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A novel ligand delivery system to non-invasively visualize and therapeutically exploit the IL13R?2 tumor-restricted biomarker.

Al's Comment:

 This is one of my favorite targets for brain tumor treatments.  The Musella Foundation has awarded 3 grants to the development of this system.  IL-13 is found on most brain tumor cells. Previous attempts to target this receptor had only limited success, because it is also found on normal brain as well as other organs. This researcher found a way to create a protien that binds only to the tumor associatd form of the receptor and not the naturally occuring one. Net result is it only attaches to tumors and not normal brain.  They are trying various ways of using thie targetting system. In this article, they discuss using it as an imaging agent - so we can see WHERE the tumor is - especially in cases where a regular MRI isn't helpfull as well as attaching a radioactive molecule to it to bring the radiation to the tumor cells.    <br><br>

Not only can it target brain cancer, but it may also be useful for:  Prostate, Melanoma, Lung, Colon Cancer, Ovarian Cancer and some Breast cancers.  We have been trying to raise money for a human trial of this targeting system attached to a toxin.

 


Posted on: 09/16/2012

Neuro Oncol. 2012 Sep 5. [Epub ahead of print]


A novel ligand delivery system to non-invasively visualize and therapeutically exploit the IL13Rα2 tumor-restricted biomarker.

Nguyen V, Conyers JM, Zhu D, Gibo DM, Hantgan RR, Larson SM, Debinski W, Mintz A.
Source
The Brain Tumor Center of Excellence, Department of Neurosurgery, (V.N., J.M.C., D.Z. D.M.G., W.D., A.M.); Department of Biochemistry, (R.R.H.); Department of Radiology (A.M.) Wake Forest School of Medicine, Winston-Salem, North Carolina; Department of Radiology, Memorial Sloan-Kettering Cancer Center, New York, New York (S.M.L.).

Abstract
Our objective was to exploit a novel ligand-based delivery system for targeting diagnostic and therapeutic agents to cancers that express interleukin 13 receptor alpha 2 (IL13Rα2), a tumor-restricted plasma membrane receptor overexpressed in glioblastoma multiforme (GBM), meningiomas, peripheral nerve sheath tumors, and other peripheral tumors. On the basis of our prior work, we designed a novel IL13Rα2-targeted quadruple mutant of IL13 (TQM13) to selectively bind the tumor-restricted IL13Rα2 with high affinity but not significantly interact with the physiologically abundant IL13Rα1/IL4Rα heterodimer that is also expressed in normal brain. We then assessed the in vitro binding profile of TQM13 and its potential to deliver diagnostic and therapeutic radioactivity in vivo. Surface plasmon resonance (SPR; Biacore) binding experiments demonstrated that TQM13 bound strongly to recombinant IL13Rα2 (K(d)∼5 nM). In addition, radiolabeled TQM13 specifically bound IL13Rα2-expressing GBM cells and specimens but not normal brain. Of importance, TQM13 did not functionally activate IL13Rα1/IL4Rα in cells or bind to it in SPR binding assays, in contrast to wtIL13. Furthermore, in vivo targeting of systemically delivered radiolabeled TQM13 to IL13Rα2-expressing subcutaneous tumors was demonstrated and confirmed non-invasively for the first time with (124)I-TQM13 positron emission tomography imaging. In addition, (131)I-TQM13 demonstrated in vivo efficacy against subcutaneous IL13Rα2-expressing GBM tumors and in an orthotopic synergeic IL13Rα2-positive murine glioma model, as evidenced by statistically significant survival advantage. Our results demonstrate that we have successfully generated an optimized biomarker-targeted scaffolding that exhibited specific binding activity toward the tumor-associated IL13Rα2 in vitro and potential to deliver diagnostic and therapeutic payloads in vivo.

PMID: 22952195 [PubMed - as supplied by publisher]

 


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