October 29, 2004
American Society of Nephrology (ASN) Renal Week 2004, St. Louis, Missouri
Abstract F-PO900
Poster: Diabetes Mellitus: Pathology, Growth Factors and Extracellular Matrix

Long-Term Renal Effects of a Neutralizing Connective Tissue Growth Factor (CTGF)- Antibody in Obese Type 2 Diabetic Mice. A. Flyvbjerg, D. Khatir, L.J.N. Jensen, E. Lomongsod, D.Y. Liu, R. Rasch, W.R. Usinger. Medical Research Laboratories, Aarhus University Hospital, Aarhus, Denmark; FibroGen, Inc., So. San Francisco, CA.

CTGF is strongly implicated as a pathogenic factor in diabetic kidney disease. Elevated levels of CTGF in the urine, plasma and kidney correlate with the severity and progression of nephropathy in diabetes. FG-3019, a fully human IgG1 kappa monoclonal antibody (mAb) reactive to human CTGF (200 nM Kd), has been shown to significantly reduce collagen deposition in preclinical rodent models of fibrosis. These models may underestimate the effects of FG-3019 in humans, as the affinity of FG-3019 for rodent CTGF is 3-fold lower than for human CTGF. To explore a specific role for CTGF in renal pathology in type 2 diabetes, we examined the effects of FG-3019 in db/db mice, a model of obese type 2 diabetes. Diabetic db/db mice and nondiabetic db/+ mice were treated for two months with either FG-3019 or control human IgG (cIgG). FG-3019 treatment did not affect overall weight gain, blood glucose levels, urinary CTGF levels, or food intake in either strain. Diabetic control mice exhibited elevated levels of urinary CTGF and urinary albumin excretion (UAE), hyperfiltration as demonstrated by elevated creatinine clearance (CrCl), enlarged kidneys and increased urine volume. Diabetic mice treated with FG-3019 had normalized kidney filtration as evidenced by CrCl levels reduced by 82% (p<0.01) and exhibited a 69% reduction in UAE (p<0.01). FG-3019 treatment also significantly reduced kidney weight (p<0.05, not the result of reduced glomerular volume) and urine volume (p<0.01), compared to cIgG-treated diabetic mice.

In conclusion, CTGF mediates early and critical features of renal pathology, including morphological and functional changes, in an animal model of type 2 diabetes. Blocking the activity of CTGF with FG-3019 represents a novel therapeutic approach to the prevention and treatment of diabetic nephropathy.

Honoraria: Authors EL, DYL and WRU are employees of FibroGen, Inc. So. San Francisco, CA

See also November 1, 2004 press release