A RECOMBINANT GM-CSF-PE40 LIGAND TOXIN IS FUNCTIONALLY ACTIVE BUT NOTCYTOTOXIC TO CELLS

A granulocyte/macrophage colony-stimulating factor (GM-CSF)-Pseudomona s 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 mali gnant cells prior to autologous bone marrow transplantation. The GM-CS F-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 t o be fully functional as determined by an in vitro adenosine diphospha te-ribosylation assay. The GM-CSF-PE40 fusion protein, however, was no t cytotoxic to a number of myeloid leukaemia cell lines. It is suggest ed that the mechanism of internalization of the GM-CSF receptor is not appropriate for the translocation of PE to the cytosol where it can f ulfil its cytotoxic potential.