title: PEGylation of vesicular stomatitis virus extends virus persistence in blood circulation of passively immunized mice.
abstract: We are developing oncolytic vesicular stomatitis viruses (VSVs) for systemic treatment of multiple myeloma, an incurable malignancy of antibody-secreting plasma cells that are specifically localized in the bone marrow. One of the presumed advantages for using VSV as an oncolytic virus is that human infections are rare and preexisting anti-VSV immunity is typically lacking in cancer patients, which is very important for clinical success. However, our studies show that nonimmune human and mouse serum can neutralize clinical-grade VSV, reducing the titer by up to 4 log units in 60 min. In addition, we show that neutralizing anti-VSV antibodies negate the antitumor efficacy of VSV, a concern for repeat VSV administration. We have investigated the potential use of covalent modification of VSV with polyethylene glycol (PEG) or a function-spacer-lipid (FSL)-PEG construct to inhibit serum neutralization and to limit hepatosplenic sequestration of systemically delivered VSV. We report that in mice passively immunized with neutralizing anti-VSV antibodies, PEGylation of VSV improved the persistence of VSV in the blood circulation, maintaining a more than 1-log-unit increase in VSV genome copies for up to 1 h compared to the genome copy numbers for the non-PEGylated virus, which was mostly cleared within 10 min after intravenous injection. We are currently investigating if this increase in PEGylated VSV circulating half-life can translate to increased virus delivery and better efficacy in mouse models of multiple myeloma.
authors: Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota, USA.
authors: Mulu Z
authors: MZ
authors: Tesfay
authors: Amber C
authors: AC
authors: Kirk
authors: Elizabeth M
authors: EM
authors: Hadac
authors: Guy E
authors: GE
authors: Griesmann
authors: Mark J
authors: MJ
authors: Federspiel
authors: Glen N
authors: GN
authors: Barber
authors: Stephen M
authors: SM
authors: Henry
authors: Kah-Whye
authors: KW
authors: Peng
authors: Stephen J
authors: SJ
authors: Russell
mesh_terms: D000818:Animals; D002522:Chlorocebus aethiops; D002845:Chromatography; D017931:DNA Primers / Q000235:genetics; D055808:Drug Discovery / Q000379:methods; D049452:Green Fluorescent Proteins; D006801:Humans; D016899:Interferon-beta; D053208:Kaplan-Meier Estimate; D051379:Mice; D009101:Multiple Myeloma / Q000276:immunology / Q000628:therapy*; D009500:Neutralization Tests; D050130:Oncolytic Virotherapy / Q000379:methods*; D011092:Polyethylene Glycols / Q000494:pharmacology*; D060888:Real-Time Polymerase Chain Reaction; D014709:Vero Cells; D014721:Vesicular stomatitis Indiana virus / Q000276:immunology / Q000378:metabolism*; D014766:Viremia / Q000097:blood*
chemical_list: D017931:DNA Primers; D049452:Green Fluorescent Proteins; D011092:Polyethylene Glycols; D016899:Interferon-beta; C028210:monomethoxypolyethylene glycol