Generation of a Modified DT_IL3 Fusion Toxin

DESCRIPTION (provided by applicant): A number of protein fusion toxins, composed of the diphtheria toxin (DT) toxophore and a targeting ligand, have been assembled and tested in Phase I clinical trials for the treatment of leukemias. To date, the only FDA approved protein fusion toxin is ONTAK. ONTAK is a DT, interleukin-2 receptor-targeted fusion toxin used to treat persistent or recurrent, cutaneous T-cell lymphoma. Sales of this drug range between 30 and 40M annually. DT-based protein fusion toxins tar geting the interleukin-3 (IL-3) receptor have produced encouraging early clinical results. The goals of this Phase I proposal are to create a DT-IL3 fusion toxin, using a DT toxophore that has been modified to reduce potential for induction of vascular lea k, that is as potent as the existing DT-IL3 fusion toxin. Vascular leakage in humans is a common side effect of fusion toxin therapy and can inhibit development of this class of therapeutic agent. A reduced side effect profilethe chances of a DT-IL3 toxin becoming available to treat patients with AML. reat AML. PUBLIC HEALTH RELEVANCE: This project seeks to determine if a DT-IL3 fusion toxin with reduce VLS profile can developed. This fusion toxin could provide a wider therapeutic window and ther eby enhance