Generation of a Modified DT_IL3 Fusion Toxin

描述（由申请人提供）：由白喉毒素（DT）毒基和靶向配体组成的许多蛋白融合毒素已经组装并在I期临床试验中测试用于治疗白血病。到目前为止，FDA唯一批准的蛋白融合毒素是ONTAK。ONTAK是一种DT，白细胞介素-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。这种药物的销售额每年在3000万至4000万美元之间。靶向白细胞介素-3（IL-3）受体的基于DT的蛋白融合毒素已经产生了令人鼓舞的早期临床结果。该I期提案的目标是使用已被修饰以降低诱导血管渗漏的可能性的DT毒基来产生DT-IL 3融合毒素，其与现有的DT-IL 3融合毒素一样有效。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开发。副作用减少意味着DT-IL 3毒素可用于治疗AML患者。 急性髓细胞白血病。公共卫生相关性：该项目旨在确定是否可以开发具有降低VLS谱的DT-IL 3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

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