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Polyvalent diazonium polymers provide efficient protection of oncolytic adenovirus Enadenotucirev from neutralizing antibodies while maintaining biological activity in vitro and in vivo

Francini, Nora; Cochrane, Daniel; Illingworth, Sam; Purdie, Laura; Mantovani, Giuseppe; Fisher, Kerry; Seymour, Leonard W.; Spain, Sebastian G.; Alexander, Cameron

Authors

Nora Francini

Daniel Cochrane

Sam Illingworth

Laura Purdie

Kerry Fisher

Leonard W. Seymour

Sebastian G. Spain



Abstract

Oncolytic viruses offer many advantages for cancer therapy when administered directly to confined solid tumors. However, the systemic delivery of these viruses is problematic because of the host immune response, undesired interactions with blood components, and inherent targeting to the liver. Efficacy of systemically administered viruses has been improved by masking viral surface proteins with polymeric materials resulting in modulation of viral pharmacokinetic profile and accumulation in tumors in vivo. Here we describe a new class of polyvalent reactive polymer based on poly(N-(2-hydroxypropyl)methacrylamide) (polyHPMA) with diazonium reactive groups and their application in the modification of the chimeric group B oncolytic virus enadenotucirev (EnAd). A series of six copolymers with different chain lengths and density of reactive groups was synthesized and used to coat EnAd. Polymer coating was found to be extremely efficient with concentrations as low as 1 mg/mL resulting in complete (>99%) ablation of neutralizing antibody binding. Coating efficiency was found to be dependent on both chain length and reactive group density. Coated viruses were found to have reduced transfection activity both in vitro and in vivo, with greater protection against neutralizing antibodies resulting in lower transgene production. However, in the presence of neutralizing antibodies, some in vivo transgene expression was maintained for coated virus compared to the uncoated control. The decrease in transgene expression was found not to be solely due to lower cellular uptake but due to reduced unpackaging of the virus within the cells and reduced replication, indicating that the polymer coating does not cause permanent inactivation of the virus. These data suggest that virus activity may be modulated by the appropriate design of coating polymers while retaining protection against neutralizing antibodies.

Journal Article Type Article
Publication Date Mar 27, 2019
Journal Bioconjugate Chemistry
Print ISSN 1043-1802
Electronic ISSN 1520-4812
Publisher American Chemical Society
Peer Reviewed Peer Reviewed
Volume 30
Issue 4
Pages 1244-1257
APA6 Citation Francini, N., Cochrane, D., Illingworth, S., Purdie, L., Mantovani, G., Fisher, K., …Alexander, C. (2019). Polyvalent diazonium polymers provide efficient protection of oncolytic adenovirus Enadenotucirev from neutralizing antibodies while maintaining biological activity in vitro and in vivo. Bioconjugate Chemistry, 30(4), 1244-1257. https://doi.org/10.1021/acs.bioconjchem.9b00189
DOI https://doi.org/10.1021/acs.bioconjchem.9b00189
Keywords Biotechnology; Organic chemistry; Bioengineering; Pharmacology; Pharmaceutical science; Biomedical engineering
Publisher URL https://pubs.acs.org/doi/10.1021/acs.bioconjchem.9b00189

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