Epidermal growth factor receptor (EGFR)-Retargeted measles virus strains effectively target EGFR- or EGFRvIII expressing gliomas

Georgia Paraskevakou, Cory Allen, Takafumi Nakamura, Paula Zollman, C. David James, Kah-Whye Peng, Mark Schroeder, Stephen J Russell, Evanthia Galanis

Research output: Contribution to journalArticle

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Abstract

A retargeted measles virus strain MV-GFP-HAA-scEGFR was generated by engineering the MV-NSe Edmonston vaccine strain to incorporate both CD46 (Y481A) and signaling lymphocyte activation molecule (SLAM) (R533A) ablating mutations in the hemagglutinin protein in combination with the display of a single-chain antibody against epidermal growth factor receptor (EGFR) at the C terminus of hemagglutinin. The unmodified MV-GFP virus was used as a positive control. Specificity of the EGFR retargeted virus was demonstrated in non-permissive Chinese hamster ovary (CHO) cells stably transfected to express either the natural receptors CD46 or SLAM or the target receptors EGFR and EGFRvIII. In vitro, the retargeted virus had potent antitumor activity against EGFR- or EGFRvIII-overexpressing primary glioblastoma multi-forme (GBM) cell lines that was comparable to the activity of the unmodified MV-GFP virus. Intratumoral administration of MV-GFP-HAA-scEGFRvIII in orthotopic GBM12 xenografts resulted in tumor regression, as demonstrated by bioluminescence imaging and significant prolongation of survival, that was comparable to the effect of the unmodified strain. In contrast to MV-GFP, central nervous system administration of the targeted MV-GFP-HAA-scEGFR virus in measles replication-permissive Ifnarko CD46 transgenic mice resulted in no neurotoxicity. In conclusion, EGFR-retargeted measles virus strains have comparable therapeutic efficacy to the unmodified virus in glioma cells overexpressing EGFR or EGFRvIII in vivo and in vitro, and improved therapeutic index, a finding with potential translational implications in glioma virotherapy.

Original languageEnglish (US)
Pages (from-to)677-686
Number of pages10
JournalMolecular Therapy
Volume15
Issue number4
DOIs
StatePublished - Apr 2007

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Measles virus
Epidermal Growth Factor Receptor
Glioma
Viruses
Hemagglutinins
Lymphocyte Activation
Single-Chain Antibodies
Glioblastoma
Cricetulus
Heterografts
Transgenic Mice
epidermal growth factor receptor VIII
Ovary
Vaccines
Central Nervous System
Cell Line
Mutation
Therapeutics
Neoplasms
Proteins

ASJC Scopus subject areas

  • Molecular Biology

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Epidermal growth factor receptor (EGFR)-Retargeted measles virus strains effectively target EGFR- or EGFRvIII expressing gliomas. / Paraskevakou, Georgia; Allen, Cory; Nakamura, Takafumi; Zollman, Paula; James, C. David; Peng, Kah-Whye; Schroeder, Mark; Russell, Stephen J; Galanis, Evanthia.

In: Molecular Therapy, Vol. 15, No. 4, 04.2007, p. 677-686.

Research output: Contribution to journalArticle

Paraskevakou, Georgia ; Allen, Cory ; Nakamura, Takafumi ; Zollman, Paula ; James, C. David ; Peng, Kah-Whye ; Schroeder, Mark ; Russell, Stephen J ; Galanis, Evanthia. / Epidermal growth factor receptor (EGFR)-Retargeted measles virus strains effectively target EGFR- or EGFRvIII expressing gliomas. In: Molecular Therapy. 2007 ; Vol. 15, No. 4. pp. 677-686.
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