Epidermal growth factor receptor (EGFR)-retargeted measles virus strains effectively target EGFR- or EGFRvIII expressing gliomas.
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.
Paraskevakou
Georgia
G
Mayo Clinic and Mayo Foundation, Rochester, Minnesota 55905, USA.
Allen
Cory
C
Nakamura
Takafumi
T
Zollman
Paula
P
James
C David
CD
Peng
Kah Whye
KW
Schroeder
Mark
M
Russell
Stephen J
SJ
Galanis
Evanthia
E
D000818:Animals; D015703:Antigens, CD / Q000235:genetics; D016466:CHO Cells; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D006224:Cricetinae; D003412:Cricetulus; D066246:ErbB Receptors / Q000235:genetics; D015870:Gene Expression; D018773:Genes, erbB-1; D005818:Genetic Engineering; D015316:Genetic Therapy / Q000379:methods; D005910:Glioma / Q000235:genetics* / Q000276:immunology / Q000628:therapy*; D049452:Green Fluorescent Proteins / Q000235:genetics; D006801:Humans; D008459:Measles virus / Q000235:genetics*; D051916:Membrane Cofactor Protein / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009154:Mutation; D009368:Neoplasm Transplantation; D011956:Receptors, Cell Surface / Q000235:genetics; D011994:Recombinant Proteins / Q000235:genetics; D000071177:Signaling Lymphocytic Activation Molecule Family Member 1; D014183:Transplantation, Heterologous; D014709:Vero Cells
D015703:Antigens, CD; C497857:CD46 protein, human; D051916:Membrane Cofactor Protein; D011956:Receptors, Cell Surface; D011994:Recombinant Proteins; D049452:Green Fluorescent Proteins; D000071177:Signaling Lymphocytic Activation Molecule Family Member 1; D066246:ErbB Receptors