BACKGROUND We report the safety profile, pharmacokinetics (PK), and pharmacodynamics (PD) of siplizumab, a humanized IgG1 anti-CD2 monoclonal antibody and potential agent for preventing renal allograft rejection, in a phase 1 study in renal allograft recipients. METHODS Subjects on conventional immunosuppressive regimens received 2 infusions (4-6 and 60-72 hours postsurgery) of siplizumab (0.012, 0.06, or 0.12 mg/kg per dose). Adverse events (AEs) were recorded for 33 days. Serum siplizumab concentrations were measured and PD was assessed by flow cytometry and NK in vitro cytotoxicity. RESULTS Thirteen renal allograft recipients were enrolled. Two patients had mild infusion reactions with single temperature elevations of 38.2 degrees C and 38.6 degrees C, respectively. Eight patients had siplizumab-related AEs: lymphopenia (7 patients), anemia (3), chills (2), and nausea (2). Mean natural killer (NK) cell cytotoxicity decreased after the first dose, but exceeded pretreatment values by day 33 in all patients. No anti-siplizumab antibodies were detected. The 0.012 mg/kg group did not achieve quantifiable siplizumab serum concentrations. By the second dose, mean peak concentrations were 958 ng/mL, with mean T(1/2) of 29 hours, in the 0.06 mg/kg group, and 2870 ng/mL, with mean T(1/2) of 49 hours, in the 0.12 mg/kg group. Mean total lymphocyte and CD2(+) lymphocyte counts declined after the first infusion and rose by day 8 in all groups despite a second infusion of siplizumab. Lymphocyte counts returned to pretreatment levels by day 60. CONCLUSIONS Siplizumab exhibited an acceptable safety profile in this study. Detectable siplizumab concentrations were maintained for 3 days after the second dose at the 2 highest dose levels.