期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 107, 期 46, 页码 20021-20026出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1008261107
关键词
targeted glioma therapeutics; immunotoxins; adenoviral vectors; GBM12 tumors; TetON system
资金
- National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS) [1R21-NS054143, 1U01 NS052465, 1R01 NS057711, 1R01 NS 054193, R01 NS061107, 1F32 NS058156]
- The Bram and Elaine Goldsmith and the Medallions Group Endowed Chairs in Gene Therapeutics
- The Linda Tallen and David Paul Kane Foundation
- The Drown Foundation
- Board of Governors at Cedars-Sinai Medical Center
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.mhIL-4.TRE.mhIL-13-PE) encoding a mutated human IL-13 fused to Pseudomonas exotoxin (mhIL-13-PE) that specifically binds to IL13Ra2 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 IL13Ra2, thus inhibiting potential binding of mhIL-13-PE to normal brain cells. Using intracranial GBM xenografts and syngeneic mouse models, we tested the Ad. mhIL-4.TRE.mhIL-13-PE and two protein formulations, hIL-13-PE used in clinical trials (Cintredekin Besudotox) and a second-generation mhIL-13-PE. Cintredekin Besudotox doubled median survival without eliciting long-term survival and caused severe neurotoxicity; mhIL-13-PE led to similar to 40% long-term survival, eliciting severe neurological toxicity at the high dose tested. In contrast, Ad-mediated delivery ofmhIL-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 end-points 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.
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