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

VLS 修饰的 IL-2 受体靶向毒素的进一步分析

• 批准号: 7480070
• 负责人: JOHANNA Catharina VANDERSPEK
• 金额: $ 14.75万
• 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 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7480070
• 关键词: Acute Graft Versus Host Disease; Adverse effects; Amino Acid Sequence; Animal Model; Biological Assay; Biological Models; Blood Circulation; Blood Vessels; Brain; Cells; Chimeric Proteins; Class; Cutaneous; DAB389 Interleukin-2 Immunotoxin; Denileukin Diftitox; Development; Diphtheria Toxin; Disease; Endothelial Cells; Extravasation; Facility Construction Funding Category; Funding; Fusion Toxin; Goals; Human; In Vitro; Interleukin 2 Receptor; Life; Liquid substance; Lung; Mediating; Modeling; Mus; Muscle; Organ; Patients; Permeability; Pharmaceutical Preparations; Phase; Population; Proteins; Psoriasis; Public Health; Range; Recombinant Fusion Proteins; Recurrence; Rheumatoid Arthritis; Sales; Series; Syndrome; T-Cell Lymphoma; Targeted Toxins; Testing; Therapeutic; Therapeutic Agents; Therapeutic Index; Tissues; Toxin; United States Food and Drug Administration; Vascular Endothelial Cell; base; cytokine therapy; cytotoxicity; experience; in vitro Model; in vivo; in vivo Model; interleukin 2-diphtheria toxin; monolayer; mutant; next generation; tool

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.

描述（由申请人提供）：该项目旨在进一步发展一系列白喉毒素突变体，这些突变体在构建蛋白质融合毒素时，会显示出通过血管内皮细胞单层的泄漏诱导减少。该阶段I建议的目标是评估两个体内血管泄漏模型，选择一种模型，以进一步对AGI产生的白喉毒素突变体进行体内分析。这些研究的成功完成将导致确定适用于蛋白质融合毒素在体内模型中蛋白融合毒素发育和测试的修饰的白喉毒素。人类的血管泄漏是融合毒素疗法的常见副作用，可能会抑制这种类别的治疗剂的发展。减少血管泄漏的进展可以增强这些药物的治疗指数，并使它们可用于更广泛的患者。目前，该类别的ONTAK中只有一种FDA批准的药物，该药物用于治疗持久性或经常性皮肤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。公共卫生相关性：该项目旨在开发经过修改的白喉毒素白介素2分子，其副作用曲线降低。目前接受DAB389IL-2或ONTAK（R）的所有患者中，超过30％，经历了血管泄漏综合征。在这些研究中开发和测试的分子将有可能为开发下一代Ontak（R）的发展提供一条途径，这可能更适合于患有更广泛疾病的更广泛的患者人群。