ANTIBODY-TOXIN CONJUGATES FOR THE TREATMENT OF HUMAN BRAIN TUMORS

用于治疗人脑肿瘤的抗体-毒素结合物

• 批准号: 3760314
• 负责人: R J YOULE
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3760314
• 关键词: antireceptor antibody; bioassay; brain neoplasms; cerebrospinal fluid; clinical trials; cognition disorders; cytotoxicity; dosage; drug administration routes; drug adverse effect; emesis; headache; human subject; human therapy evaluation; immunoconjugates; intracranial pressure; meningioma; metastasis; monoclonal antibody; neoplasm /cancer immunotherapy; protein engineering; ricin; transferrin receptor

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.

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10种不同剂量的鞘内免疫毒素治疗 涵盖药物剂量增加1，000倍（1.2 - 1，200微克）。没有 检测毒性直至达到最高剂量。急性 毒性包括短暂性头痛、呕吐和精神下降 颅内压升高的状态，对 类固醇和脑脊液（CSF）引流。系列CSF的生物测定 来自这些患者的样品在体外针对肿瘤细胞系显示， 患者CSF保留了对肿瘤细胞的细胞毒活性， 脑室内给药后约48小时 免疫毒素 此外，454 A12-RTA抗肿瘤的体外测试 从3名研究患者的CSF中收集的细胞显示肿瘤细胞 治疗前后对药物的敏感性， 药物浓度远低于CSF中达到的浓度。 四名患者 腰椎CSF肿瘤细胞计数减少，最显著（>95%） 发生在给予的最高剂量下。这些结果表明 免疫毒素可以安全地鞘内给予人体， CSF中的生物活性，对来自患者的肿瘤细胞具有细胞毒性， 可以在单次给药后降低肿瘤负荷。一项新的临床试验 一种基因工程免疫毒素Tfn-CRM 107， 该分支已经开始用于治疗脑实质肿瘤。