PEDS Advance Access published online on February 13, 2004
Protein Engineering Design and Selection, doi:10.1093/protein/gzh023
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1 Department of Neurosurgery, University of Minnesota Cancer Center
* To whom correspondence should be addressed. E-mail: valle001{at}tc.umn.edu.
A bispecific immunotoxin (IT) called DTAT13 was synthesized in order to simultaneously target the uPAR-expressing tumor neovasculature and IL-13 receptor expressing glioblastoma cells with the goal of intratumoral administration for brain tumors. The recombinant hybrid was created using the non-internalizing amino terminal fragment (ATF) of urokinase-type plasminogen activator (uPA) and the IL-13 molecule for binding plus the catalytic and translocation portion of diphtheria toxin (DT) for killing. The 71 kDa protein was highly selective for human glioblastoma in vitro showing no loss in binding compared to DTAT and DTIL13 controls. In vivo, DTAT13 caused the regression of small tumors when administered at 10 µg/day given on a 5 dose schedule every other day. DTAT13 was able to target both overexpressed uPAR and the vasculature as demonstrated by its ability to kill HUVEC cells. Also, mortality studies indicated that DTAT13 was less toxic than DTAT or DTIL13. These findings indicate that bispecific IT may allow treatment of a broader subset of antigenically diverse patients while simultaneously reducing the exposure to toxin required than if two separate agents were employed.
Keywords:
diphtheria toxin/glioblastoma multiforme/immunotoxin/interleukin-13/urokinase-type plasminogen activator
Revised January 29, 2004
Accepted February 2, 2004
Oxford University Press
Article
A bispecific immunotoxin (DTAT13) targeting human IL-13 receptor (IL-13R) and urokinase-type plasminogen activator receptor (uPAR) in a mouse xenograft model of glioblastoma
2 Department of Therapeutic Radiology-Radiation Oncology, Section on Experimental Cancer Immunology, University of Minnesota Cancer Center
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