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DAB389IL-7的构建，DAB389IL-7是基于白喉毒素（DT）的融合蛋白，并提出该融合蛋白可以用作血液性恶性肿瘤的治疗剂，包括急性淋巴细胞性白血病，慢性淋巴细胞综合症状，急性疾病，急性症状疾病，急性淋巴细胞综合体。其他小组的研究鉴定了包括胶质母细胞瘤，肺部腺癌，侵略性乳腺癌和慢性结肠炎在内的潜在靶标（Cosenza等，2002； Ei-Rawi等，2004和Oshimi等，2004）。自从引入DAB389IL-7以来，尽管成功将ONTAK（DAB389IL-2）引入临床环境，但对融合毒素的工作几乎没有进行。融合毒素无法更广泛发达的失败部分是由于它诱导血管泄漏综合征（VLS）的倾向。 Anjin组正在改善用于构建DAB389IL-7的原始DAB389 DT Toxophore。正在开发一系列具有诱导VLS倾向降低的修饰的DT毒液。另外，将特异性蛋白酶用于原位加工和融合毒素的激活中，也被引入DT毒蛋白中。特定蛋白酶在肿瘤中选择性过表达的特定蛋白酶的切割将进一步提高该类别的药物的选择性。 Anjin组拟议的R21的实验目的将确定用这些改良的DT毒剂构建的IL-7受体靶向融合毒素是否有效地针对IL-7受体阳性细胞，尤其是从人类恶性肿瘤中得出的细胞。