TREATMENT OF GLIOBLASTOMAS WITH IMMUNOTOXINS

用免疫毒素治疗胶质母细胞瘤

• 批准号: 3478264
• 负责人: Lawrence D Recht
• 金额: $ 11.61万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-04-01 至 1997-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3478264
• 关键词: antireceptor antibody; athymic mouse; autoradiography; calcium channel blockers; chemical stability; clone cells; cytotoxicity; dosage; drug delivery systems; epidermal growth factor; glioblastoma multiforme; growth factor receptors; histology; immunoconjugates; indium; laboratory rat; liposomes; membrane permeability; monensin; monoclonal antibody; neoplasm /cancer immunotherapy; nonhuman therapy evaluation; protein biosynthesis; radionuclide double label; ricin; transferrin receptor; tumor antigens; xenotransplantation

The prognosis for patients with glioblastoma multiforme (GBM) remains poor despite intensive conventional therapy. An alternative potentially efficacious therapeutic strategy against this dreaded disease might be administration of immunotoxins (IT), macromolecules formed by conjugation of tumor-specific monoclonal antibodies (mab) with intracellular ribosomal inhibitory proteins. One potential antigen which may serve as a target for such therapy is the transferrin receptor (Tfr), which is overexpressed in GBM compared to normal surrounding brain. Furthermore, 7D3-A, an IT constructed by conjugating a mab directed against Tfr with ricin A chains, potentially inhibits GBM protein synthesis in vitro and its administration to nude mice harboring subcutaneous xenografts can result in apparent tumor eradication in a high percentage of animals. In the following proposal, we seek to evaluate further the potential of this therapy using both the nude mouse xenograft model and an in situ rat glioma model whereby intratumoral cannulae are placed to assess local delivery. Experiments are specifically designed to assess in vivo stability, potency, penetrability and toxicity of this IT. With the results obtained from these studies, it will have been ascertained whether this macromolecule merits clinical trial or if not, what impediments exist that hamper its efficacy.

多形胶质母细胞瘤（GBM）患者的预后仍然存在 尽管进行了密集的常规疗法，却很差。 潜在的替代方法 针对这种可怕疾病的有效治疗策略可能是 给药免疫毒素（IT），结合形成的大分子 肿瘤特异性单克隆抗体（MAB）的细胞内抗体 核糖体抑制蛋白。 一种潜在的抗原，可以用作 这种治疗的靶标是转铁蛋白受体（TFR），它是 与正常的大脑相比，GBM过表达。此外， 7d3-a，它是通过连接针对TFR的mAb构造的 ricin a链，可能会在体外抑制GBM蛋白质合成 它将其施用到具有皮下异种移植的裸鼠可以 导致在高比例的动物中明显消除肿瘤。在 以下提案，我们寻求进一步评估这一潜力 使用裸小鼠异种移植模型和原位大鼠的治疗 胶质瘤模型，其中放置了肿瘤内套管以评估局部 送货。 实验是专门设计用于评估体内的 IT的稳定性，效力，渗透性和毒性。 与 从这些研究获得的结果，将被确定 该大分子是否值得临床试验，如果没有， 存在阻碍其功效的障碍。