IMMUNOTOXIN THERAPY OF HEMATOPOIETIC MALIGNANCIES

造血系统恶性肿瘤的免疫毒素治疗

• 批准号: 2463817
• 负责人: I PASTAN
• 金额: --
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 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/2463817
• 关键词: CD antigens; antineoplastics; clinical research; cytokine receptors; cytotoxicity; drug design /synthesis /production; human tissue; immunotoxicity; interleukin 2; interleukin 6; leukemia; lymphoma; neoplasm /cancer immunotherapy

Lymphomas and leukemias contain differentiation antigens which are not found outside the immune system or on stem cells and therefore are useful targets for targeted cancer therapy. One of these is the IL-2 receptor and we already have anti-Tac(Fv)PE38 in clinical trials. R. Kreitman has previously shown that IL6-PE664glu is cytotoxic to myeloma cells isolated from patients with multiple myeloma. R. Kreitman has prepared a clinical batch of IL6-PE664glu to be used in a bone marrow purging study at the University of Arkansas. We are awaiting approval of the master drug file for this study to be initiated. R. Kreitman has also designed a circularly permuted form of IL4-PE38KDEL which is very cytotoxic to astrocytomas. Our collaborator, Raj Puri (FDA), has shown that astrocytomas have IL4 receptors whereas other cells in the brain do not. The FDA has given us permission to file an IND to test cpIL4-PE38KDEL in patients with inoperable astrocytomas. The study will be carried out at the John Wayne Cancer Center by Dr. Robert Rand following production of a clinical batch of the agent. E. Mansfield and D. FitzGerald have produced a disulfide linked immunotoxin (RFB4(dsFv)PE38) directed at CD22, an antigen present on many lymphomas. RFB4(dsFv)PE38 is very cytotoxic to cell lines expressing the antigen, causes regression of tumors in mice, and is very well tolerated by monkeys. A clinical lot of RFB4(dsFv)PE38 will be prepared at the MARP and a Phase I study will be carried out in the Division of Clinical Sciences at NCI.

淋巴瘤和白血病含有分化抗原，但它们不含有分化抗原。 发现于免疫系统外部或干细胞上，因此 癌症靶向治疗的有用靶点。 其中之一是IL-2 受体，我们已经有抗 Tac(Fv)PE38 处于临床试验中。 R. Kreitman 此前已证明 IL6-PE664glu 对 从多发性骨髓瘤患者中分离出的骨髓瘤细胞。 R。 Kreitman 已制备出临床批次的 IL6-PE664glu，用于 阿肯色大学的一项骨髓净化研究。 我们是 正在等待本研究的主药物档案的批准 发起。 R. Kreitman 还设计了一种循环排列的形式 IL4-PE38KDEL 对星形细胞瘤具有很强的细胞毒性。 我们的 合作者 Raj Puri (FDA) 已证明星形细胞瘤具有 IL4 受体，而大脑中的其他细胞则没有。 FDA 已给出 美国允许提交 IND 以在患有以下疾病的患者中测试 cpIL4-PE38KDEL 无法手术的星形细胞瘤。 该研究将在约翰 罗伯特·兰德博士在韦恩癌症中心制作了 试剂的临床批次。 E.曼斯菲尔德和D.菲茨杰拉德 产生了一种二硫键连接的免疫毒素（RFB4（dsFv）PE38），针对 CD22，一种存在于许多淋巴瘤上的抗原。 RFB4(dsFv)PE38 非常 对表达抗原的细胞系具有细胞毒性，导致 小鼠的肿瘤，并且猴子的耐受性很好。 临床批次 RFB4(dsFv)PE38 将在 MARP 上准备，并且将进行第一阶段研究 被携带 NCI 临床科学部。