Modified Diphtheria Toxin IL-7 Fusion Toxins

改良白喉毒素 IL-7 融合毒素

• 批准号: 7110847
• 负责人: JOHANNA Catharina VANDERSPEK
• 金额: $ 15.21万
• 依托单位: ANJIN GROUP, INC.
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-06-01 至 2007-08-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7110847
• 关键词: acute lymphocytic leukemia; diphtheria toxin; endopeptidases; mycosis fungoides lymphoma; proteins; receptor; syndrome; toxin

DESCRIPTION (provided by applicant): Sweeney et al. (1998) originally reported the construction of DAB389IL-7, a fusion protein based on diphtheria toxin (DT), and proposed that this fusion protein could be employed as a therapeutic agent for hematological malignancies, including acute lymphoblastic leukemia, chronic lymphocytic leukemia, acute myelogenous leukemia and Sezary syndrome. Studies by other groups identify potential targets including glioblastomas, adenocarcinomas of lung origin, aggressive breast cancers and chronic colitis (Cosenza et al., 2002, EI-Rawi et al., 2004 and Oshimi et al., 2004). Since the introduction of DAB389IL-7, little work has been performed with the fusion toxin despite the successful introduction of Ontak (DAB389IL-2) into the clinical setting. The failure of the fusion toxin to be more widely developed is in part due to its propensity to induce vascular leak syndrome (VLS). Anjin Group is improving on the original DAB389 DT toxophore used in the construction of DAB389IL-7. A series of modified DT toxophores with decreased propensity to induce VLS is being developed. Additionally, specific proteinases for in situ processing and activation of the fusion toxin are being introduced into the DT toxophore. Cleavage by specific proteinases selectively overexpressed in tumors will further enhance the selectivity of this class of drugs. The experimental aims of Anjin Group's proposed R21 will determine whether an IL-7 receptor-targeted fusion toxin, constructed with these modified DT toxophores, will be effective against IL-7 receptor positive cells and in particular, cells derived from human malignancies.

描述（由申请人提供）：Sweeney等（1998）最初报道了DAB 389 IL-7（一种基于白喉毒素（DT）的融合蛋白）的构建，并提出该融合蛋白可用作血液恶性肿瘤的治疗剂，包括急性淋巴细胞性白血病、慢性淋巴细胞性白血病、急性骨髓性白血病和Sezary综合征。其他小组的研究确定了潜在的靶点，包括成胶质细胞瘤、肺源性腺癌、侵袭性乳腺癌和慢性结肠炎（Cosenza et al.，2002年，EI-Rawi等人，2004和Oshimi等人，2004年）。自从引入DAB 389 IL-7以来，尽管Ontak（DAB 389 IL-2）成功引入临床环境，但几乎没有用融合毒素进行工作。融合毒素未能得到更广泛的开发，部分原因是它倾向于诱导血管渗漏综合征（VLS）。安进集团正在对用于构建DAB 389 IL-7的原始DAB 389 DT毒基进行改进。正在开发一系列具有降低诱导VLS倾向的改性DT toxophore。此外，用于融合毒素的原位加工和活化的特异性蛋白酶被引入DT毒基中。在肿瘤中选择性过表达的特异性蛋白酶的切割将进一步增强这类药物的选择性。Anjin Group提出的R21的实验目的将确定用这些修饰的DT toxophores构建的IL-7受体靶向融合毒素是否对IL-7受体阳性细胞，特别是来源于人恶性肿瘤的细胞有效。