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（由申请人提供）：许多蛋白融合毒素，由白喉毒素（DT）弓形虫和靶向配体组成，已在I期临床试验中进行了组装和测试，用于治疗白血病。迄今为止，唯一获得FDA批准的蛋白融合毒素是Ontak。 ONTAK是一种DT，白介素-2受体靶向的融合毒素，用于治疗持续或经常性皮肤T细胞淋巴瘤。该药物的销售范围在30万美元至4000万美元之间。靶向白介素3（IL-3）受体的基于DT的蛋白融合毒素已产生令人鼓舞的早期临床结果。该阶段I提案的目标是使用已修改的DT毒蛋白创建DT-IL3融合毒素，以减少诱导血管泄漏的潜力，这与现有的DT-IL3融合毒素一样有效。人类血管泄漏是融合毒素疗法的常见副作用，可以抑制这种类别的治疗剂的发展。 DT-IL3毒素的副作用降低了可用于治疗AML患者的机会。 reat aml。公共卫生相关性：该项目旨在确定是否可以开发出具有VLS概况的DT-IL3融合毒素。这种融合毒素可以提供更宽的治疗窗口，从而增强