The primary objective of this proposal is to physically eliminate malignant T and B cells that express Interleukin-2 receptor (IL2R) for treatment of certain leukemia/lymphomas and allogeneic organ transplant rejections. In recent years, therapeutic approa ches for hematological malignancies and allogeneic organ transplant rejections are moving away from non-specific cytotoxic to cell-specific treatment alternatives. The high-affinity IL-2R is primarily expressed in newly activated lymphocytes, including aut oimmune cells, abnormal T cells of patients with leukemia/lymphoma, and T cells of individuals rejecting allografts, but not in resting or memory lymphocytes. This aspect of IL-2R expression can be exploited to deliver proteins of interest, linked to IL-2, specifically into the cells. In this project, we propose to generate recombinant chimeric proteins consisting of IL-2 and cell death inducing proteins of human origin that will have the potential to treat these malignancies. These proteins will specifical ly induce cells’ own physiologic suicide mechanism by targeting the activation of the final executioner enzyme, caspase-3, of the system. The choice of biologics (chimeric proteins), the specificity, and the selected target of these biologics, ( activation of endogenous suicide mechanisms) to achieve cell death in IL-2R expressing cells make this proposal novel and significant. Therapeutic approaches using biologics, particularly of human origin, are conceivably much safer and effective than treat ments with nonbiological agents. If proved successful in vitro and in vivo in mice models of leukemia and/or transplantation, these novel regimens will have the potential to be applied to clinics in areas such as cancer, transplantation and autoimmunity.
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