Targeting glioblastoma multiforme with an IL-13/diphtheria toxin fusion protein in vitro and in vivo in nude mice

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Abstract

Fusion proteins composed of tumor binding agents and potent catalytic toxins show promise for intracranial therapy of brain cancer and an advantage over systemic therapy. Glioblastoma multiforme (GBM) is the most common form of brain cancer and overexpresses IL-13R. Thus, we developed an interleukin-13 receptor targeting fusion protein, DT390IL13, composed of human interleukin-13 and the first 389 amino acids of diphtheria toxin. To measure its ability to inhibit GBM, DT390IL13 was tested in vitro and found to inhibit selectively the U373 MG GBM cell line with an IC50 around 12 pmol/l. Cytotoxicity was neutralized by anti-human-interleukin-13 antibody, but not by control antibodies. In vivo, small U373 MG glioblastoma xenografts in nude mice completely regressed in most animals after five intratumoral injections of I μg of DT390IL13 q.o.d., but not by the control fusion protein DT390IL-2. DT390IL13 was also tested against primary explant GBM cells of a patient's excised tumor and the IC50 was similar to that measured for U373 MG. Further studies showed a therapeutic window for DT390IL13 of 1-30 μg/injection and histology studies and enzyme measurements showed that the maximum tolerated dose of DT390IL13 had little effect on kidney, liver, spleen, lung and heart in non-tumor-bearing immunocompetent mice. Together, these data suggest that DT390IL13 may provide an important, alternative therapy for brain cancer.

Original languageEnglish (US)
Pages (from-to)419-427
Number of pages9
JournalProtein Engineering
Volume15
Issue number5
DOIs
StatePublished - 2002

Keywords

  • Diphtheria toxin
  • Glioblastoma multiforme
  • Immunotoxin
  • Interleukin-13
  • Toxin fusion protein

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