Phase I safety and pharmacokinetic study of CT-011, a humanized antibody interacting with PD-1, in patients with advanced hematologic malignancies
Phase I safety and pharmacokinetic study of CT-011, a humanized antibody interacting with PD-1, in patients with advanced hematologic malignancies
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DOI：
10.1158/1078-0432.ccr-07-4079
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发表时间：
2008-05-15
影响因子：
11.5
通讯作者：
Nagler, Arnon
中科院分区：
文献类型：
--
作者：
Berger, Raanan;Rotem-Yehudar, Rinat;Nagler, Arnon
目的：CT - 011是一种人源化IgG1单克隆抗体，它通过与程序性死亡受体1（PD - 1）相互作用来调节免疫应答，PD - 1是一种存在于淋巴细胞上的属于137受体家族的蛋白质。这项I期研究的目的是评估剂量限制性毒性，确定最大耐受剂量，并研究CT - 011在晚期血液系统恶性肿瘤患者中单次给药的药代动力学。
实验设计：17名患者接受了剂量递增的CT - 011治疗，剂量范围从0.2到6 mg/kg。为进行药代动力学分析，在治疗前、治疗后即刻以及24小时、48小时和第7、14、21天从患者身上采集血样。使用特异性酶联免疫吸附测定（ELISA）评估CT - 011的血药浓度，并利用所得浓度计算药代动力学参数。通过测量外周血CD4(+)、CD8(+)和CD69(+)淋巴细胞来评估免疫系统的激活情况。
结果：研究表明该抗体在这一患者群体中是安全的且耐受性良好。本研究未确定单一的最大耐受剂量。33%的患者观察到临床获益，其中1例完全缓解。药代动力学分析显示，CT - 011的血清最大浓度（Cmax）和曲线下面积（AUC）与剂量成比例增加。CT - 011的中位半衰期（t1/2）范围为217到410小时。在CT - 011治疗后长达21天观察到外周血CD4(+)淋巴细胞百分比持续升高。
结论：在晚期血液系统恶性肿瘤患者中，单次给予0.2到6.0 mg/kg的CT - 011是安全的且耐受性良好。
Purpose: CT-011 is a humanized IgG1 monoclonal antibody that modulates the immune response through interaction with PD-1, a protein belonging to the 137 receptor family present on lymphocytes. The objectives of this phase I study were to assess the dose-limiting toxicities, to determine the maximum tolerated dose, and to study the pharmacokinetics of CT-011 administered once to patients with advanced hematologic malignancies.Experimental Design: Seventeen patients were treated with escalating doses of CT-011 ranging from 0.2 to 6 mg/kg. For pharmacokinetic analysis, blood samples were withdrawn from the patients before and immediately after treatment and at 24 hours, 48 hours, and on days 7,14, and 21. CT-011 blood levels were assessed with a specific ELISA and derived concentrations were used to calculate pharmacokinetic parameters. Activation of the immune system was assessed by measuring peripheral blood CD4(+), CD8(+), and CD69(+) lymphocytes.Results: The study showed the antibody to be safe and well tolerated in this patient population. No single maximum tolerated dose was defined in this study. Clinical benefit was observed in 33% of the patients with one complete remission. Pharmacokinetic analyses show that serum Cm,x and the AUC of CT-011 increased proportionally with dose. The median t(1/2) of CT-011 ranged from 217 to 410 hours. Sustained elevation in the percentage of peripheral blood CD4(+) lymphocytes was observed up to 21 days following CT-011 treatment.Conclusions: A single administration of 0.2 to 6.0 mg/kg of CT-011 is safe and well tolerated in patients with advanced hematologic malignancies.