A recombinant GM-CSF-PE40 ligand toxin is functionally active but not cytotoxic to cells

Immunol Cell Biol. 1997 Jun;75(3):289-94. doi: 10.1038/icb.1997.44.

Abstract

A granulocyte/macrophage colony-stimulating factor (GM-CSF)-Pseudomonas exotoxin (PE) 40 fusion protein was constructed for potential use in the treatment of myeloid leukaemias, as a conditioning agent prior to allogeneic bone marrow transplantation or for ex vivo purging of malignant cells prior to autologous bone marrow transplantation. The GM-CSF-PE40 fusion protein successfully binds to the GM-CSF receptor and is capable of initiating a mitogenic signal similar to native GM-CSF in the GM-CSF-dependent TF1 cell line. The toxin component also appears to be fully functional as determined by an in vitro adenosine diphosphate-ribosylation assay. The GM-CSF-PE40 fusion protein, however, was not cytotoxic to a number of myeloid leukaemia cell lines. It is suggested that the mechanism of internalization of the GM-CSF receptor is not appropriate for the translocation of PE to the cytosol where it can fulfil its cytotoxic potential.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADP Ribose Transferases*
  • Adenosine Diphosphate Ribose / metabolism
  • Bacterial Toxins / genetics
  • Bacterial Toxins / metabolism
  • Bacterial Toxins / pharmacology*
  • Base Sequence
  • Biological Transport, Active
  • Bone Marrow Purging
  • Bone Marrow Transplantation
  • Cell Death / drug effects
  • DNA Primers / genetics
  • Exotoxins / genetics
  • Exotoxins / metabolism
  • Exotoxins / pharmacology*
  • Granulocyte-Macrophage Colony-Stimulating Factor / genetics
  • Granulocyte-Macrophage Colony-Stimulating Factor / metabolism
  • Granulocyte-Macrophage Colony-Stimulating Factor / pharmacology*
  • Humans
  • Immunotoxins / genetics
  • Immunotoxins / metabolism
  • Immunotoxins / pharmacology*
  • In Vitro Techniques
  • Leukemia, Myeloid / therapy
  • Polymerase Chain Reaction
  • Pseudomonas aeruginosa Exotoxin A
  • Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / metabolism
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism
  • Recombinant Fusion Proteins / pharmacology
  • Transplantation Conditioning
  • Tumor Cells, Cultured
  • Virulence Factors*

Substances

  • Bacterial Toxins
  • DNA Primers
  • Exotoxins
  • Immunotoxins
  • Receptors, Granulocyte-Macrophage Colony-Stimulating Factor
  • Recombinant Fusion Proteins
  • Virulence Factors
  • Adenosine Diphosphate Ribose
  • Granulocyte-Macrophage Colony-Stimulating Factor
  • ADP Ribose Transferases