ANTIBODY-TOXIN CONJUGATES FOR THE TREATMENT OF HUMAN BRAIN TUMORS

一项鞘内给药的I期剂量递增研究， 免疫毒素454 A12-RTA治疗软脑膜瘤已完成。 该化合物是抗人免疫球蛋白的单克隆抗体的缀合物。 转铁蛋白受体和重组蓖麻毒素A链蛋白毒素。 8例全身性肿瘤发生软脑膜扩散的患者， 用总共十种不同剂量的鞘内免疫毒素治疗 覆盖药物剂量的千倍增加（1.2至1200微克）。 在达到最高剂量前未检测到毒性。 急性毒性包括短暂性头痛、呕吐， 精神状态伴颅内压升高， 类固醇和脑脊液引流 来自这些的系列CSF样品的生物测定 体外肿瘤细胞系的患者显示，患者的CSF 保留对肿瘤细胞的细胞毒活性约48 在脑室内施用免疫毒素后24小时。此外，本发明还涉及一种用于该方法， 454 A12-RTA针对从肿瘤细胞中收获的肿瘤细胞的体外测试 3例研究患者的脊髓液显示肿瘤细胞对 药物治疗前和治疗后的药物浓度必须低于 CSF中达到的浓度。 4例患者腰椎 CSF肿瘤细胞计数，最显著（>95%）发生在最高 剂量。 这些结果表明，免疫毒素可以安全地施用 在人鞘内给药，在CSF中保留生物活性，对 肿瘤细胞，并可以减少肿瘤负荷后，只有一个 单剂量。

A phase 1 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 thousand-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 454A12-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 must 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 immunotoxins can be safely administered intrathecally in humans, retain bioactivity in CSF, are cytotoxic to tumor cells from patients, and can reduce tumor burden after only a single dose.