A phase I study of an anti-epidermal growth factor receptor monoclonal antibody for the treatment of malignant gliomas
A phase I study of an anti-epidermal growth factor receptor monoclonal antibody for the treatment of malignant gliomas
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DOI：
10.1097/00006123-199609000-00009
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发表时间：
1996-09-01
期刊：
影响因子：
4.8
通讯作者：
Delattre, JY
中科院分区：
文献类型：
--
作者：
Faillot, T;Magdelenat, H;Delattre, JY
目的：表皮生长因子受体（EGFR）是恶性胶质瘤中的操作特异性抗原;其在>60%的这些肿瘤中过表达，而其在正常脑中的表达非常低。本研究旨在评估是否足够量的抗EGFR单克隆抗体（MAb）可以达到肿瘤后，单次静脉administration.METHODS：这项研究是开放的，非随机的，非对照的。单剂量（20，40，100，200，或400毫克）的鼠单克隆抗体EMD 55900（单克隆抗体425）在手术前静脉注射30例恶性脑肿瘤患者。在输注期间以规定的时间间隔采集血清样品，以测定EMD 55900浓度，并在输注后10、21和/或42天采集血清样品，以评价人抗小鼠抗体的产生。结果：肿瘤组织对EMD 55900的耐受性良好。在3例1级毒性患者中观察到肝转氨酶水平升高。20例患者出现显著的人抗小鼠抗体滴度，与给药剂量无关。血清中EMD 55900的中位半衰期范围为6小时（20 mg）至24小时（400 mg）。在肿瘤的膜组分中，通过EMD 55900的EGFR饱和度随单克隆抗体的注射剂量而变化。在20 mg剂量后未检测到结合。40，100，200，和400毫克的剂量后，平均饱和度分别为33，73，89，和71%，分别：结论：这项研究表明，一个单一的静脉注射给药的EMD 55900是耐受性良好，并产生大量的体内肿瘤结合与剂量>100毫克。
OBJECTIVE: Epidermal growth factor receptor (EGFR) is an operationally specific antigen in malignant gliomas; it is overexpressed in >60% of these tumors, whereas its expression is very low in normal brain. This study aimed to evaluate whether an adequate amount of an anti-EGFR monoclonal antibody (MAb) could reach a tumor after a single intravenous administration.METHODS: This study was open, nonrandomized, and uncontrolled. Single doses (20, 40, 100, 200, or 400 mg) of the murine MAb EMD55900 (MAb 425) were administered intravenously before surgery to 30 patients with malignant brain tumors. Serum samples were taken at defined time intervals during infusion, to determine EMD55900 concentrations, and 10, 21, and/or 42 days after infusion, to evaluate the development of human anti-mouse antibodies. Tumor samples were investigated for EGFR and EMD55900 contents.RESULTS: Tolerance to EMD55900 was good. Increased liver transaminase levels were noted for three patients with Grade 1 toxicity. Twenty patients developed significant human anti-mouse antibody titers, without correlation with the administered dose. The median half-life of EMD55900 in serum ranged from 6 hours for 20 mg to 24 hours for 400 mg. In the membrane fractions of the tumors, EGFR saturation by EMD55900 varied with the injected dose of MAb. No binding was detected after a 20-mg dose. After doses of 40, 100, 200, and 400 mg, the mean saturation levels were 33, 73, 89, and 71%, respectively.CONCLUSION: This study indicates that a single intravenous administration of EMD55900 is well tolerated and produces substantial in vivo tumor binding with doses >100 mg.