Generation of a Modified DT_IL3 Fusion Toxin

改良 DT_IL3 融合毒素的生成

• 批准号: 7483540
• 负责人: JOHANNA Catharina VANDERSPEK
• 金额: $ 12.28万
• 依托单位: ANJIN GROUP, INC.
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2009-08-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7483540
• 关键词: Adverse effects; Biological Assay; Blood Vessels; Cells; Chimeric Proteins; Class; Clinical; Clinical Treatment; Clinical Trials; Cutaneous; Denileukin Diftitox; Development; Diphtheria Toxin; Extravasation; Fusion Toxin; Generations; Goals; Human; In Vitro; Interleukin 2 Receptor; Interleukin-3; Interleukin-3 Receptor; Ligands; Patients; Pharmaceutical Preparations; Phase; Proteins; Public Health; Range; Recurrence; Sales; T-Cell Lymphoma; Targeted Toxins; Testing; Therapeutic; Therapeutic Agents; Toxin; United States Food and Drug Administration; base; cytokine; cytotoxicity; human IL3RA protein; leukemia; mutant; numb protein; receptor

DESCRIPTION (provided by applicant): A number of protein fusion toxins, composed of the diphtheria toxin (DT) toxophore and a targeting ligand, have been assembled and tested in Phase I clinical trials for the treatment of leukemias. To date, the only FDA approved protein fusion toxin is ONTAK. ONTAK is a DT, interleukin-2 receptor-targeted fusion toxin used to treat persistent or recurrent, cutaneous T-cell lymphoma. Sales of this drug range between $30 and $40M annually. DT-based protein fusion toxins targeting the interleukin-3 (IL-3) receptor have produced encouraging early clinical results. The goals of this Phase I proposal are to create a DT-IL3 fusion toxin, using a DT toxophore that has been modified to reduce potential for induction of vascular leak, that is as potent as the existing DT-IL3 fusion toxin. Vascular leakage in humans is a common side effect of fusion toxin therapy and can inhibit development of this class of therapeutic agent. A reduced side effect profilethe chances of a DT-IL3 toxin becoming available to treat patients with AML. reat AML. PUBLIC HEALTH RELEVANCE: This project seeks to determine if a DT-IL3 fusion toxin with reduce VLS profile can developed. This fusion toxin could provide a wider therapeutic window and thereby enhance

描述(申请人提供)：一些由白喉毒素(DT)毒素载体和靶向配体组成的蛋白质融合毒素已经组装起来，并在治疗白血病的第一阶段临床试验中进行了测试。到目前为止，FDA批准的唯一一种蛋白质融合毒素是Ontak。Ontak是一种DT，白介素2受体靶向融合毒素，用于治疗持续性或复发性皮肤T细胞淋巴瘤。这种药物的年销售额在3000万至4000万美元之间。以白介素3(IL-3)受体为靶点的基于DT的蛋白质融合毒素已产生令人鼓舞的早期临床结果。这一第一阶段提案的目标是创建一种DT-IL3融合毒素，使用经过修改以降低诱导血管泄漏的可能性的DT毒素，其效力与现有的DT-IL3融合毒素相同。人体血管渗漏是融合毒素治疗的常见副作用，可抑制这类治疗剂的发展。副作用减少的情况下，DT-IL3毒素可用于治疗急性髓细胞白血病患者的机会。 Reat AML。与公共卫生相关：该项目试图确定是否可以开发出具有降低VLS特征的DT-IL3融合毒素。这种融合毒素可以提供更广泛的治疗窗口，从而增强