Influence of the duration of IL‐2 receptor (IL‐2R) blockade on the incidence of acute rejection episodes in renal transplantation

Basiliximab (Simulect®) is an IL-2R (CD25) chimerized mAb for acute rejection prophlaxis. In a randomized, double-blind Phase III study enrolling 346 patients, addition of 40 mg basiliximab (20 mg on days 0 and 4) to baseline dual immunosuppressive therapy reduced the incidence of first acute rejection by 33%(basiliximab 35% vs placebo 52%) during the first 6 months posttransplant. The disposition and immunodynamics of basiliximab were characterized in 164 patients. Serum samples were collected at baseline, day 4 (prior to the second dose installment) and once each in weeks 1, 2, 3, 4, 6, 8, 12. Previous Phase 2 work demonstrated that serum concentrations exceeding 0.2 μg/ml provide complete receptor saturation on peripheral blood T-lymphocytes. Results: Receptor-saturating concentrations were maintained over the interdose period for 97% of patients. Of the 5 patients with a concentration transiently below the saturation threshold prior to the second dose, two experienced subsequent acute rejection episodes (days 24 and 25) and the other three remained rejection-free. Across all patients, receptor saturation was maintained for 36±14 days posttransplant which is consistent with their elimination half life of 7.7±3.3 days. Over the 6-month observation period, 106 of these patients remained rejection-free while a total of 88 acute rejection episodes occurred in the remaining 58 patients. The duration of receptor blockade did not differ between patients with one or more acute rejection episodes compared to their rejection-free peers: 34±14 vs 37±14 days, respectively (P= 0.2718). Rejection episodes were further subdivided into those occurring during receptor blockade and those occurring after basiliximab had cleared from serum. During receptor blockade, 34 rejection episodes occurred in 32 patients on average 21±15 days posttransplant. The serum basiliximab concentration on the day of onset was 1.11±1.09 μg/ml (range, 0.2-5.0) with no clear relationship between concentration and occurrence of rejection. Fifty-four rejection episodes occurred in 34 patients after the offset of IL-2R blockade on average 78±40 days posttransplant. Prior to these events IL-2R had been suppressed for 33±13 days which did not differ from the duration in patients who were rejection-free (P= 0.1617). Conclusion: Over the range of suppression durations observed in this study (12-91 days), extended periods of IL-2R blockade (up to 3 months posttransplant) did not appear to confer an immunoprophylactic advantage compared to shorter periods of receptor suppressio