Molecular targeting of malignant gliomas with novel multiply-mutated interleukin 13-based cytotoxins.
A vast majority of high-grade gliomas over-express a receptor for interleukin 13 (IL13). This glioma-associated receptor for IL13 is interleukin 4 (IL4)-independent. This is in contrast to the physiological and IL4-shared receptor for the IL13, IL13/4 receptor, which is found on many normal organs. IL13-based Pseudomonas exotoxin (PE)-containing cytotoxic fusion proteins have been shown to be very potent anti-glioma agents. However, native IL13-based cytotoxins interact with both forms of the IL13 receptor. Therefore, mutations in IL13 were made in order to diminish/eliminate IL13's interaction with the shared IL13/4 receptor of normal tissue. These mutations encompassed amino acids located on alpha-helix A and C of IL13. We have engineered double or triple mutants of IL13 linked to various forms of PE. We found that these mutations could be successfully incorporated into IL13 without the loss of the protein's ability to selectively deliver the toxin to glioma cells while reducing their toxicity.
Nash
K T
KT
Section of Neurosurgery H110, Pennsylvania State University College of Medicine, Hershey, PA 17033, USA.
Thompson
J P
JP
Debinski
W
W
D002470:Cell Survival / Q000187:drug effects; D003603:Cytotoxins / Q000235:genetics / Q000494:pharmacology / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D005910:Glioma / Q000188:drug therapy*; D006801:Humans; D020128:Inhibitory Concentration 50; D018793:Interleukin-13 / Q000235:genetics / Q000494:pharmacology* / Q000627:therapeutic use; D053661:Interleukin-13 Receptor alpha1 Subunit; D016296:Mutagenesis; D009154:Mutation; D018123:Receptors, Interleukin / Q000378:metabolism; D053660:Receptors, Interleukin-13; D014407:Tumor Cells, Cultured / Q000187:drug effects
D003603:Cytotoxins; C508181:IL13RA1 protein, human; D018793:Interleukin-13; D053661:Interleukin-13 Receptor alpha1 Subunit; D018123:Receptors, Interleukin; D053660:Receptors, Interleukin-13