Interleukin 2 receptor-targeted cytotoxicity. Receptor binding requirements for entry of a diphtheria toxin-related interleukin 2 fusion protein into cells.
The receptor binding requirements for entry of the NAD+ ADP-ribosyltransferase component of DAB486-IL 2 into target cells were examined. Experiments utilizing cell lines bearing either high-affinity or individual subunits of the interleukin 2 receptor (IL 2R) as well as human peripheral blood mononuclear cells with natural killer activity demonstrate that the high-affinity receptor facilitates delivery of fragment A from DAB486-IL 2 to the cytosol approximately 1000 times more efficiently than either the intermediate-(p75) or low-affinity (p55) forms of the IL 2R. We show that elongation factor 2 (EF-2) in these cells is not quantitatively or qualitatively altered indicating that the relative resistance to intoxication displayed by IL 2R variant cell lines cannot be attributed to an altered intracellular target of the hybrid toxin. We also demonstrate that an alteration in the binding of DAB486-IL 2 to the p75 subunit of the IL 2R may account for the selective cytotoxicity of DAB486-IL 2 for cells bearing the heterodimeric high-affinity IL 2R.
Waters
C A
CA
Seragen, Inc., Boston, MA.
Schimke
P A
PA
Snider
C E
CE
Itoh
K
K
Smith
K A
KA
Nichols
J C
JC
Strom
T B
TB
Murphy
J R
JR
D000595:Amino Acid Sequence; D000945:Antigens, Differentiation, T-Lymphocyte / Q000276:immunology; D001667:Binding, Competitive; D017252:CD3 Complex; D004167:Diphtheria Toxin / Q000494:pharmacology*; D006801:Humans; D007376:Interleukin-2 / Q000378:metabolism* / Q000494:pharmacology; D007694:Killer Cells, Natural / Q000276:immunology; D020652:Peptide Elongation Factor 2; D010445:Peptide Elongation Factors / Q000502:physiology; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D015375:Receptors, Interleukin-2 / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism* / Q000494:pharmacology
D000945:Antigens, Differentiation, T-Lymphocyte; D017252:CD3 Complex; D004167:Diphtheria Toxin; D007376:Interleukin-2; D020652:Peptide Elongation Factor 2; D010445:Peptide Elongation Factors; D011948:Receptors, Antigen, T-Cell; D015375:Receptors, Interleukin-2; D011993:Recombinant Fusion Proteins