Phase I Trial of Weekly Tigatuzumab, an Agonistic Humanized Monoclonal Antibody Targeting Death Receptor 5 (DR5)
Phase I Trial of Weekly Tigatuzumab, an Agonistic Humanized Monoclonal Antibody Targeting Death Receptor 5 (DR5)
复制标题
DOI：
10.1089/cbr.2009.0673
复制
发表时间：
2010-02-01
影响因子：
3.4
通讯作者：
Saleh, Mansoor
中科院分区：
文献类型：
--
作者：
Forero-Torres, Andres;Shah, Jatin;Saleh, Mansoor
背景资料：TRA-8是针对死亡受体5（DR 5）的鼠激动剂单克隆抗体，其能够在不借助于交联的情况下触发DR 5阳性人肿瘤细胞中的细胞凋亡。在小鼠异种移植模型中，已证明其对多种实体瘤具有体外和体内细胞毒性抗肿瘤功效。Tigatuzumab是一种人源化的TRA-8单克隆抗体。方法：在16例复发/难治性恶性肿瘤和1例淋巴瘤患者中进行Tigatuzumab的I期临床试验，以确定其最大耐受剂量（MTD）、药代动力学、免疫原性和安全性。结果：17例患者入组，9例在1-、2-和4-mg/kg剂量组（每组3例），8例在8-mg/kg剂量组。Tigatuzumab耐受性良好，未观察到DLT，未达到MTD。无研究药物相关的3级或4级肾、肝或血液学毒性。血浆半衰期为6-10天，未检测到抗替加珠单抗应答。七（7）例患者病情稳定，反应持续时间为81至798 days.Conclusions：Tigatuzumab耐受性良好，未达到MTD。病情稳定的患者数量较多，表明具有抗肿瘤活性。
Background: TRA-8 is a murine agonist monoclonal antibody to death receptor 5 (DR5), which is able to trigger apoptosis in DR5 positive human tumor cells without the aid of crosslinking. It has demonstrated cytotoxicity in vitro and in vivo antitumor efficacy to a wide range of solid tumors in murine xenograft models. Tigatuzumab is a humanized IgG1 monoclonal antibody derived from TRA-8.Methods: A phase I trial of tigatuzumab in patients with relapsed/refractory carcinomas (n = 16) or lymphoma (n = 1) was designed to determine the maximal tolerated dose (MTD), pharmacokinetics, immunogenicity, and safety. Three to six (3-6) patients were enrolled in successive escalating cohorts at doses ranging from 1 to 8 mg/kg weekly.Results: Seventeen (17) patients enrolled, 9 in the 1-, 2-, and 4-mg/kg dose cohorts (3 in each cohort) and 8 in the 8-mg/kg dose cohort. Tigatuzumab was well tolerated with no DLTs observed, and the MTD was not reached. There were no study-drug-related grade 3 or 4, renal, hepatic, or hematologic toxicities. Plasma half-life was 6-10 days, and no anti-tigatuzumab responses were detected. Seven (7) patients had stable disease, with the duration of response ranging from 81 to 798 days.Conclusions: Tigatuzumab is well tolerated, and the MTD was not reached. The high number of patients with stable disease suggests antitumor activity.