Intracranial elimination of human glioblastoma brain tumors in nude rats using the bispecific ligand-directed toxin, DTEGF13 and convection enhanced delivery

Seunguk Oh, John R. Ohlfest, Deborah A. Todhunter, Vincent D. Vallera, Walter A. Hall, Hua Chen, Daniel A. Vallera

Research output: Contribution to journalArticlepeer-review

27 Scopus citations

Abstract

A bispecific ligand-directed toxin (BLT) consisting of human interleukin-13, epithelial growth factor, and the first 389 amino acids of diphtheria toxin was assembled in order to target human glioblastoma. In vitro, DTEGF13 selectively killed the human glioblastoma cell line U87-luc as well as other human glioblastomas. DTEGF13 fulfilled the requirement of a successful BLT by having greater activity than either of its monospecific counterparts or their mixture proving it necessary to have both ligands on the same single chain molecule. Aggressive brain tumors established intracranially (IC) in nude rats with U87 glioma genetically marked with a firefly luciferase reporter gene were treated with two injections of DTEGF13 using convection enhanced delivery resulting in tumor eradication in 50% of the rats which survived with tumor free status at least 110 days post tumor inoculation. An irrelevant BLT control did not protect establishing specificity. The bispecific DTEGF13 MTD dose was measured at 2 μg/injection or 0.5 μg/kg and toxicity studies indicated safety in this dose. Combination of monospecific DTEGF and DTIL13 did not inhibit tumor growth. ELISA assay indicated that anti-DT antibodies were not generated in normal immunocompetent rats given identical intracranial DTEGF13 therapy. Thus, DTEGF13 is safe and efficacious as an alternative drug for glioblastoma therapy and warrants further study.

Original languageEnglish (US)
Pages (from-to)331-342
Number of pages12
JournalJournal of neuro-oncology
Volume95
Issue number3
DOIs
StatePublished - Dec 2009

Bibliographical note

Funding Information:
Acknowledgments This work was supported in part by the US Public Health Service Grants RO1-CA108637 (DAV) awarded by the NCI and the NIAID, DHHS and R21-NS055738 (JRO) NIDS, and the Martha L. Kramer Fund.

Keywords

  • Carcinoma
  • Cytotoxin
  • Diphtheria toxin
  • EGF
  • Fusion protein
  • Glioblastoma
  • IL-13
  • Immunotoxin
  • Xenograft model

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