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 interleuk in 13 (IL13). This glioma-associated receptor for IL13 is interleukin 4 (IL 4)-independent. This is in contrast to the physiological and IL4-shared rec eptor for the IL13, IL13/4 receptor, which is found on many normal organs. IL13-based Pseudomonas exotoxin (PE)-containing cytotoxic fusion proteins h ave been shown to be very potent anti-glioma agents. However, native IL13-b ased cytotoxins interact with both forms of the IL13 receptor. Therefore, m utations in IL13 were made in order to diminish/eliminate IL13's interactio n with the shared IL13/4 receptor of normal tissue. These mutations encompa ssed amino acids located on alpha -helix A and C of IL13. We have engineere d double or triple mutants of IL13 linked to various forms of PE. We found that these mutations could be successfully incorporated into IL13 without t he loss of the protein's ability to selectively deliver the toxin to glioma cells while reducing their toxicity. (C) 2001 Elsevier Science Ireland Ltd . All rights reserved.