부산대학교 도서관

Restricting the cytotoxicity of anticancer agents by targeting receptors exclusively expressed on tumor cells is critical when treating infiltrative brain tumors such as glioblastoma multiforme (GBM). GBMs express an IL-13 receptor (IL13R[alpha]2) that differs from the physiological IL4R/IL13R receptor. We developed a regulatable adenoviral vector (Ad.mhlL-4.TRE.mhlL-13-PE) encoding a mutated human IL-13 fused to Pseudomonas exotoxin (mhlL-13-PE) that specifically binds to IL13R[alpha]2 to provide sustained expression, effective anti-GBM cytotoxicity, and minimal neurotoxicity. The therapeutic Ad also encodes mutated human IL-4 that binds to the physiological IL4R/IL13R without interacting with IL13R[alpha]2, thus inhibiting potential binding of mhlL-13-PE to normal brain cells. Using intracranial GBM xenografts and syngeneic mouse models, we tested the Ad. mhlL-4.TRE.mhlL-13-PE and two protein formulations, hlL-13-PE used in clinical trials (Cintredekin Besudotox) and a second-generation mhlL-13-PE. Cintredekin Besudotox doubled median survival without eliciting long-term survival and caused severe neurotoxicity; mhlL-13-PE led to ~40% long-term survival, eliciting severe neurological toxicity at the high dose tested. In contrast, Ad-mediated delivery of mhlL-13-PE led to tumor regression and long-term survival in over 70% of the animals, without causing apparent neurotoxicity. Although Cintredekin Besudotox was originally developed to target GBM, when tested in a phase III trial it failed to achieve clinical endpoints and revealed neurotoxicity. Limitations of Cintredekin Besudotox include its short half-life, which demanded frequent or continued administration, and binding to IL4R/IL13R, present in normal brain cells. These shortcomings were overcome by our therapeutic Ad, thus representing a significant advance in the development of targeted therapeutics for GBM. targeted glioma therapeutics | immunotoxins | adenoviral vectors | GBM12 tumors | TetON system doi/ 10.1073/pnas.1008261107