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 共使用10种不同剂量的鞘内免疫毒素进行治疗 药物剂量增加1000倍(1.2微克至1200微克)。 在达到最高剂量之前，没有检测到任何毒性。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。来自这些地区的连续脑脊液样本的生物分析 患者体外抗肿瘤细胞株揭示患者脑脊液 对肿瘤细胞的细胞毒活性保持约48 脑室注射免疫毒素后数小时。此外, 454Al-2-RTA体外抗肿瘤细胞实验 3名研究患者的脊髓液显示肿瘤细胞对 药物在治疗前后的浓度远低于 在脑脊液中达到的浓度。四名患者腰椎缩小 脑脊液肿瘤细胞计数，最显著的(大于95%)发生在 给出的最大剂量。 这些结果表明免疫毒素是可以安全使用的。 在人类的鞘内，在脑脊液中保持生物活性，对 来自患者的肿瘤细胞，只需一年即可减轻肿瘤负担 单剂。 基因工程免疫毒素TFN-CRM的新临床试验 107例，发现与分支已开始治疗的实质 脑瘤。

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 ten different doses of intrathecal immunotoxin covering a 1000-fold increase in drug dose (1.2 to 1200 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 CSF drainage. Bioassays of serial CSF samples from these patients against tumor cell lines in vitro revealed that patient's CSF retained cytotoxic activity against tumor cells for approximately 48 hours after intraventricular administration of immunotoxin. In addition, in vitro testing of 454Al 2-RTA against tumor cells harvested from the spinal fluid 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 (greater than 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-CRM 107, discovered with the branch has begun for treatment of parenchymal brain tumors.