, ChemoCentryx, Mt View, California, United States
  • Dang, Ton Hy, ChemoCentryx, Mt View, California, United States
  • Miao, Shichang, ChemoCentryx, Mt View, California, United States
  • Schall, Thomas J., ChemoCentryx, Mt View, California, United States
Background

FSGS is the most common primary glomerular disorder causing in at least 4% of patients with ESRD. The current SOC includes renin-angiotensin-aldosterone (RAAS) inhibitors, steroids and/or immunosuppresants. Several lines of evidence support a role for chemokine receptor 2 (CCR2) positive monocyte/macrophages in the pathogenesis of FSGS, and inhibition of CCR2 presents a potential therapeutic treatment of FSGS.

Methods

Two murine models of FSGS, 5/6 nephrectomy and Adriamycin nephropathy were used to investigate the efficacy of either CCR2 antagonist alone or in combination with RAAS inhibitor candesartan (CST). Kidney injury was assessed by proteinuria (UAER), UACR, BUN, serum creatinine and histopathology.

Results

In the 5/6 nephrectomy model, mice had a rapid reduction in UAER when treated with either the CCR2 antagonist (42% reduction by week 1) or RAAS inhibitor (69% reduction). Addition of the CCR2 antagonist to RAAS inhibitor further reduced the UAER (92% reduction; p < .005 versus RAAS inhibitor alone). The same renal protective effects of CCR2 blockade were seen in the Adriamycin nephropathy model. UAER was significantly reduced by administration of CCR2 antagonist (66% reduction; p = .05 versus vehicle), but not by RAAS inhibitor alone. Furthermore, the combination of the CCR2 antagonist and RAAS inhibition resulted in an additive effect (74% reduction; p = .027 versus vehicle) in Adriamycin nephropathy model. The combination of the CCR2 antagonist and RAAS inhibitor significantly reduced serum creatinine and BUN. Histological parameters also improved with CCR2 antagonist treatment and/or RAAS inhibitor. The combination of the CCR2 antagonist and RAAS inhibition reduced tubulointerstitial injury (including inflammation, fibrosis, tubular casts and dilatation) and glomerular injury (including glomerular hypertrophy, mesangial expansion and glomerular sclerosis).

Conclusion

CCR2 inhibition provides significant and rapid renal protection in two models of FSGS, as measured by renal functions and histological parameters, and thus represents a novel and mechanistically distinct approach for the treatment of FSGS. We are moving forward to initiate a clinical trial in the treatment of FSGS with our late stage drug candidate CCR2 antagonist CCX140.

Funding

  • Commercial Support