SUPPRESSION OF COLLAGEN-INDUCED ARTHRITIS BY AN ANGIOGENESIS INHIBITOR, AGM-1470, IN COMBINATION WITH CYCLOSPORINE - REDUCTION OF VASCULAR ENDOTHELIAL GROWTH-FACTOR (VEGF)

Pannus formation characterized by neovascularization is a prominent pa thologic finding in both rheumatoid arthritis (RA) and rat collagen-in duced arthritis (CIA). CIA is a T-cell-dependent process induced by im munization of inbred LOU rats with native type II collagen in incomple te Freund's adjuvant. AGM-1470 is a highly specific inhibitor of new b lood vessel formation by its effects on endothelial cell migration, en dothelial cell proliferation, and capillary tube formation. Cyclospori n A (CSA) is an immunomodulating agent that inhibits IL-2 and other cy tokine production involved in early antigen activation of T-cells. In this study the effects of single and combination therapy with AGM-1470 (27 mg/kg alternate days) and low-dose CSA (4 mg/kg/day continuous in fusion via osmotic pump) on established CLA (total n = 62) were examin ed. At Day 18 post arthritis onset, clinical arthritis was significant ly reduced in rats treated with single-agent AGM-1470 (1.88 +/- 0.33) or combination therapy (1.13 +/- 0.32) (P < 0.00001 and 0.000001, resp ectively) versus control. Single-agent CSA-treated rats, even if given CSA beginning on the day of immunization, did not attenuate arthritis severity. The longitudinal mean arthritis score of combination-treate d rats was significantly lower than that of rats receiving AGM-1470 (P < 0.0001), reflecting a more moderate early disease course in combina tion-treated rats. Disease severity in rats treated with single-agent CSA was not significantly different from control rats. Mean WBC counts , differentials, and delayed-type hypersensitivity responses were simi lar in all groups. CII antibody levels were lower in AGM-1470 protocol s compared to CSA or controls, Flow cytometry of peripheral blood, spl een, and lymph nodes demonstrated decreased levels of CD4(+) cells in rats given CSA. TNF-alpha levels remained elevated, even in treated ra ts, while vascular endothelial growth factor levels were reduced in ra ts receiving AGM-1470 compared to both arthritic controls and naive ra ts. Both single-agent and combination therapies were well tolerated, T his is the first study to examine the effects of AGM-1470 together wit h CSA. Combination therapy was more effective than single-agent therap y. The results suggest that the use of interventions with distinct mec hanisms of action may be efficacious in the treatment of RA. (C) 1995 Academic Press, Inc.