Targeting polysialic acid-abundant cancers using oncolytic adenoviruses with fibers fused to active bacteriophage borne endosialidase

Genetic replacement of adenoviral fiber knobs by ligands that enable tumor specific targeting of oncolytic adenoviruses is challenging because the fiber knob contributes to virus assembly. Here, we present a novel concept by describing stable recombinant adenoviruses with tumor specific infection mo...

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Published inBiomaterials Vol. 158; pp. 86 - 94
Main Authors Martin, Nikolas T., Wrede, Christoph, Niemann, Julia, Brooks, Jennifer, Schwarzer, David, Kühnel, Florian, Gerardy-Schahn, Rita
Format Journal Article
LanguageEnglish
Published Netherlands Elsevier Ltd 01.03.2018
Subjects
Adenoviridae
Animals
Bacteriophages - enzymology
Endosialidases
Fiber chimerization
HEK293 Cells
Humans
Mice
Neoplasms - metabolism
Neoplasms - therapy
Neuraminidase - metabolism
Neuraminidase - therapeutic use
Neuroblastoma - therapy
Oncolysis
Oncolytic adenoviruses
Oncolytic Virotherapy
Oncolytic Viruses
Polysialic acid
Sialic Acids
Tumor targeting
Viral Proteins - metabolism
Viral Proteins - therapeutic use
Endosialidases
Oncolysis
Fiber chimerization
Oncolytic adenoviruses
Tumor targeting
Polysialic acid
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Summary:Genetic replacement of adenoviral fiber knobs by ligands that enable tumor specific targeting of oncolytic adenoviruses is challenging because the fiber knob contributes to virus assembly. Here, we present a novel concept by describing stable recombinant adenoviruses with tumor specific infection mode. The fiber knob was replaced by endosialidaseNF (endoNF), the tailspike protein of bacteriophage K1F. EndoNF recognizes polysialic acid, an oncofetal antigen characteristic for high malignant tumors of neuroendocrine origin. An intramolecular chaperone contained in endoNF warrants folding and compensates for the knob function in virus assembly. Obtained recombinant viruses demonstrated polysialic acid dependent infection modes, strong oncolytic capacity with polysialic acid positive cells in culture and a high potential to inhibit tumor growth in a therapeutic mouse model of subcutaneous neuroblastoma. With a single genetic manipulation we achieved ablation of the fiber knob, introduction of a tumor specific ligand, and folding control over the chimeric fiber construct.
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ISSN:0142-9612
1878-5905
DOI:10.1016/j.biomaterials.2017.12.008