The anti-inflammatory effect of A₃ adenosine receptor agonists: a novel targeted therapy for rheumatoid arthritis

Targeting the A₃ adenosine receptor (A₃AR) to combat inflammation is a new concept based on two findings. First, A₃AR is highly expressed in inflammatory cells, whereas low expression is found in normal tissues. This receptor was also found to be overexpressed in peripheral blood mononuclear cells, reflecting receptor status in the remote inflammatory process. Second, A₃AR activation with a specific agonist induces de-regulation of the NF-κB signaling pathway in inflammatory cells, as well as initiation of immunomodulatory effects. The A₃AR agonist CF-101 (known generically as IB-MECA) induces anti-inflammatory effects in experimental animal models of collagen- and adjuvant-induced arthritis. Combined therapy with CF-101 and methotrexate in adjuvant-induced arthritis rats yielded an additive anti-inflammatory effect. Methotrexate induced upregulation of A₃AR, rendering the inflammatory cells more susceptible to CF-101. In Phase I and in Phase IIa human studies, CF-101 was safe, well tolerated and showed strong evidence of an anti-inflammatory effect in rheumatoid arthritis patients. In peripheral blood mononuclear cells withdrawn from the patients at base line, a statistically significant correlation between A₃AR expression level and response to the drug was noted. It is suggested that A₃AR may serve as a biologic marker to predict patient response to the drug. Taken together, this information suggests that A₃AR agonists may be a new family of orally bioavailable drugs to be developed as potent inhibitors of autoimmune–inflammatory diseases.