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: 5203962
• 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/5203962
• 关键词: Macaca mulatta; blood brain barrier; brain neoplasms; cerebrospinal fluid; cytotoxicity; dosage; drug administration routes; drug adverse effect; drug delivery systems; guinea pigs; human subject; human therapy evaluation; immunoconjugates; laboratory rat; monoclonal antibody; neoplasm /cancer immunotherapy; neurotoxins; nonhuman therapy evaluation; pancreatic ribonuclease; ricin; transferrin receptor

We have engineered immunotoxins into exquisitely cell type specific reagents with promise for cancer therapy. Exploring their applications in vivo we have found that 1) there are powerful pharmacologic barriers that limit protein access to tumor cells; 2) this problem is exacerbated in the brain where the blood-brain barrier prevents macromolecule movement into the brain tissue; 3) the plant and bacterial toxins used for construction of immunotoxins are highly immunogenic and soon after treatment antibodies arise that inactivate reagent.Thus, to overcome the problems of delivery and immunogenicity, we have pursued regional delivery of immunotoxins to the brain as away to treat brain tumors. Since cancer can spread and grow in the CSF, a condition known as leptomeningeal carcinomatosis, immunotoxins were initially injected directly into the cerebral spinal fluid to access tumor cells and were found to kill 99% to 99.9% of the tumor cells in vivo with occasional animals cured. An intriguing dose limiting toxicity was found specifically related to this route of administration. Purkinje cells were killed by diptheria toxin derived immunotoxin guinea pigs and ricin derived immunotoxins in rats and monkeys. Another protein, called the eosinophil-derived neurotoxin is homologous to RNases A and also selectively kills Purkinje cells. 4) Comparing a family of homologous RNases we found 5000-fold variation in cytotoxicity. The molecular basis of toxicity was explored and cell binding, RNase inhibitor sensitivity and/or enzyme activity all appear to contribute. 7) We have determined the dose limiting toxicity of immunotoxins in three model species, guinea pigs, rats and rhesus monkeys and in man. 8) The pharmacology of a monoclonal antibody against the transferrin receptor, 454A12, coupled to recombinant ricin A chain was thoroughly studied in primates and man. Clearance from the CSF was biphasic and in humans, a somewhat larger clearance rate was found for the antitransferrin receptor immunotoxin than seen with other macromolecules possibly reflecting uptake by tumor cells. A potentially large therapeutic window exists for intrathecal immunotoxins for cancer therapy.

我们已经将免疫毒素设计成精确的细胞类型特异性 有望用于癌症治疗的试剂。 探索其应用 在体内，我们发现：1）存在强大的药理学屏障， 这限制了蛋白质进入肿瘤细胞; 2）这个问题加剧了 在大脑中，血脑屏障阻止大分子 运动进入脑组织; 3）使用的植物和细菌毒素 用于构建免疫毒素具有高度免疫原性， 治疗抗体产生的抗体是抗体反应的产物。因此，为了克服 由于运送和免疫原性的问题，我们一直在寻求区域性 将免疫毒素输送到大脑以治疗脑肿瘤。 由于癌症可以在CSF中扩散和生长，这种情况被称为 软脑膜癌病，最初注射免疫毒素 直接进入脑脊髓液以接触肿瘤细胞， 发现在体内杀死99%至99.9%的肿瘤细胞， 动物治愈 一个有趣的剂量限制毒性被发现 与这种给药途径有关。 浦肯野细胞 白喉毒素免疫毒素豚鼠和蓖麻毒素 在大鼠和猴子中衍生的免疫毒素。 另一种蛋白质，叫做 嗜酸性粒细胞衍生的神经毒素与RNA酶A同源， 选择性杀死浦肯野细胞4)比较一个同源的 我们发现5000倍的细胞毒性的变化。 的分子基础 的毒性进行了探讨，细胞结合，RNA酶抑制剂的敏感性 和/或酶活性似乎都有贡献。7)我们已经确定 免疫毒素对豚鼠的剂量限制性毒性 猪、大鼠和恒河猴以及人。8） 抗转铁蛋白受体的单克隆抗体，454 A12，偶联至 重组蓖麻毒素A链在灵长类动物和人类中进行了彻底的研究。 从CSF中的清除是双相的，在人类中， 发现抗转铁蛋白受体免疫毒素的清除率 可能反映肿瘤摄取的其他大分子 细胞对于鞘内给药， 用于癌症治疗的免疫毒素。