Furie Richard, Stohl William, Ginzler Ellen M, Becker Michael, Mishra Nilamadhab, Chatham Winn, Merrill Joan T, Weinstein Arthur, McCune W Joseph, Zhong John, Cai Wendy, Freimuth William
Division of Rheumatology and Allergy-Clinical Immunology, North Shore Long Island Jewish Health System, Marcus Avenue, Lake Success, New York 11042, USA.
Arthritis Res Ther. 2008;10(5):R109. doi: 10.1186/ar2506. Epub 2008 Sep 11.
This trial evaluated the safety, biologic activity, and pharmacokinetics of belimumab, a fully human monoclonal antibody that inhibits the biologic activity of the soluble form of the essential B-cell survival factor B-lymphocyte stimulator (BLyS) in patients with systemic lupus erythematosus (SLE).
Seventy patients with mild-to-moderate SLE were enrolled in a phase I, double-blind, randomized study and treated with placebo (n = 13) or belimumab (n = 57) at four different doses (1.0, 4.0, 10, and 20 mg/kg) as a single infusion or two infusions 21 days apart. Patients were followed for 84 to 105 days to assess adverse events, pharmacokinetics, peripheral blood B-cell counts, serology, and SLE disease activity. Data from the study were summarized using descriptive statistics. chi2 type tests were used to analyze discrete variables. The Kruskal-Wallis test, the Wilcoxon test, and the analysis of covariance were used to analyze the continuous variables, as appropriate. The analysis was performed on all randomized patients who received study agent.
The incidences of adverse events and laboratory abnormalities were similar among the belimumab and placebo groups. Belimumab pharmacokinetics were linear across the 1.0 to 20 mg/kg dose range. Long terminal elimination half-life (8.5 to 14.1 days), slow clearance (7 ml/day per kg), and small volume of distribution (69 to 112 ml/kg) were consistent with a fully human antibody. Significant reductions in median percentages of CD20+ B cells were observed in patients treated with a single dose of belimumab versus placebo (day 42: P = 0.0042; and day 84: P = 0.0036) and in patients treated with two doses of belimumab versus placebo (day 105: P = 0.0305). SLE disease activity did not change after one or two doses of belimumab.
Belimumab was well tolerated and reduced peripheral B-cell levels in SLE patients. These data support further studies of belimumab in autoimmune disorders.
本试验评估了贝利尤单抗的安全性、生物学活性和药代动力学。贝利尤单抗是一种全人源单克隆抗体，可抑制系统性红斑狼疮（SLE）患者体内必需B细胞存活因子B淋巴细胞刺激因子（BLyS）可溶性形式的生物学活性。
70例轻至中度SLE患者参加了一项I期双盲随机研究，接受安慰剂（n = 13）或贝利尤单抗（n = 57）治疗，贝利尤单抗采用四种不同剂量（1.0、4.0、10和20 mg/kg），单次输注或间隔21天进行两次输注。对患者进行84至105天的随访，以评估不良事件、药代动力学、外周血B细胞计数、血清学和SLE疾病活动度。研究数据采用描述性统计进行总结。采用卡方检验分析离散变量。根据情况，使用Kruskal-Wallis检验、Wilcoxon检验和协方差分析来分析连续变量。对所有接受研究药物的随机分组患者进行分析。
贝利尤单抗组和安慰剂组不良事件和实验室异常的发生率相似。在1.0至20 mg/kg剂量范围内，贝利尤单抗的药代动力学呈线性。较长的终末消除半衰期（8.5至14.1天）、缓慢的清除率（每千克体重7 ml/天）和较小的分布容积（69至112 ml/kg）与全人源抗体一致。与安慰剂相比，接受单次剂量贝利尤单抗治疗的患者（第42天：P = 0.0042；第84天：P = 0.0036）以及接受两次剂量贝利尤单抗治疗的患者（第105天：P = 0.0305），CD20+B细胞的中位数百分比均显著降低。接受一剂或两剂贝利尤单抗治疗后，SLE疾病活动度未发生变化。
贝利尤单抗耐受性良好，可降低SLE患者外周B细胞水平。这些数据支持对贝利尤单抗在自身免疫性疾病中的进一步研究。
