Pruett T L, McGory R W, Wright F H, Pescovitz M D, Yang H, McClain J B
University of Virginia Health Systems, Department of Surgery, Charlottesville, Virginia, USA.
Transplant Proc. 2009 Nov;41(9):3655-61. doi: 10.1016/j.transproceed.2009.06.226.
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.
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.
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.
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.
我们在一项针对肾移植受者的1期研究中报告了西普利珠单抗（一种人源化IgG1抗CD2单克隆抗体，也是预防肾移植排斥反应的潜在药物）的安全性、药代动力学（PK）和药效动力学（PD）。
接受常规免疫抑制方案的受试者接受2次西普利珠单抗输注（术后4 - 6小时和60 - 72小时）（每剂量0.012、0.06或0.12 mg/kg）。记录33天的不良事件（AE）。测量血清西普利珠单抗浓度，并通过流式细胞术和NK细胞体外细胞毒性评估PD。
招募了13名肾移植受者。2名患者出现轻度输注反应，体温分别单次升高至38.2℃和38.6℃。8名患者出现与西普利珠单抗相关的AE：淋巴细胞减少（7名患者）、贫血（3名）、寒战（2名）和恶心（2名）。首次给药后平均自然杀伤（NK）细胞细胞毒性降低，但在第33天时所有患者均超过预处理值。未检测到抗西普利珠单抗抗体。0.012 mg/kg组未达到可量化的西普利珠单抗血清浓度。到第二次给药时，0.06 mg/kg组的平均峰值浓度为958 ng/mL，平均半衰期（T(1/2)）为29小时；0.12 mg/kg组的平均峰值浓度为2870 ng/mL，平均T(1/2)为49小时。首次输注后所有组的平均总淋巴细胞和CD2(+)淋巴细胞计数均下降，尽管再次输注西普利珠单抗，但在第8天时均升高。淋巴细胞计数在第60天时恢复到预处理水平。
在本研究中西普利珠单抗表现出可接受的安全性。在2个最高剂量水平下，第二次给药后可检测到的西普利珠单抗浓度维持了3天。
