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TARGETING A CANCER-ASSOCIATED BIOMARKER WITH DIAGNOSTIC AND THERAPEUTIC RADIOACTIVITY

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abstract
Our objective is to exploit a ligand-based delivery system for targeting diagnostic and therapeutic agents to cancers expressing IL13Ra2, a tumor-restricted plasma membrane receptor overexpressed in GBM and other malignancies. Based on prior work, we designed a novel IL13Ra2-Targeted Quadruple Mutant of IL13 (TQM13) to selectively bind the tumor-restricted IL13Ra2 with high affinity but not significantly interact with the physiologically abundant IL13Ra1/IL4Ra heterodimer expressed in normal brain. In vitro binding experiments established that TQM13 bound strongly to IL13Ra2-expressing samples but not normal brain. Importantly, unlike wtIL13, TQM13 neither functionally activates IL13Ra1/IL4Ra in cells nor binds to it in Biacore studies. Furthermore, PET imaging confirmed in vivo targeting of systemically delivered 124I-TQM13 to IL13Ra2-expressing subcutaneous GBM tumors and 131I-TQM13 demonstrated therapeutic efficacy in such animal model. Our results demonstrated that we have successfully generated optimized scaffolding with specific binding activity towards the tumor-associated IL13Ra2 in vitro and potential to deliver diagnostic and therapeutic payloads in vivo.
subject
GBM
IL13Ra2
molecular imaging
radio-immunotherapy
targeted therapy escapees
contributor
Nguyen, Van (author)
Mintz, Akiva (committee chair)
Kridel, Steven J (committee member)
Debinski, Waldemar (committee member)
High, Kevin P (committee member)
Robbins, Michael E (committee member)
date
2012-06-12T08:35:56Z (accessioned)
2014-06-12T08:30:08Z (available)
2012 (issued)
degree
Molecular Medicine and Translational Science (discipline)
embargo
2014-06-12 (terms)
identifier
http://hdl.handle.net/10339/37277 (uri)
language
en (iso)
publisher
Wake Forest University
title
TARGETING A CANCER-ASSOCIATED BIOMARKER WITH DIAGNOSTIC AND THERAPEUTIC RADIOACTIVITY
type
Dissertation

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