Oncolytic potency of HER-2 retargeted VSV-FH hybrid viruses: the role of receptor ligand affinity

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-alpha HER2 viruses displaying anti-HER2 scFv that bind to the same HER2 epitope but with different K-d (10(-6) to 10(-11) M, VSVFH-alpha HER2#6 to #11, respectively) were rescued and characterized. A K-d of at least 10(-8) M is required for infection of HER-2 positive SKOV3ip. 1 cells. The higher affinity viruses (>10(-8) M) 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-alpha HER2#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-alpha HER2 virus may be a promising agent for the treatment of HER-2 positive malignancies.