Epidermal Growth Factor Receptor (EGFR)–Retargeted Measles Virus Strains Effectively Target EGFR- or EGFRvIII Expressing Gliomas
| Autor: | Georgia Paraskevakou, Mark A. Schroeder, Takafumi Nakamura, Kah Whye Peng, Paula J. Zollman, C. David James, Evanthia Galanis, Cory Allen, Stephen J. Russell |
|---|---|
| Rok vydání: | 2007 |
| Předmět: |
viruses
Gene Expression Mice 0302 clinical medicine Signaling Lymphocytic Activation Molecule Family Member 1 Cricetinae Chlorocebus aethiops Drug Discovery Epidermal growth factor receptor Mice Inbred BALB C 0303 health sciences Chinese hamster ovary cell Glioma Recombinant Proteins 3. Good health ErbB Receptors 030220 oncology & carcinogenesis Molecular Medicine Genetic Engineering Green Fluorescent Proteins Transplantation Heterologous Mice Nude Receptors Cell Surface CHO Cells Biology Virus Membrane Cofactor Protein Measles virus 03 medical and health sciences Cricetulus Antigens CD Cell Line Tumor medicine Genetics Animals Humans Virotherapy Vero Cells Molecular Biology 030304 developmental biology Pharmacology CD46 Genes erbB-1 Genetic Therapy medicine.disease biology.organism_classification Molecular biology Transplantation Mutation biology.protein Neoplasm Transplantation |
| Zdroj: | Molecular Therapy. 15(4):677-686 |
| ISSN: | 1525-0016 |
| DOI: | 10.1038/sj.mt.6300105 |
| Popis: | A retargeted measles virus strain MV-GFP-H(AA)-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-H(AA)-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-H(AA)-scEGFR virus in measles replication-permissive Ifnar(ko) 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|