INCREASED DELIVERY OF MONOCLONAL ANTIBODY RADIOIMMUNOATHERAPY

增加单克隆抗体放射免疫治疗的递送

• 批准号: 3846759
• 负责人: DARELL D BIGNER
• 金额: --
• 依托单位: DUKE UNIVERSITY
• 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/3846759
• 关键词: antibody specificity; antitumor antibody; athymic mouse; blood brain barrier; central nervous system neoplasms; combination cancer therapy; disease /disorder model; drug administration routes; drug adverse effect; glioma; human tissue; immunosuppression; iodine; laboratory rat; medulloblastoma; monoclonal antibody; neoplasm /cancer immunotherapy; neoplasm /cancer radionuclide therapy; neoplasm /cancer transplantation; nonhuman therapy evaluation; radiation therapy dosage; radionuclides; radiotracer; xenotransplantation

The primary hypothesis of this proposal is that improved delivery of operationally specific radiolabeled monoclonal antibodies (MAbs) or their fragments, and selected chemotherapeutic drugs to intracranial tumors can be achieved by 1) varying the route of delivery (intravenous, intracarotid, intrathecal, or intratumoral), 2) the use of more freely diffusible, high-affinity Fab or F(ab')2 fragments, and 3) temporary disruption of the blood-brain barrier (BBB), which restricts the entry of low-molecular weight, water- soluble compounds, as well as higher molecular weight proteins, such as MAbs. Current therapeutic agents are limited by inadequate delivery to tumor, lack of specificity for tumor, and genotypic and phenotypic heterogeneity in tumor. Monospecific MAbs offer the potential for specific therapy of tumor with minimal toxicity to the normal CNS. Genotypic and phenotypic heterogeneity may be overcome by using a panel of MAbs of differing tumor specificities. Studies from our laboratory during the previous grant period have demonstrated that even a single 131I-MAb (81C6) may show therapeutic efficacy after systemic administration in subcutaneous and intracranial human glioma xenografts. Most human gliomas are significantly less permeable than glioma xenografts, however, and preliminary clinical trials with MAbs in patients have shown specific localization sufficient for imaging studies, but not sufficient for therapeutic trials. Our specific aims are to determine if the demonstrated localization advantage of MAb fragments may be exploited to yield a greater therapeutic advantage, as well as determine the potential role of BBB disruption in the therapy of malignant gliomas. Methods to be investigated include hyperosmolar disruption with mannitol, adenosine, etoposide, interleukin-2, leukotriene, and interstitial radiation induced BBB disruption. Using a recently developed model of neoplastic meningitis, the role of intrathecal administration of MAbs will be investigated. Finally, the efficacy of various routes of delivery of chemotherapeutic agents to human glioma xenografts in athymic rats (including intravenous, intracarotid, and intracarotid with BBB disruption will be investigated.

该提案的主要假设是改善了交付 特异性放射性标记的单克隆抗体（mAb）的 或它们的碎片，并选择了化学治疗药物 颅内肿瘤可以通过1）改变 递送（静脉内，肉芽核内，肠内或肿瘤内）， 2）使用更自由扩散的高亲和力晶圆厂或F（AB'）2 片段和3）血脑屏障的暂时破坏 （BBB），它限制了低分子重量，水的进入 可溶性化合物以及更高的分子量蛋白， 例如mabs。 当前的治疗剂受到不足的限制 传递到肿瘤，缺乏对肿瘤的特异性以及基因型和 肿瘤中的表型异质性。 单特异性mab提供 对肿瘤的特异性治疗的潜力最少 正常的中枢神经系统。 基因型和表型异质性可能是 通过使用一组不同肿瘤特异性的mAb来克服。 在上一个赠款期间我们的实验室研究 证明即使单个131i-mab（81C6）也可能显示 系统给药后的治疗功效 和颅内人神经胶质瘤异种移植物。 大多数人神经胶质瘤是 然而，比神经胶质瘤异种移植物明显少得多，并且 患者中使用mAB进行的初步临床试验已显示 特定的本地化足以进行成像研究，但不足 足以进行治疗试验。 我们的具体目的是确定表现出的本地化是否 可以利用MAB片段的优势以产生更大的 治疗优势，并确定 BBB在恶性神经胶质瘤治疗中的破坏。 做方法 研究包括使用甘露醇的高渗透破坏， 腺苷，依托泊苷，白介素-2，白三烯和间质 辐射引起的BBB破坏。 使用最近开发的模型 肿瘤性脑膜炎，鞘内给药的作用 将调查mabs的mab。 最后，各种功效 化学治疗剂向人神经胶质瘤的递送途径 无胸腺大鼠的异种移植物（包括静脉内，肉芽核内， 将研究带有BBB破坏的核内剂。