TY - JOUR
T1 - Oncolytic potency of HER-2 retargeted VSV-FH hybrid viruses
T2 - The role of receptor ligand affinity
AU - Ayala Breton, Camilo
AU - Wikan, Nitwara
AU - Abbuhl, Arinda
AU - Smith, Duncan R.
AU - Russell, Stephen J.
AU - Peng, Kah Whye
N1 - Publisher Copyright:
© 2015 The American Society of Gene and Cell Therapy.
PY - 2015/8/5
Y1 - 2015/8/5
N2 - The hybrid oncolytic vesicular stomatitis virus (VSV-FH) deleted for its G glycoprotein and displaying the measles virus (MV) envelope glycoproteins (hemagglutinin H and fusion F) is fusogenic, infects cells via any of the three MV receptors and has potent oncolytic activity against subcutaneous and disseminated myeloma tumors. To tailor VSV-FH as an oncolytic virus for ovarian cancer, we ablated its natural tropism and retargeted the virus by display of a single-chain antibody (scFv) with specificity to the HER-2/neu receptor. A panel of six VSVFH-αHER2 viruses displaying anti-HER2 scFv that bind to the same HER2 epitope but with different Kd (10-6 to 10-11 M, VSVFH-áHER2#6 to #11, respectively) were rescued and characterized. A Kd of at least 10.8 M is required for infection of HER-2 positive SKOV3ip.1 cells. The higher affinity viruses (10-8M) were able to infect and fuse SKOV3ip.1 cells more efficiently, inducing more extensive cytopathic effects. We next compared the antitumor potency of the viruses against SKOV3ip.1 tumor xenografts. In contrast to the saline-treated animals, one intratumoral injection of VSVFH-áHER2#9, #10, or #11 resulted in efficient tumor control. There was no significant difference between viruses with an affinity higher than 10.9 M in terms of oncolytic potency. VSVFH-áHER2 virus may be a promising agent for the treatment of HER-2 positive malignancies.
AB - The hybrid oncolytic vesicular stomatitis virus (VSV-FH) deleted for its G glycoprotein and displaying the measles virus (MV) envelope glycoproteins (hemagglutinin H and fusion F) is fusogenic, infects cells via any of the three MV receptors and has potent oncolytic activity against subcutaneous and disseminated myeloma tumors. To tailor VSV-FH as an oncolytic virus for ovarian cancer, we ablated its natural tropism and retargeted the virus by display of a single-chain antibody (scFv) with specificity to the HER-2/neu receptor. A panel of six VSVFH-αHER2 viruses displaying anti-HER2 scFv that bind to the same HER2 epitope but with different Kd (10-6 to 10-11 M, VSVFH-áHER2#6 to #11, respectively) were rescued and characterized. A Kd of at least 10.8 M is required for infection of HER-2 positive SKOV3ip.1 cells. The higher affinity viruses (10-8M) were able to infect and fuse SKOV3ip.1 cells more efficiently, inducing more extensive cytopathic effects. We next compared the antitumor potency of the viruses against SKOV3ip.1 tumor xenografts. In contrast to the saline-treated animals, one intratumoral injection of VSVFH-áHER2#9, #10, or #11 resulted in efficient tumor control. There was no significant difference between viruses with an affinity higher than 10.9 M in terms of oncolytic potency. VSVFH-áHER2 virus may be a promising agent for the treatment of HER-2 positive malignancies.
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U2 - 10.1038/mto.2015.12
DO - 10.1038/mto.2015.12
M3 - Article
AN - SCOPUS:85006158699
SN - 2372-7705
VL - 2
SP - 15012
JO - Molecular Therapy Oncolytics
JF - Molecular Therapy Oncolytics
M1 - 15012
ER -