Experimental modelsThursday, September 29, 2005, 15:30 - 17:00
Effect of CDP323, a small molecule VLA-4 antagonist, on chronic experimental allergic encephalomyelitis in C57Bl/6 miceG. Watt, V. Gauden, K. McNeil, R. Mead, J. Rundle, T. Shock, N. Gozzard, M. Christie, R. Foulkes (Cambridge, Slough, GB)
The very late antigen (VLA)-4 / vascular cell adhesion molecule (VCAM)-1 interaction regulates leukocyte recruitment to sites of inflammation. Treatment of antibodies or small molecule antagonists of this interaction reduced disease severity in experimental allergic encephalomyelitis (EAE) models (see review by Rice et al. 2005). CDP323 is an orally active small molecule VLA-4 antagonist in clinical development. The present study describes the effect of CDP323 in chronic EAE in the C57Bl/6 mouse.
EAE was induced in adult female mice by subcutaneous (s.c.) injection of complete Freund’s adjuvant containing 0.4mg/ml Mycobacterium and 0.2mg of myelin oligodendrocyte glycoprotein (MOG) peptide 35-55 in each flank (0.15ml; days 0 and 7). Pertussis toxin was administered intraperitoneally (200ng/mouse; days 0, 1, 7 and 8). CDP323 or vehicle (2% 400cps methylcellulose, 5% DMSO and 20% PEG 400) administered s.c. once daily (u.i.d.) either prophylactically (from day -1) or therapeutically (50% incidence). Animals were assessed daily and clinical disease score recorded. The functional effect of CDP323 (24h post dose, after 24 days of dosing) was assessed using an ex vivo whole blood VLA-4/VCAM-1 binding assay.
Prophylactic treatment with CDP323 (100mg/kg s.c. u.i.d.) produced a significant reduction in disease incidence (p<0.005, Fischer’s exact test), and a significant reduction in both maximal (Vehicle, 1.41±0.30; CDP323, 0.19±0.10) and cumulative (Vehicle, 21.48±3.63; CDP323, 0.67±0.42) clinical score (p<0.001, Mann-Whitney U). Therapeutic treatment (100mg/kg s.c. u.i.d.) significantly reduced cumulative clinical score (Vehicle, 16.88±2.98; CDP323, 7.50±02.13, p<0.03, Mann-Whitney U). The effect of CDP323 was dose-related, with an ED50 value of 20mg/kg s.c. u.i.d. A dose-dependent inhibition of VLA-4/VCAM-1 binding (10mg/kg, 39±8%; 30mg/kg, 49±6%; 100mg/kg 79±2%) was obtained.
In conclusion, CDP323 significantly reduced EAE disease severity demonstrating that VLA-4 dependent mechanisms drive the initiation and maintenance of disease in this model. This efficacy is related to inhibition of VLA-4/VCAM-1 binding ex vivo.