PRELIMINARY RESULTS OF THE COMBINED USE OF A HUMANIZED ANTI-IL-2Rα MONOCLONAL ANTIBODY, DACLIZUMAB (DZB), AND MYCOPHENOLATE MOFETIL (MMF) WITHOUT CALCINEURIN INHIBITORS IN RENAL TRANSPLANTATION

Abstract

750 Calcineurin inhibitors are associated with efficacy-limiting adverse effects, particularly nephrotoxicity, which may limit long term graft survival. The established efficacy and safety of either DZB or MMF in multicenter trials have led to regulatory approval of each drug administered concomitantly with cyclosporine (CsA) and corticosteroids (CS). The present study explores the combination of DZB and MMF with CS, in the absence of CsA or FK-506, in recipients of primary (non-HLA identical) renal allografts. The regimen includes 5 doses of DZB administered IV every 2 weeks starting at the time of transplant (first dose 2 mg/kg, subsequent doses 1 mg/kg); and MMF 1.5 gm po bid for the first 6 months posttransplant (posttx), tapered to 1.0 gm po bid thereafter. Preliminary data on the first 50 patients on study with follow-up ranging from 38 to 214 days (mean 77d) are included in this report. Demographics include: 32 CRT, 11 LRT, 7 LURT; 31 male, 19 female; and mean age 47.6 years. Acute rejection episodes (ARs) occurred in 13 patients (7 CRT, 3 LRT, 3 LURT) from 6 to 73d posttx (mean d31; median d29). One of 13 patients experienced a second AR at d41 (first AR d18). The histological severity of the first AR according to the Banff criteria were: grade I (n=7) and grade IIB (n=6). Anti-rejection treatment included high dose IVCS (grade I ARs) or IVCS/OKT3(grade IIB ARs) in 7 and 6 patients, respectively. Calcineurin inhibitors were initiated in 12 patients with AR (10 FK-506, 2 CsA); the patient who experienced two ARs started CsA after the second episode. The mean serum creatinine one month posttx was 1.4 mg/dl. To date, one episode of CMV viremia, but no malignancy, graft loss or patient death have been reported. The percent circulating lymphocytes (PBL) with detectable surface IL-2Rα decreased from 28±7% pretreatment to 0 (n=23) within 48h after the first dose of DZB. Lymphocytes obtained from lymph nodes at the time of engraftment (n=12) showed no detectable surface IL-2Rα from 1 to 10h after the first dose of DZB. At 4 months posttx (2 months after last dose of DZB), only 2±1% of PBL (n=7) showed detectable surface IL-2Rα. In six patients with available data, serum DZB levels were in the expected range assuming linear pharmacokinetics. These preliminary results demonstrate that the combination of DZB and MMF in the absence of calcineurin inhibitors appears to have a satisfactory safety and efficacy profile in the prevention of acute rejection in the early stage after renal transplantation.