Targeting HSV-1 virions for specific binding to epidermal growth factor receptor-vIII-bearing tumor cells.
Oncolytic herpes simplex virus (HSV) vectors have been used in early phase human clinical trials as a therapy for recurrent malignant glioblastoma. This treatment proved safe but limited improvements in patient survival were observed. The potency of these vectors might be enhanced by targeting vector infectivity to tumor cells. Glioma tumors often express a mutant form (vIII) of the epidermal growth factor receptor (EGFR) resulting in the presence of a novel epitope on the cell surface. This epitope is specifically recognized by a single-chain antibody designated MR1-1. HSV-1 infection involves initial binding to heparan sulfate (HS) on the cell surface mediated primarily by the viral envelope, glycoprotein C (gC). Here we joined the MR1-1 single-chain antibody (scFv) to the gC sequence deleted for the HS-binding domain as a means of targeting viral attachment to EGFRvIII on glial tumor cells. Virions bearing MR1-1-modified gC had fivefold increased infectivity for EGFRvIII-bearing human glioma U87 cells compared to mutant receptor-deficient cells. Further, MR1-1/EGFRvIII-mediated infection was more efficient for EGFRvIII-positive cells than was wild-type virus for either positive or negative cells. Sustained infection of EGFRvIII+ glioma cells by MR1-1-modified gC-bearing oncolytic virus, as compared to wild-type gC oncolytic virus, was also shown in subcutaneous tumors in vivo using firefly luciferase as a reporter of infection. These data show that HSV tropism can be manipulated so that virions recognize a cell-specific binding site with increased infectivity for the target cell. The retargeting of HSV infection to tumor cells should enhance vector specificity, tumor cell killing and vector safety.
Department of Neurology, Harvard Medical School, Boston, MA, USA. pag24@mgb.pitt.edu
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P
Grandi
J
J
Fernandez
O
O
Szentirmai
R
R
Carter
D
D
Gianni
M
M
Sena-Esteves
X O
XO
Breakefield
D000818:Animals; D002462:Cell Membrane / Q000378:metabolism; D002522:Chlorocebus aethiops; D066246:ErbB Receptors / Q000378:metabolism*; D005260:Female; D005822:Genetic Vectors; D005910:Glioma / Q000378:metabolism / Q000821:virology*; D006378:Helper Viruses / Q000235:genetics; D006497:Heparan Sulfate / Q000378:metabolism*; D018259:Herpesvirus 1, Human / Q000502:physiology*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D014709:Vero Cells; D014759:Viral Envelope Proteins / Q000378:metabolism*; D014771:Virion / Q000502:physiology*
D066246:ErbB Receptors; D006497:Heparan Sulfate; D014759:Viral Envelope Proteins; C410723:epidermal growth factor receptor VIII; C038535:glycoprotein gC, herpes simplex virus type 1