DACLIZUMAB RAPIDLY Y SATURATES THE INTERLEUKIN-2 RECEPTOR-?? (CD25) ON LYMPH NODE LYMPHOCYTES IN CHILDREN

Abstract

232 Daclizumab (Zenapax), a genetically engineered human IgG1 monoclonal antibody (mAb) specific for the α chain of the interleukin-2 receptor (IL-2R), in combination with cyclosporine, prednisone, and azathioprine, significantly reduces the incidence of acute rejection in adults receiving their first cadaver renal allograft. Saturation of the IL-2Rα chain on peripheral blood lymphocytes (PBL) by daclizumab occurred as early as ten hours after the first dose. No data exist on tissue saturation. The purpose of the current study was to compare the degree of saturation of IL-2Rα in lymph node lymphocytes (LNL) with that of PBL at the time of transplantation in pediatric renal transplant recipients who had received daclizumab as part of a phase II open-label pharmacokinetic and safety study. From eight patients (3 to 17 years, mean 14±5) receiving their first transplant, PBL obtained prior to receiving daclizumab (1mg/kg) and PBL and LNL obtained at the time of transplant (13 ± 3.7 hours, range 4 - 15.5 after receiving daclizumab) were evaluated using flow cytometry for total IL-2Rα expression. LNL from 3 cadaver donors were used as controls. Two mAb that bind to the IL-2Rα chain were used: 2A3 binds to the same epitope as daclizumab, whereas 7G7 binds to a different epitope. A paired t-test was used to compare expression within patients and an unpaired t-test was used to compare the patient population to the controls. Prior to the initial dose of daclizumab, binding of 2A3 and 7G7 to PBL was 9.8% ± 4.7 and 6.2% ± 3.5, respectively. At the time of transplant, 2A3 expression decreased to 0.4% ± 0.5 (p=0.002 vs. baseline); there was no decrease in 7G7 binding (p = 0.17 vs. baseline). There was no significant change in the percent of total (CD3), activated (CD3/DR), CD4 or CD8 T-cells after the administration of daclizumab. Binding of 2A3 to LNL was less in patient (0.5% ± 0.5) than control LNL (5.8% ± 1.9, p< 0.001). Within patients, 2A3 LNL binding was less than binding of 7G7 (p=0.003); within controls, LNL binding of 2A3 and 7G7 was similar (mean difference 2.27%, p=0.30). There was no significant difference between the daclizumab-treated and untreated groups in the percent of B-cells, T-cells, activated T-cells, CD4 and CD8 cells. In conclusion, the daclizumab dose of 1 mg/kg previously shown to saturate the IL-2Rα chain on PBL in adults resulted in saturation of IL-2Rα on PBL in children, without affecting other T-cell subsets. Daclizumab also rapidly entered and saturated IL-2R within a solid lymphoid organ, the lymph node, a major component of the efferent limb of the immune system. Funded in part by Hoffman La Roche, Inc., Nutley, NJ.