Suppression of collagen-induced arthritis by an angiogenesis inhibitor, AGM-1470, in combination with cyclosporin: reduction of vascular endothelial growth factor (VEGF).
Pannus formation characterized by neovascularization is a prominent pathologic finding in both rheumatoid arthritis (RA) and rat collagen-induced arthritis (CIA). CIA is a T-cell-dependent process induced by immunization of inbred LOU rats with native type II collagen in incomplete Freund's adjuvant. AGM-1470 is a highly specific inhibitor of new blood vessel formation by its effects on endothelial cell migration, endothelial cell proliferation, and capillary tube formation. Cyclosporin A (CSA) is an immunomodulating agent that inhibits IL-2 and other cytokine 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 infusion via osmotic pump) on established CIA (total n = 62) were examined. At Day 18 post arthritis onset, clinical arthritis was significantly 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, respectively) 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-treated rats was significantly lower than that of rats receiving AGM-1470 (P < 0.0001), reflecting a more moderate early disease course in combination-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 similar in all groups. CII antibody levels were lower in AGM-1470 protocols compared to CSA or controls. Flow cytometry of peripheral blood, spleen, and lymph nodes demonstrated decreased levels of CD4+ cells in rats given CSA. TNF-alpha levels remained elevated, even in treated rats, while vascular endothelial growth factor levels were reduced in rats receiving AGM-1470 compared to both arthritic controls and naive rats. Both single-agent and combination therapies were well tolerated. This is the first study to examine the effects of AGM-1470 together with CSA. Combination therapy was more effective than single-agent therapy. The results suggest that the use of interventions with distinct mechanisms of action may be efficacious in the treatment of RA.
D000818:Animals; D001169:Arthritis, Experimental / Q000139:chemically induced / Q000276:immunology / Q000517:prevention & control*; D003094:Collagen; D003510:Cyclohexanes; D016572:Cyclosporine / Q000009:adverse effects / Q000627:therapeutic use*; D004359:Drug Therapy, Combination; D016228:Endothelial Growth Factors / Q000037:antagonists & inhibitors* / Q000097:blood; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000627:therapeutic use*; D008222:Lymphokines / Q000037:antagonists & inhibitors* / Q000097:blood / Q000187:drug effects; D008297:Male; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D000077609:O-(Chloroacetylcarbamoyl)fumagillol; D051381:Rats; D011919:Rats, Inbred Strains; D012717:Sesquiterpenes / Q000009:adverse effects / Q000627:therapeutic use*; D014409:Tumor Necrosis Factor-alpha / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D003510:Cyclohexanes; D016228:Endothelial Growth Factors; D007166:Immunosuppressive Agents; D008222:Lymphokines; D012717:Sesquiterpenes; D014409:Tumor Necrosis Factor-alpha; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D016572:Cyclosporine; D003094:Collagen; D000077609:O-(Chloroacetylcarbamoyl)fumagillol