Recombinant fusion toxins--a new class of targeted biologic therapeutics.
The design and construction of a new class of recombinant therapeutic agents, receptor-specific cytotoxins, has occurred within the last 5 years. Development of a number of receptor-targeted fusion toxins has been based on a detailed understanding of the structure-function relationships of both diphtheria toxin and Pseudomonas exotoxin A, and availability of the nucleic acid sequences of each structural gene. A variety of fusion toxins in which the native receptor-binding domain of either diphtheria toxin or Pseudomonas exotoxin A has been genetically replaced with either a polypeptide hormone or growth factor have been constructed. These fusion toxins selectively intoxicate receptor-bearing cells in vitro and are active in a variety of animal model systems. DAB486IL-2, and IL-2 receptor targeted cytotoxin, is the first fusion toxin to be evaluated in patients. Phase I/II clinical trials have been performed in refractory leukemia/lymphoma, severe rheumatoid arthritis, and Type 1 diabetes. DAB486IL-2 has been administered to more than 200 patients, has been well tolerated, and has shown encouraging signs of potential efficacy in all three clinical indications. Thus, DAB486IL-2 represents a new class of targeted biological therapeutic response modifiers whose mode of action is based on selective elimination of target cells.
Woodworth
T G
TG
Seragen, Inc., Hopkinton, MA 01748.
Nichols
J C
JC
D002986:Clinical Trials as Topic; D004167:Diphtheria Toxin / Q000627:therapeutic use*; D005098:Exotoxins / Q000627:therapeutic use; D006801:Humans; D000922:Immunotoxins / Q000627:therapeutic use; D007376:Interleukin-2 / Q000627:therapeutic use*; D009369:Neoplasms / Q000188:drug therapy; D011993:Recombinant Fusion Proteins / Q000627:therapeutic use*; D011994:Recombinant Proteins / Q000627:therapeutic use; D016211:Transforming Growth Factor alpha / Q000627:therapeutic use
C057689:CD4-Pseudomonas toxin; C054780:DAB(486)-interleukin 2; D004167:Diphtheria Toxin; D005098:Exotoxins; D000922:Immunotoxins; D007376:Interleukin-2; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; D016211:Transforming Growth Factor alpha; C062005:transforming growth factor type alpha-Pseudomonas exotoxin A