Immunotoxin-Induced Vascular Leak Syndrome

免疫毒素引起的血管渗漏综合征

• 批准号: 6805078
• 负责人: ELLEN S VITETTA
• 金额: $ 7.33万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-02-16 至 2006-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6805078
• 关键词: SCID mouse; SDS polyacrylamide gel electrophoresis; cardiovascular disorder; cell line; clinical research; clinical trial phase I; cytokine; dosage; drug design /synthesis /production; endotoxins; high performance liquid chromatography; human subject; human therapy evaluation; immunoconjugates; immunofluorescence technique; immunoprecipitation; immunotoxicity; molecular cloning; neoplasm /cancer chemotherapy; neoplasm /cancer pharmacology; nonHodgkin' s lymphoma; patient oriented research; pharmacokinetics; ricin; therapy adverse effect; transmission electron microscopy

DESCRIPTION (provided by applicant): Low-grade follicular non-Hodgkin's lymphoma (NHL) is characterized by an indolent clinical course where >85% of patients fail to achieve long-term remissions with any therapeutic modality thus far developed. We have developed an immunotoxin (IT) consisting of the RFB4 anti-CD22 monoclonal antibody (MAb) linked to deglycosylated ricin-A-chain (dgRTA). This IT has been tested in SCID/lymphoma mice, in primates, and has been administered to >75 patients with multiply relapsed NHL in Phase I clinical trials. The response rate has been 40% and the dose limiting toxicity (DLT) has been vascular leak syndrome (VLS). VLS has also been the DLT in -250 patients whom we have treated with IT-dgAs against CD19, 25 and 30. Because of VLS, our enthusiasm for evaluating this and other ITs in Phase II trials has been significantly dampened. To address the problem of VLS, we developed in vitro and in vivo models of VLS and identified the sequence in RTA responsible for this side effect. We then generated a panel of 16 RTA mutants, expressed them in E. coli, purified and evaluated them. One mutant made an IT which was as active as an IT prepared with dgRTA but did not induce VLS in our animal models. We now seek funding to carry out a Phase I trial with this third generation IT to determine if we have "solved" the VLS problem in humans. The first year will be spent preparing the IT, carrying out all the FDA-required testing, and filing the IND. The Phase I trial will be carried out in the second and third years by Dr. E. Sausville at the NCI. It will be a dose escalation study in 40 patients. Half of the patients will have circulating tumor cells (CTCs) and half will not. Our objectives will be to determine 1) the maximum tolerated dose (MTD) of this third generation IT in patients with relapsed low or intermediate grade NHL who do, or do not have CTCs, 2) the pharmacokinetics (PK) immunogenicity, clinical response, and any changes in levels of circulating cytokines. 3) whether there are correlations between PKs, changes in cytokines, toxicity, and response. Our data will be compared with those obtained in the past clinical trials with the second generation IT, RFB4-dgRTA.

描述（由申请人提供）：低度滤泡性非霍奇金淋巴瘤 (NHL) 的特点是惰性临床病程，其中 >85% 的患者使用迄今为止开发的任何治疗方式都无法实现长期缓解。我们开发了一种免疫毒素 (IT)，由与去糖基化蓖麻毒素 A 链 (dgRTA) 连接的 RFB4 抗 CD22 单克隆抗体 (MAb) 组成。该 IT 已在 SCID/淋巴瘤小鼠和灵长类动物中进行了测试，并已在 I 期临床试验中对超过 75 名多次复发 NHL 患者进行了治疗。缓解率为 40%，剂量限制毒性 (DLT) 为血管渗漏综合征 (VLS)。 VLS 也是我们用针对 CD19、25 和 30 的 IT-dgAs 治疗的 -250 名患者的 DLT。由于 VLS，我们在 II 期试验中评估此和其他 IT 的热情已显着减弱。 为了解决 VLS 问题，我们开发了 VLS 的体外和体内模型，并鉴定了 RTA 中导致这种副作用的序列。然后，我们生成了一组 16 个 RTA 突变体，在大肠杆菌中表达它们，纯化并评估它们。一种突变体产生的 IT 与用 dgRTA 制备的 IT 一样活跃，但在我们的动物模型中不诱导 VLS。我们现在寻求资金来利用第三代 IT 进行第一阶段试验，以确定我们是否已经“解决”了人类的 VLS 问题。第一年将用于准备 IT、执行 FDA 要求的所有测试并提交 IND。 I 期试验将由 NCI 的 E. Sausville 博士在第二年和第三年进行。这将是一项针对 40 名患者的剂量递增研究。一半患者有循环肿瘤细胞 (CTC)，一半则没有。我们的目标是确定 1) 第三代 IT 在有或没有 CTC 的复发性低度或中度 NHL 患者中的最大耐受剂量 (MTD)，2) 药代动力学 (PK) 免疫原性、临床反应、以及循环细胞因子水平的任何变化。 3) PK、细胞因子变化、毒性和反应之间是否存在相关性。我们的数据将与过去第二代 IT RFB4-dgRTA 临床试验中获得的数据进行比较。