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

• Published in: Immunology and cell biology Vol. 75; no. 3; p. 289
• Main Authors: O'Brien, P, Smythe, A, Biggs, J C, Smith, G M
• Format: Journal Article
• Language: English
• Published: United States 01.06.1997
• Subjects: Adenosine Diphosphate Ribose - metabolism; ADP Ribose Transferases; 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
• ISSN: 0818-9641
• DOI: 10.1038/icb.1997.44

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.