PEDS Advance Access originally published online on February 13, 2004
Protein Engineering Design and Selection 2004 17(2):157-164; doi:10.1093/protein/gzh023
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© 2004 Oxford University Press
A bispecific immunotoxin (DTAT13) targeting human IL-13 receptor (IL-13R) and urokinase-type plasminogen activator receptor (uPAR) in a mouse xenograft model
1Department of Neurosurgery and 2Department of Therapeutic Radiology–Radiation Oncology, Section on Experimental Cancer Immunology, University of Minnesota Cancer Center, Mayo Mail Code 367, Harvard St at East River Road, Minneapolis, MN 55455, USA
3 To whom correspondence should be addressed. e-mail: valle001{at}tc.umn.edu
A bispecific immunotoxin (IT) called DTAT13 was synthesized in order to target simultaneously the urokinase-type plasminogen activator receptor (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 N-terminal fragment (ATF) of 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 on binding compared with DTAT and DTIL13 controls. In vivo, DTAT13 caused the regression of small tumors when administered at 10 µg/day given on a five-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.
Received October 3, 2003; revised January 29, 2004; accepted February 2, 2004 Edited by Paul Carter
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