Envelope-chimeric entry-targeted measles virus escapes neutralization and achieves oncolysis.

Abstract

Measles virus (MV) is a promising vector for cancer therapy and multivalent vaccination, but high prevalence of pre-existing neutralizing antibodies may reduce therapeutic efficacy, particularly following systemic administration. MV has only one serotype, but here we show that its envelope glycoproteins can be exchanged with those of the closely related canine distemper virus (CDV), generating a chimeric virus capable of escaping neutralization. To target its entry, we displayed on the CDV attachment protein a single-chain antibody specific for a designated receptor. To enhance oncolytic efficacy we armed the virus with a prodrug convertase gene capable of locally activating chemotherapeutic prodrugs. The new virus achieved high titers, was genetically stable, and was resistant to neutralization by sera from both MV-immunized mice and MV-immune humans. The new virus targeted syngeneic murine tumor cells expressing the designated receptor implanted in immunocompetent mice, and synergized with a chemotherapeutic prodrug in a model of oncolysis. Importantly, the chimeric MV remained oncolytic when administered systemically even in the presence of anti-MV antibodies capable of abrogating the therapeutic efficacy of the parental, nonshielded MV. This work shows that targeting, arming, and shielding can be combined to generate a tumor-specific, neutralization-resistant virus that can synergize with chemotherapeutics.

• Authors: Tanner S Miest, Koon-Chu Yaiw, Marie Frenzke, Johanna Lampe, Andrew W Hudacek, Christoph Springfeld, Veronika von Messling, Guy Ungerechts, Roberto Cattaneo
• Journal: Molecular therapy : the journal of the American Society of Gene Therapy (Mol Ther) Vol. 19 Issue 10 Pg. 1813-20 (Oct 2011) ISSN: 1525-0024 [Electronic] United States
• PMID: 21610701 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• DNA Primers
• Recombinant Fusion Proteins

Topics

• Animals
• Base Sequence
• DNA Primers
• Genetic Vectors
• Humans
• Measles virus (genetics)
• Mice
• Mice, Inbred C57BL
• Neutralization Tests
• Oncolytic Virotherapy
• Polymerase Chain Reaction
• Recombinant Fusion Proteins (genetics)
• Tumor Escape