November 10, 2005
American Society of Nephrology (ASN) Renal Week 2005, Philadelphia, Pennsylvania
Abstract TH-PO359
Session: Diabetic Nephropathy: Basic I

FG-3019, a Neutralizing CTGF Monoclonal Antibody, Provides Renal, Metabolic and Cardio-Protective Effects in Obese Type 2 Diabetic Mice. William Usinger ¹, K.T. Chong ², E. Lomongsod ¹, T. Seeley ¹, R. Stephenson ¹, W. Zhang ¹, J. Pacleb ¹, Q.J. Wang ¹, A. Flyvbjerg ³ and D.Y. Liu ¹.

1 FibroGen, Inc., SSF, CA, United States,
2 U. Miss. Med Ctr., Jackson, MS, United States,
3 Med. Res. Labs, Aarus U. Hospital, Aarus, Denmark.

Abstract: Connective tissue growth factor (CTGF) is implicated in multiple pathogenic processes that underlie the development and progression of diabetic comorbidities affecting the kidneys, heart, and eyes. CTGF is also a necessary factor in all forms of persistent or chronic fibrosis and has been implicated in proteinuria seen in diabetics. FG-3019, a human mAb reactive to human and rodent CTGF and currently in clinical trials for DN, has been shown to reduce albuminuria and to improve kidney function in hyperfiltering db/db mice, a model of obese Type 2 DN. Here, we further explored the potential of FG-3019 as a novel therapy for DN and cardiovascular disease using a model in db/db mice reported to be hypofiltering, i.e. reduced CrCl. Diabetic db/db mice were treated for two months with either FG-3019 or control human IgG (cIgG). Compared to non-diabetic mice, db/db mice exhibited elevated AER, enlarged kidneys and hearts, and increased urine volume. Diabetic mice treated with FG-3019 exhibited a significant and dose-dependent reduction of AER, had significantly reduced polyuria, and had completely normalized kidney size compared to cIgG-treated diabetic mice. These findings with FG-3019 contrast the lack of an effect of anti-TGFbeta on albuminuria and polyuria in these mice (Ziyadeh, F., et al., PNAS, 2000). FG-3019 treatment also caused dose-dependent reductions in heart weight, blood LDL and HbA1c. Elevated levels of LDL and HbA1c are important surrogate markers and risk factors for diabetic complications and metabolic syndrome. Transcript analysis of heart tissue showed an increase in extracellular matrix gene expression in db/db mice that was reduced by antibody treatment. These data demonstrate a direct and causative role for CTGF in cardiovascular pathology. Blocking the activity of CTGF with FG-3019 represents a potential therapeutic approach to the prevention and treatment of DN and diabetes-associated metabolic and cardiovascular disorders.