Targeting growth factor receptors with fusion toxins.
Recombinant toxins which bind to growth factor receptors have been prepared and used to kill cells responsible for malignant or autoimmune disease. Our strategy has been to genetically fuse ligands to different forms of Pseudomonas exotoxin which due to mutations or deletions do not bind to normal cells. The resulting recombinant chimeric toxins, in concentrations often less than 1 ng/ml, selectively kill cells expressing the appropriate growth factor receptor. The ligand may be a growth factor, such as transforming growth factor alpha (TGF alpha), interleukin 6 (IL6) or interleukin 2 (IL2), or single chain antigen binding proteins, such as the variable heavy and light regions of the monoclonal antibody anti-Tac. These chimeric toxins kill not only established cell lines but also fresh tumor cells from patients and display anti-tumor activity toward human malignant tumors in nude mice. While clinical trials are beginning with some of these agents, work continues to improve the effectiveness of recombinant chimeric toxins, and to widen the scope of disorders which might be treated by this approach.
Kreitman
R J
RJ
Laboratory of Molecular Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
FitzGerald
D
D
Pastan
I
I
D036002:ADP Ribose Transferases; D001427:Bacterial Toxins; D002470:Cell Survival / Q000187:drug effects; D005098:Exotoxins / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D000922:Immunotoxins; D007376:Interleukin-2 / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D015850:Interleukin-6 / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D007378:Interleukins / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D009369:Neoplasms / Q000188:drug therapy; D011549:Pseudomonas; D011956:Receptors, Cell Surface / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D016211:Transforming Growth Factor alpha / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D014407:Tumor Cells, Cultured; D037521:Virulence Factors; D000097668:Pseudomonas aeruginosa Exotoxin A
D036002:ADP Ribose Transferases; D001427:Bacterial Toxins; D005098:Exotoxins; D000922:Immunotoxins; D007376:Interleukin-2; D015850:Interleukin-6; D007378:Interleukins; D011956:Receptors, Cell Surface; D011993:Recombinant Fusion Proteins; D016211:Transforming Growth Factor alpha; D037521:Virulence Factors; D000097668:Pseudomonas aeruginosa Exotoxin A