Suppression of collagen-induced arthritis by an angiogenesis inhibitor, AGM-1470, in combination with cyclosporin: reduction of vascular endothelial growth factor (VEGF)

Cell Immunol. 1995 Dec;166(2):196-206. doi: 10.1006/cimm.1995.9978.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Arthritis, Experimental / chemically induced
  • Arthritis, Experimental / immunology
  • Arthritis, Experimental / prevention & control*
  • Collagen*
  • Cyclohexanes
  • Cyclosporine / adverse effects
  • Cyclosporine / therapeutic use*
  • Drug Therapy, Combination
  • Endothelial Growth Factors / antagonists & inhibitors*
  • Endothelial Growth Factors / blood
  • Immunosuppressive Agents / adverse effects
  • Immunosuppressive Agents / therapeutic use*
  • Lymphokines / antagonists & inhibitors*
  • Lymphokines / blood
  • Lymphokines / drug effects
  • Male
  • Neovascularization, Pathologic / prevention & control*
  • O-(Chloroacetylcarbamoyl)fumagillol
  • Rats
  • Rats, Inbred Strains
  • Sesquiterpenes / adverse effects
  • Sesquiterpenes / therapeutic use*
  • Tumor Necrosis Factor-alpha / drug effects
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factors


  • Cyclohexanes
  • Endothelial Growth Factors
  • Immunosuppressive Agents
  • Lymphokines
  • Sesquiterpenes
  • Tumor Necrosis Factor-alpha
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factors
  • Cyclosporine
  • Collagen
  • O-(Chloroacetylcarbamoyl)fumagillol