DAB(486)IL-2 FUSION TOXIN IN REFRACTORY RHEUMATOID-ARTHRITIS

Objective. To evaluate the safety and antiarthritic effects of DAB486I L-2. This agent is a fusion toxin and the product of a synthetic gene, engineered by replacing the codons for the receptor-binding domain of diphtheria toxin (DT) with the codons for human interleukin-2 (IL-2). DAB486IL-2 targets cells expressing the 2-chain, high-affinity form o f the IL-2 receptor (IL-2R), and achieves selective diphtheria toxin-m ediated cytotoxicity of activated T cells by inhibition of protein syn thesis. Methods. Nineteen patients with rheumatoid arthritis (RA) that had been refractory to methotrexate participated in an open-label, ph ase I/II trial evaluating 3 dose levels of intravenous DAB486IL-2 give n for 5 or 7 consecutive days. Thirteen patients received additional c ourses, at higher doses if the original response had been inadequate o r at an equivalent dose if the original course produced a response, fo r a total of 38 courses. Arthritis response was assessed at 28 days, w ith biweekly followup of patients with substantial response (greater-t han-or-equal-to 50% improved) or meaningful response (greater-than-or- equal-to 25% improved). Laboratory monitoring included measurement of CD4+ cells and circulating shed IL-2R. Results. Nine of 19 patients tr eated with high- or medium-dose DAB486IL-2 had a substantial or meanin gful response after 1 or 2 treatment courses. No significant responses occurred with the low-dose regimen. Clinical benefit was rapid, with full effect noted by 14 days following completion of infusions. Antibo dies to DT developed in all patients, or levels of preexisting antibod ies were boosted. Adverse effects included transient elevation of tran saminase levels (55 % of the patients), fever (40 %), nausea or anorex ia (30 %), hypersensitivity (6 %), and thrombocytopenia (5 %). Repeat courses were associated with less transaminase elevation and were clin ically effective despite induction of anti-DT antibodies. Conclusion. The results of this open trial provide preliminary evidence for a pote ntial therapeutic effect of DAB486IL-2 in RA, with an acceptable safet y profile. Reversible transaminase elevations limit escalation of the dosage beyond 0.1 mg/kg/day. A controlled study of DAB486IL-2 is requi red to determine the efficacy of this high-affinity IL-2R-targeted fus ion toxin in the treatment of RA.