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

基本信息

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
项目类别：
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

项目摘要

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）：该项目旨在进一步开发一系列白喉毒素突变体，当将其用于构建蛋白质融合毒素时，表现出减少通过血管内皮细胞单层渗漏的诱导。这一第一阶段提案的目标是评估两种血管渗漏体内模型，选择一个模型对 AGI 产生的白喉毒素突变体进行进一步体内分析。这些研究的成功完成将确定适合蛋白质融合毒素开发和疾病特异性体内模型测试的修饰白喉毒素毒载体。人类血管渗漏是融合毒素治疗的常见副作用，可能会抑制此类治疗剂的开发。减少血管渗漏方面的进展可以提高这些药物的治疗指数，并使它们适用于更广泛的患者群体。目前此类药物中只有一种 FDA 批准的药物 ONTAK，用于治疗持续性或复发性皮肤 T 细胞淋巴瘤。该药物的年销售额在 30 至 4000 万美元之间。公共健康相关性：该项目旨在开发改良白喉毒素白细胞介素 2 分子，以减少副作用。目前接受 DAB389IL-2 或 ONTAK(r) 治疗的所有患者中，超过 30% 出现血管渗漏综合征。这些研究中正在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，这种下一代 ONTAK(r) 可能更适合患有更广泛疾病的更广泛的患者群体。