Generation of a Modified DT_IL3 Fusion Toxin

描述（由申请人提供）：由白喉毒素（DT）弓形虫和靶向配体组成的许多蛋白融合毒素已经组装并在治疗白血病的I期临床试验中进行了测试。迄今为止，FDA唯一批准的蛋白融合毒素是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3000万到4000万美元之间。靶向白介素-3 （IL-3）受体的基于dt的蛋白融合毒素已经产生了令人鼓舞的早期临床结果。这个I期提案的目标是创造一种DT- il3融合毒素，使用经过修饰的DT弓形虫来减少诱导血管泄漏的可能性，这与现有的DT- il3融合毒素一样有效。人类血管渗漏是融合毒素治疗的常见副作用，可以抑制这类治疗剂的发展。副作用的减少增加了dt - il - 3毒素用于治疗AML患者的机会。

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