In vivo efficacy of systemic tumor targeting of a viral RNA vector with oncolytic properties using a bispecific adapter protein.
The aim of the study was: i) to specifically target tumor tissue by Newcastle disease virus (NDV) with oncolytic properties, ii) to improve the delivery system for systemic application of NDV via a bispecific adapter protein and iii) to investigate anti-tumor activity and side-effects. We selected two oncolytic virus strains, one native and the other recombinant, which showed multicyclic replication patterns in tumor cells. In order to reduce normal cell binding, they were modified by preincubation with a recombinant bispecific protein which blocks the viral native cell binding site and introduces a new binding site for a tumor-associated target (in this study, the interleukin-2-receptor, IL-2R). After intravenous transfer to mice, uptake of modified NDV in liver, spleen, kidney and lung was greatly reduced in comparison to unmodified NDV as determined by RRT-PCR of viral M gene copies. In IL-2R+ tumor bearing mice, the same assay revealed a high replication efficiency of the modified virus in the tumor tissue. Tumor therapy experiments showed that the side-effects induced by systemic application were greatly reduced by the adapter protein and that the anti-tumor effects were mostly undiminished. The demonstration of significant systemic anti-tumor activity of this viral vector suggests potential for augmentation by inclusion of one or more therapeutic genes.
Bian
Huijie
H
Division of Cellular Immunology, German Cancer Research Center, D-69120 Heidelberg, Germany.
Wilden
Holger
H
Fournier
Philippe
P
Peeters
Ben
B
Schirrmacher
Volker
V
D000818:Animals; D018390:Gene Targeting / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D007128:Immunoglobulin Fragments / Q000235:genetics; D019169:Jurkat Cells; D051379:Mice; D008811:Mice, Inbred DBA; D009522:Newcastle disease virus / Q000235:genetics* / Q000472:pathogenicity; D050130:Oncolytic Virotherapy / Q000379:methods*; D050504:Oncolytic Viruses / Q000235:genetics*; D012367:RNA, Viral / Q000235:genetics*; D015375:Receptors, Interleukin-2 / Q000235:genetics; D019076:Transgenes; D014774:Virulence; D014779:Virus Replication
D007128:Immunoglobulin Fragments; D012367:RNA, Viral; D015375:Receptors, Interleukin-2