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.

• Authors: E B Sweeney, F M Foss, J R Murphy, J C vanderSpek
• Journal: Bioconjugate chemistry (Bioconjug Chem) 1998 Mar-Apr Vol. 9 Issue 2 Pg. 201-7 ISSN: 1043-1802 [Print] United States
• PMID: 9548535 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antigens, CD
• Antineoplastic Agents
• DAB(389) interleukin-7
• Diphtheria Toxin
• Immunotoxins
• Interleukin-7
• Peptide Elongation Factor 2
• Peptide Elongation Factors
• Receptors, Interleukin
• Receptors, Interleukin-7
• Recombinant Fusion Proteins
• Adenosine Diphosphate Ribose

Topics

• Adenosine Diphosphate Ribose (metabolism)
• Animals
• Antigens, CD (analysis, physiology)
• Antineoplastic Agents (pharmacology)
• B-Lymphocytes (pathology)
• Cell Death
• Diphtheria Toxin (pharmacology)
• Escherichia coli (genetics)
• Humans
• Immunotoxins
• Interleukin-7 (pharmacology)
• Leukemia, T-Cell (pathology)
• Mice
• Peptide Elongation Factor 2
• Peptide Elongation Factors (metabolism)
• Rats
• Receptors, Interleukin (analysis, physiology)
• Receptors, Interleukin-7
• Recombinant Fusion Proteins
• Tumor Cells, Cultured