A bispecific immunotoxin (DTAT13) targeting human IL-13 receptor (IL-13R) and urokinase-type plasminogen activator receptor (uPAR) in a mouse xenograft model

Deborah A. Todhunter, Walter A. Hall, Edward Rustamzadeh, Yanqun Shu, Sekou O. Doumbia, Daniel A Vallera

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58 Scopus citations

Abstract

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 DTILI3 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.

Original languageEnglish (US)
Pages (from-to)157-164
Number of pages8
JournalProtein Engineering, Design and Selection
Volume17
Issue number2
DOIs
StatePublished - Feb 2004

Keywords

  • Diphtheria toxin
  • Glioblastoma multiforme
  • Immunotoxin
  • Interleukin-13/urokinase-type plasminogen activator

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