TY - JOUR
T1 - Envelope-chimeric entry-targeted measles virus escapes neutralization and achieves oncolysis
AU - Miest, Tanner S.
AU - Yaiw, Koon Chu
AU - Frenzke, Marie
AU - Lampe, Johanna
AU - Hudacek, Andrew W.
AU - Springfeld, Christoph
AU - Von Messling, Veronika
AU - Ungerechts, Guy
AU - Cattaneo, Roberto
N1 - Funding Information:
This work was supported by a grant of the Alliance for Cancer Gene Therapy, NIH Grant RO1 CA139389, and the Mayo Clinic Cancer Center. We thank William B. Parker and Eric J. Sorscher for MeP-dR, and Jeong Hong for providing the PNP-antibody. Patent applications for which R.C. is an inventor have been licensed to NISCO. Mayo has an equity position in NISCO. Mayo has not yet received royalties from products developed by the company, but may receive these in future.
PY - 2011/10
Y1 - 2011/10
N2 - 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.
AB - 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.
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U2 - 10.1038/mt.2011.92
DO - 10.1038/mt.2011.92
M3 - Article
C2 - 21610701
AN - SCOPUS:80053571003
SN - 1525-0016
VL - 19
SP - 1813
EP - 1820
JO - Molecular Therapy
JF - Molecular Therapy
IS - 10
ER -