Further Analysis of a VLS Modified IL-2 Receptor Targeted Toxin

描述（由申请人提供）：该项目旨在进一步开发一系列白喉毒素突变体，当用于构建蛋白融合毒素时，可以减少血管内皮细胞单层渗漏的诱导。本I期提案的目标是评估两种血管渗漏的体内模型，选择一种模型进行AGI产生的白喉毒素突变体的进一步体内分析。这些研究的成功完成将导致确定适合蛋白融合毒素开发和在疾病特异性体内模型中测试的改良白喉毒素弓形虫。人类血管渗漏是融合毒素治疗的常见副作用，可能会抑制这类治疗剂的发展。在减少血管渗漏方面的进展可以提高这些药物的治疗指数，并使其可用于更广泛的患者群体。目前，这类药物中只有一种获FDA批准的药物，即ONTAK，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。公共卫生相关性：该项目旨在开发具有减少副作用的白喉毒素白介素-2修饰分子。目前接受DAB389IL-2或ONTAK(r)治疗的所有患者中，有超过30%的患者出现血管渗漏综合征。在这些研究中开发和测试的分子将有可能为下一代ONTAK(r)的开发提供一条途径，这可能更适合于患有更广泛疾病的更广泛的患者群体。

DESCRIPTION (provided by applicant): The project seeks to further the development of a series of diphtheria toxin mutants which, when employed in the construction of protein fusion toxins, display reduced induction of leakage through vascular endothelial cell monolayers. The goals of this Phase I proposal are to evaluate two, in vivo models of vascular leakage, selecting one model for further in vivo analysis of diphtheria toxin mutants generated by AGI. Successful completion of these studies will result in the determination of modified diphtheria toxin toxophores suitable for protein fusion toxin development and testing in disease-specific, in vivo models. Vascular leakage in humans is a common side effect of fusion toxin therapy and may be inhibiting the development of this class of therapeutic agent. Advances in reduction of vascular leakage could enhance the therapeutic index of these drugs and make them available to a wider population of patients. Currently there is only one FDA approved drug in this class, ONTAK, which is used to treat persistent or recurrent cutaneous T-cell lymphoma. Sales of this drug range between $30 and $40M annually. PUBLIC HEALTH RELEVANCE: This project seeks to develop modified diphtheria toxin interleukin-2 molecules with reduced side effect profiles. In excess of 30% of all patients that currently receive DAB389IL-2, or ONTAK(r), experience vascular leak syndrome. The molecules being developed and tested in these studies will potentially provide a path for the development of the next generation of ONTAK(r) that may be more appropriate for a wider patient population afflicted with a broader range of diseases.