November 10, 2005
American Society of Nephrology (ASN) Renal Week 2005, Philadelphia, Pennsylvania
Abstract TH-PO368
Session: Diabetic Nephropathy: Basic I

Anti-CTGF Antibody Therapy With FG-3019 Prevents Diabetes-induced Increase in Vascular Complications in Streptozotocin (STZ) Treated Rats. Ingrid Langsetmo, Christopher T. Jacob, Blake Nichols, Weihua Zhang, Noelynn Oliver, David Y. Liu. FibroGen, Inc. 225 Gateway Blvd., SSF, CA 94080

Abstract: Cardiovascular disease is the leading cause of morbidity and mortality in diabetic patients with renal disease. Both atherosclerosis and increased vascular permeability represent significant pathologies in this context. CTGF has been shown to be required to induce all forms of persistent fibrosis, and also has been implicated as a major factor involved in the pathogenesis of cardiovascular complications of diabetes. Diabetic patients undergo arterial stiffening, which has been implicated as an independent risk factor in cardiovascular mortality. To investigate the effects of FG-3019 (a fully human mAb reactive to human and rodent CTGF currently in clinical trials) on diabetic vascular complications, diabetes was induced in rats by injection of STZ. Animals were treated with control IgG, FG-3019 or captopril. Diabetic rats treated with IgG or captopril demonstrated increases in arterial stiffness compared to non-diabetic control animals. Specifically, force-pressure curves from carotid arteries of diabetic animals demonstrated increased axial stiffness of the arteries in IgG and captopril treated animals. Pressure-diameter curves demonstrated increased circumferential stiffness of the carotid arteries in diabetic animals treated with IgG or captopril. In contrast, both axial and circumferential stiffness of the carotid arteries of diabetic animals treated with FG-3019 remained similar to that of healthy control animals. Morphologic evaluations of arterial sections demonstrated an increase in adventitial thickening in diabetic rats, which was prevented by treatment with FG-3019 but not captopril. In addition, FG-3019 prevented diabetes-induced increases in skin vascular permeability. In summary, treatment with FG-3019 prevented the increase in biaxial stiffness of the carotid artery induced by diabetes and also reduced diabetes-induced capillary leakage. Since these benefits were not seen with captopril, FG-3019 may address pathways not affected by ACEi and may provide a novel therapeutic approach to treating micro and macrovascular complications associated with diabetes in a clinical setting.