Interleukin 7 (IL-7) receptor-specific cell killing by DAB389 IL-7: a novel agent for the elimination of IL-7 receptor positive cells.

Abstract

Interleukin 7 (IL-7) induces the proliferation of B cell progenitors in long-term bone marrow cultures, promotes the growth of resting fetal and adult thymocytes, and costimulates mature human T cell proliferation. IL-7 also induces cell growth in hematologic malignancies such as acute lymphoblastic leukemia, chronic lymphocytic leukemia, acute myelogenous leukemia, and Sezary syndrome. We have constructed a recombinant fusion protein, DAB389 IL-7, composed of the catalytic and transmembrane domains of diphtheria toxin (DT), fused to IL-7. We demonstrate that DAB389 IL-7 is selectively cytotoxic for only those cells bearing the IL-7 receptor and that entry into target cells is mediated through the receptor. The nontoxic mutant, DA(E149S)B389 IL-7, was constructed and used to demonstrate that the catalytic domain of DT is responsible for the ADP ribosylation of elongation factor 2 that results in cytotoxicity. Finally, we demonstrate that DA(E149S)B389 IL-7 induces the growth of IL-7-dependent cells, verifying the bioactivity of the IL-7 binding domain of DAB389 IL-7. We propose that DAB389 IL-7 may be an important reagent in studying the IL-7--IL-7 receptor complex and may possess potential as a therapeutic agent against IL-7 receptor-bearing hematologic malignancies.