IL-13Rα2 is a Glioma-Restricted Receptor for Interleukin-13

Abstract

We have found that binding sites for interleukin-13 (IL-13) are overexpressed in a vast majority of high-grade astrocytomas (HGAs). These binding sites for IL-13 are distinct from the physiological receptor in that it does not bind IL-4. We also demonstrated that IL-13 receptor alpha 2 protein chain (IL-13Ralpha2), an IL-4-independent receptor for IL-13, is abundant among HGAs, but not in normal organs. To examine if IL-13Ralpha2 is the tumor-associated site for IL-13, we stably transfected normal Chinese hamster ovary (CHO) cells and glioma G-26 cells to express either human (h) or murine (m) IL-13Ralpha2. CHO-hIL-13Ralpha2(+) cells and G-26-h/mIL-13Ralpha2(+) cells, and not CHO and G-26 parental or mock-transfected cells, specifically bound IL-13 in an IL-4-independent manner. The IL-13Ralpha2(+) cells also became highly susceptible to the killing by an IL-13-based cytotoxic fusion protein. In loss of function studies, a HGA cell line, SNB-19, was transfected with antisense (as) hIL-13Ralpha2. as-SNB-19-hIL-13Ralpha2(+) cells lost their natural affinity towards IL-13 and became resistant to IL-13-based cytotoxins. The fact, that IL-13Ralpha2-positive cells bind IL-13 independent of IL-4, become susceptible to IL-13 cytotoxins, and cells deprived of IL-13Ralpha2 receptor lose these features, demonstrates that IL-13Ralpha2 is the brain tumor-associated receptor for IL-13.

Adenoviral vector–mediated gene transfer of IL‐13Rα2 chain followed by IL‐13 cytotoxin treatment offers potent targeted therapy for cytotoxin‐resistant cancers

“…Previous studies have demonstrated that the attachment of radiolabeled IL-13 to the functional heterodimer receptor can be competed by IL-4 as well as IL-13, [30][31][32]49 whereas its attachment to IL-13R 2 is competed by IL-13 but not IL-4. 2,9,10,15,33,36 To confirm that the cytotoxicity of IL-13 cytotoxin was specifically mediated through IL-13R 2 chain delivered by Ad-IL-13R 2 vector, A549 cells were infected with Ad-IL-13R 2 at MOI 10 followed by treatment with IL-13 cytotoxin (10 ng/ml) in the presence of a 50-fold dose of human IL-13 or IL-4. As shown in Figure 4, IL-13 and IL-4 did not affect the growth of uninfected or Ad-LacZ-infected cells, regardless of treatment with IL-13 cytotoxin.…”

“…Previous studies have proved that IL-13 cytotoxin is highly selective and potent in killing cancer cells that overexpress IL-13R 2 chain. 3,[5][6][7][8][9][10][11][12]14,16,17 Preclinical studies regarding the safety and toxicity of IL-13 cytotoxin have been performed in mice, rats and monkeys; and all animals tolerated this therapy well, with minimal toxicity to vital organs. 18 Based on these results, 3 phase I/II clinical trials of this cytotoxin in adults with malignant glioma have been initiated, and all are currently ongoing in the United States.…”

Maximizing Local Access to Therapeutic Deliveries in Glioblastoma. Part I: Targeted Cytotoxic Therapy

“…We discovered that interleukin 13 receptor alpha 2 (IL-13RA2) and EphA2 receptor are overexpressed in most patients with GBM, but not in normal brain (27)(28)(29)(30)(31), and also in spontaneous canine GBM, an excellent translational model of GBM (32)(33)(34)(35). Expression of IL-13RA2 and EphA2 is partially overlapping; hence, the combined overexpression is ~90% in patients with GBM (31).…”

Intracranial therapy of glioblastoma with the fusion protein DTIL13 in immunodeficient mice

“…27 This protein binds IL-13, but does not bind 29 Studies have shown that malignant glioblastomas overexpress this restricted receptor for IL-13, and that IL-13Ra2 is the molecular entity responsible for IL-13 binding to glioblastoma tumors. 7,8,12,30,31 An IL-13-based Pseudomonas exotoxin A (PE) fusion protein (FP) showed promising clinical antitumor activity, but no toxicity to normal endothelial, lymphoid, or bone marrow precursor cells. 32 DT and PE have identical mechanisms of action and are known to induce cell death with as little as 1 toxin molecule.…”

“…[6][7][8] Targeting the IL-13 receptor with an immunotoxin (IT) has already proven to have potential for treating brain tumors. [8][9][10][11][12] ITs are not mainstream pharmaceuticals, and treatment of systemic tumors with ITs has been limited by their failure to localize in tumor. The promise of these drugs is considerably greater for brain-cancer therapy, since IT can be directly administered intracranially.…”