ANTIBODY-TOXIN CONJUGATES FOR THE TREATMENT OF HUMAN BRAIN TUMORS

一项鞘内治疗的I期剂量递增研究 免疫毒素454A12-RTA治疗软脑膜肿瘤已经完成。 这种化合物是一种抗人的单抗的结合物 转铁蛋白受体和重组蓖麻毒素A链蛋白毒素。 8例系统性软脑膜播散性肿瘤患者 用10种不同剂量的鞘内免疫毒素进行治疗 涵盖药物剂量增加1000倍(1.2-1200微克)。不是 在达到最高剂量之前，一直检测到毒性。急性 毒性包括一过性头痛、呕吐和精神减退。 状态为颅内压升高，对 类固醇和脑脊液引流。系列脑脊液的生物检测 这些患者的样本在体外抗肿瘤细胞系中显示 患者脑脊液对肿瘤细胞保持细胞毒活性 脑室内给药后约48小时 免疫毒素。此外，454A12-RTA的体外抗肿瘤实验 从3名研究患者的脑脊液中提取的细胞显示为肿瘤细胞 治疗前后对药物的敏感性 药物浓度远低于脑脊液中的浓度。四名病人 腰椎脑脊液肿瘤细胞数量减少，最显著的(&gt；95%) 在给予的最高剂量下发生的。这些结果表明， 免疫毒素可以安全地在人类鞘内注射，保留 脑脊液中的生物活性，对患者的肿瘤细胞具有细胞毒作用，以及 只需一剂即可减轻肿瘤负担。一项新的临床试验 一种基因工程免疫毒素，TFN-CRM107，在 该分支已经开始用于治疗脑实质肿瘤。

A phase I dose-escalation study of intrathecal therapy with the immunotoxin 454A12-RTA for leptomeningeal neoplasia has been completed. This compound is a conjugate of a monoclonal antibody against the human transferrin receptor and the recombinant ricin A chain protein toxin. Eight patients with leptomeningeal spread of systemic neoplasia were treated with a total of 10 different doses of intrathecal immunotoxin covering a 1,000-fold increase in drug dose (1.2 - 1,200 micrograms). No toxicity was detected until the highest doses were reached. Acute toxicity consisted of transient headache, vomiting and decreased mental status with elevated intracranial pressure which was responsive to steroids and cerebrospinal fluid (CSF) drainage. Bioassays of serial CSF samples from these patients against tumor cell lines in vitro revealed that patients CSF retained cytotoxic activity against tumor cells for approximately 48 hours after intraventricular administration of immunotoxin. In addition, in vitro testing of 454A12-RTA against tumor cells harvested from the CSF in 3 study patients revealed tumor cell sensitivity to the drug before and after treatment at concentrations of drug much lower than the concentration achieved in CSF. Four patients had decreased lumbar CSF tumor cell counts, the most dramatic (>95%) occurring at the highest dose given. These results indicate that immunotoxin can be safely administered intrathecally in humans, retain bioactivity in the CSF, are cytotoxic to tumor cells from patients, and can reduce tumor burden after only a single dose. A new clinical trial of a genetically engineered immunotoxin, Tfn-CRM107, discovered within the branch has begun for treatment of parenchymal brain tumors.