Interleukin 7 (IL-7) receptor-specific cell killing by DAB389 IL-7: a novel agent for the elimination of IL-7 receptor positive cells.
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.
Sweeney
E B
EB
Evans Department of Clinical Research, Boston Medical Center, Massachusetts 02118, USA.
Foss
F M
FM
Murphy
J R
JR
vanderSpek
J C
JC
D000246:Adenosine Diphosphate Ribose / Q000378:metabolism; D000818:Animals; D015703:Antigens, CD / Q000032:analysis / Q000502:physiology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001402:B-Lymphocytes / Q000473:pathology; D016923:Cell Death; D004167:Diphtheria Toxin / Q000494:pharmacology*; D004926:Escherichia coli / Q000235:genetics; D006801:Humans; D000922:Immunotoxins; D015851:Interleukin-7 / Q000494:pharmacology*; D015458:Leukemia, T-Cell / Q000473:pathology; D051379:Mice; D020652:Peptide Elongation Factor 2; D010445:Peptide Elongation Factors / Q000378:metabolism; D051381:Rats; D018123:Receptors, Interleukin / Q000032:analysis / Q000502:physiology*; D020395:Receptors, Interleukin-7; D011993:Recombinant Fusion Proteins; D014407:Tumor Cells, Cultured
D015703:Antigens, CD; D000970:Antineoplastic Agents; C112050:DAB(389) interleukin-7; D004167:Diphtheria Toxin; D000922:Immunotoxins; D015851:Interleukin-7; D020652:Peptide Elongation Factor 2; D010445:Peptide Elongation Factors; D018123:Receptors, Interleukin; D020395:Receptors, Interleukin-7; D011993:Recombinant Fusion Proteins; D000246:Adenosine Diphosphate Ribose