一项针对死亡受体 5（DR5）的激动型人源化单克隆抗体 tigatuzumab 的每周给药的 I 期临床试验。
Phase I trial of weekly tigatuzumab, an agonistic humanized monoclonal antibody targeting death receptor 5 (DR5).
机构信息
University of Alabama at Birmingham, Comprehensive Cancer Center, Birmingham, Alabama 35294-3300, USA.
出版信息
Cancer Biother Radiopharm. 2010 Feb;25(1):13-9. doi: 10.1089/cbr.2009.0673.
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.
背景
TRAIL-8 是一种针对死亡受体 5（DR5）的鼠源激动型单克隆抗体，无需交联即可诱导 DR5 阳性的人肿瘤细胞凋亡。它在体外和体内对多种人源肿瘤细胞系具有细胞毒性和抗肿瘤活性。替加珠单抗是一种源自 TRAIL-8 的人源化 IgG1 单克隆抗体。
方法
一项 TRAIL-8 治疗复发性/难治性癌（n=16）或淋巴瘤（n=1）患者的 I 期试验旨在确定最大耐受剂量（MTD）、药代动力学、免疫原性和安全性。每 3-6 名患者入组一个递增剂量队列，剂量范围为 1-8mg/kg 每周。
结果
共纳入 17 例患者，1 例入组 1、2 和 4mg/kg 剂量队列（每组 3 例），8 例入组 8mg/kg 剂量队列。替加珠单抗耐受性良好，未观察到剂量限制性毒性（DLT），且未达到最大耐受剂量（MTD）。无研究药物相关的 3 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反应。7 例患者疾病稳定，反应持续时间为 81-798 天。
结论
替加珠单抗具有良好的耐受性，且未达到最大耐受剂量（MTD）。大量患者疾病稳定提示具有抗肿瘤活性。
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