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-αHER2 viruses displaying anti-HER2 scFv that bind to the same HER2 epitope but with different K d (10(-6) to 10(-11) M, VSVFH-αHER2#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-αHER2#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-αHER2 virus may be a promising agent for the treatment of HER-2 positive malignancies.
Department of Molecular Medicine, Mayo Clinic , Rochester, Minnesota, USA.
Camilo
C
Ayala Breton
Institute of Molecular Biosciences, Mahidol University , Bangkok, Thailand.
Nitwara
N
Wikan
Buena Vista University , Storm Lake, Iowa, USA.
Arinda
A
Abbuhl
Institute of Molecular Biosciences, Mahidol University , Bangkok, Thailand.
Duncan R
DR
Smith
Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota, USA; Division of Hematology, Mayo Clinic, Rochester, Minnesota, USA.
Stephen J
SJ
Russell
Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota, USA; Department of Obstetrics and Gynecology, Mayo Clinic, Rochester, Minnesota, USA.
Kah-Whye
KW
Peng