A PHASE-I TRIAL OF HUMANIZED ANTI-INTERLEUKIN 2 RECEPTOR ANTIBODY IN RENAL-TRANSPLANTATION

The efficacy of murine monoclonal anti-interleukin 2 or chain receptor (Tac) antibodies is Limited by a short half-life and the development of antibodies to the heterologous protein, The safety, pharmacokinetic s-dynamics, and immunosuppressive effect of a humanized anti-Tac antib ody (HAT) was evaluated in 12 renal transplant recipients, Ten patient s received living related transplants (three HLA-identical matches and seven one-haplotype or zero-haplotype matches) and two patients recei ved cadaver organs, The patients were divided into four HAT treatment arms: 0.5 mg/kg/week (n=4), 1 mg/kg/week (n=2), 0.5 mg/kg every other week (n=3), and 1 mg/kg every other week (n=3). The first dose of HAT was given within 12 hr before transplantation, and four additional dos es were given after transplantation. Patients were also placed on cycl osporine, steroids, and azathioprine, Only one patient, a recipient of a cadaver kidney in the lowest HAT treatment arm, had a reversible re jection episode, The 10 recipients of living related transplants were compared with 17 historical controls treated with an identical immunos uppressive regimen except for HAT. Whereas none of the HAT-treated liv ing related donor recipients had a rejection episode, 6 of 17 (41%) of the historical controls had a rejection episode in the first year aft er transplantation. There were no first-dose reactions after HAT thera py or other subsequent side effects, None of the patients experienced opportunistic infections or malignancies. One patient developed low-ti ter anti-HAT antibodies, although the patient maintained high serum HA T concentrations throughout the study, Immune monitoring showed that t here were no changes in the percentage or absolute counts of CD3 cells or T-cell subsets after HAT therapy, However, there was a significant decrease in the number of circulating lymphocytes that expressed free Tac. The overall harmonic mean half-life of HAT was 273 hr, The resul ts of this study indicate that HAT given at 1 mg/kg every other week f or a total of five doses may provide therapeutic HAT concentration lev els and result in good saturation of Tac receptors for at least 12 wee ks after transplantation. In summary, HAT is safe and is well tolerate d by patients. Its long half-life and lack of immunization could make it a very useful immunosuppressive drug.