Modified Diphtheria Toxin IL-7 Fusion Toxins

描述(申请人提供)：Sweeney等人。(1998)首次报道了基于白喉毒素(DT)的融合蛋白DAB389IL-7的构建，并提出该融合蛋白可用于治疗血液系统恶性肿瘤，包括急性淋巴细胞白血病、慢性淋巴细胞白血病、急性髓系白血病和Sezary综合征。其他小组的研究确定了潜在的目标，包括胶质母细胞瘤、肺源性腺癌、侵袭性乳腺癌和慢性结肠炎(Cosenza等人，2002年，Ei-Rawi等人，2004年和Oshimi等人，2004年)。自引入DAB389IL-7以来，尽管成功地将Ontak(DAB389IL-2)引入临床环境，但对融合毒素的研究工作很少。融合毒素未能得到更广泛的开发，部分原因是它容易引发血管泄漏综合征(VLS)。安进集团正在对DAB389IL-7建造中使用的原有DAB389 DT毒物进行改进。正在开发一系列具有降低诱发VLS倾向的改良的DT毒素载体。此外，用于原位加工和激活融合毒素的特定蛋白水解酶正在被引入DT毒素载体。选择性地在肿瘤中过度表达的特定蛋白水解酶的切割将进一步增强这类药物的选择性。安进集团提出的R21的实验目标将确定用这些修饰的DT毒素构建的IL-7受体靶向融合毒素是否对IL-7受体阳性细胞有效，特别是对来自人类恶性肿瘤的细胞。

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.