Pharmacokinetics and immunodynamics of chimeric IL-2 receptor monoclonal antibody SDZ CHI 621 in renal allograft recipients

Abstract

SDZ CHI 621 is a murine-human chimeric monoclonal antibody (mAb) to the interleukin-2 (IL-2) receptor (CD25) intended for prophylactic immunosuppression against acute rejection in the first several weeks following kidney transplantation. A multicentre, prospective, dose-finding study was conducted in 37 primary, mismatched cadaver kidney transplant patients to assess its tolerability, pharmacokinetics and immunodynamics. Successive cohorts of patients were stratified to receive total doses of 20, 30, 40 or 60 mg (n = 4, 4, 14, 15, respectively) administered as 15- or 20-mg intravenous infusions with the first dose given preoperatively and subsequent doses within the first 10 days posttransplant. Daily mAb serum concentrations were analysed by a radioimmunoassay method and the percentage of peripheral T-lymphocytes expressing CD25 from serial blood samples was determined by FACScan. Intravenous administrations were well tolerated. mAb concentration profiles exhibited a biphasic decline with an initial t_1/2 of 14.4 ± 14.2 h, terminal t_1/2 of 13.4 ± 6.0 days, distribution volume (V_ss) of 6.9 ± 3.31 and clearance of 17.4 ± 7.8 ml/h. The concentration-effect (mAb-CD25) relationship indicated that mAb concentrations exceeding a threshold of about 0.7.µg/ml corresponded to complete suppression of CD25 (≤ 3% CD25⁺ T-cells). The threshold mAb concentration was exceeded at all dose levels, whereas the duration above the threshold (and thus of CD25 suppression) rose with increasing dose: 20 mg, 20 ± 7 days; 30 mg, 32 ± 6 days; 40 mg, 37 ± 10 days; and 60 mg, 53 ± 17 days. As mAb concentrations declined below the threshold following the last dose, CD25 expression returned to baseline (18–44% CD25⁺ T-cells) within a few days.