Modified Diphtheria Toxin IL-7 Fusion Toxins

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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.