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  • 1
    Keywords: RECEPTOR ; CELLS ; EXPRESSION ; IN-VITRO ; TUMOR-CELLS ; carcinoma ; Germany ; MICROSCOPY ; THERAPY ; VITRO ; DISEASE ; GENE ; GENES ; PROTEIN ; LINES ; gene transfer ; GENE-TRANSFER ; INFECTION ; ANTIGEN ; BINDING ; CELL-LINES ; MOLECULE ; antibodies ; antibody ; virus ; leukemia ; LINE ; DELIVERY ; VACCINE ; FLUORESCENCE ; cell lines ; ADENOVIRUS ; FUSION PROTEIN ; LEUKEMIA-CELLS ; targeting ; RE ; targeted ; NEWCASTLE-DISEASE-VIRUS ; SINGLE-CHAIN ANTIBODY ; bispecific ; CLONED CDNA ; enhanced green fluorescent protein ; FOREIGN GENE ; Newcastle disease virus ; RNA VIRUSES
    Abstract: We developed a novel strategy to target recombinant Newcastle disease virus (NDV) to tumor cells for gene therapy. Modifying the virus with a bispecific fusion protein allowed virus receptor-independent tumor cell binding and gene transfer. The targeting molecule alphaHN-IL-2 contains an scFv antibody cloned from a neutralizing hemagglutinin-neuraminidase (HN)-specific hybridoma linked to the human cytokine IL-2. A recombinant NDV expressing the enhanced green fluorescent protein (NDFL-EGFP) was applied to show the expression of foreign genes in virus-infected tumor cells. At 24 hours after infection with the modified virus (NDFL-EGFP/alphaHN-IL-2), FACS analysis and fluorescence microscopy revealed neutralization of natural infection in IL-2 receptor-negative Jurkat leukemia cells, but targeted expression of EGFP in IL-2 receptor-positive human leukemia-derived MT-2 cells. The targeted gene delivery of NDFL-EGFP/alphaHN-IL-2 in MT-2 cells was blocked by the target ligand human IL-2. Selective virus entry to IL-2 receptor bearing tumor cells was also observed in a mixture of Jurkat and MT-2 cell lines. These results demonstrate that a recombinant NDV carrying a foreign gene can be successfully targeted to a specific tumor through a bispecific protein, which thereby increases the selectivity of gene transfer
    Type of Publication: Journal article published
    PubMed ID: 15605075
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  • 2
    Keywords: RECEPTOR ; CELLS ; tumor ; TUMOR-CELLS ; Germany ; IN-VIVO ; PHASE-I ; THERAPY ; DISEASE ; GENE ; PROTEIN ; RNA ; TUMORS ; gene therapy ; gene transfer ; GENE-TRANSFER ; DNA ; INFECTION ; MECHANISM ; MARKER ; BINDING ; MOLECULE ; virus ; VECTORS ; VECTOR ; MEMBRANE ; FUSION ; STRATEGIES ; REPLICATION ; SIALIC-ACID ; FLUORESCENCE ; BINDS ; FUSION PROTEIN ; RECOMBINANT ; RE ; targeted ; oncolytic virus ; NEWCASTLE-DISEASE-VIRUS ; SINGLE-CHAIN ANTIBODY ; HEMAGGLUTININ-NEURAMINIDASE PROTEIN ; bispecific ; enhanced green fluorescent protein ; Newcastle disease virus ; RNA VIRUSES ; DISAGGREGATION SHEAR-STRESS ; ERYTHROCYTE AGGREGATION
    Abstract: Much interest exists presently in development of vectors for gene therapy of tumors based oil RNA viruses because these viruses replicate in the cytoplasm and do not integrate into DNA. The negative stranded paramyxovirus, Newcastle Disease Virus (NDV) from chicken has the additional advantages of preferential replication in tumor cells and of oncolytic and immunostimulatory properties. We here describe the bispecific fusion protein alphaHN-IL-2 which binds to NDV, inhibits its normal cell binding property and introduces a new binding specificity for the interleukin-2 receptor (IL-2R). We demonstrate selective gene transfer to tumor cells expressing IL-2R via the bispecific fusion protein when using recombinant NDV carrying as marker gene the enhanced green fluorescence protein (NDFL-EGFP). Hemadsorption (HA) and neuraminidase activities (NA) of the HN protein of NDV were shown to be blocked by aHN-IL-2 simultaneously and the absence of HA-activity of modified NDV was confirmed in vivo. Retargeted virus-binding to IL-2R positive tumor cells was not sufficient for C the process of cellular infection. It required in addition membrane fusion via the viral F-protein. By modification of recombinant NDV with a bispecific molecule, our results demonstrate a novel and safe strategy for selective gene transfer to targeted tumor cells
    Type of Publication: Journal article published
    PubMed ID: 15645128
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  • 3
    Keywords: RECEPTOR ; CELLS ; EXPRESSION ; IN-VITRO ; tumor ; TUMOR-CELLS ; Germany ; IN-VIVO ; LUNG ; MICROSCOPY ; PHASE-I ; VITRO ; DISEASE ; liver ; GENE ; GENE-EXPRESSION ; PROTEIN ; RNA ; EFFICIENCY ; TISSUE ; TUMORS ; gene transfer ; GENE-TRANSFER ; INFECTION ; kidney ; ALPHA ; virus ; LYMPHOMA ; gene expression ; VECTOR ; OVARIAN-CANCER ; FUSION ; DELIVERY ; BIODISTRIBUTION ; VACCINE ; REPLICATION ; FLUORESCENCE ; IL-2 ; FUSION PROTEIN ; thymus ; RECOMBINANT ; RE ; oncolytic virus ; NEWCASTLE-DISEASE-VIRUS ; TUMOR TISSUE ; bispecific ; Newcastle disease virus ; cancer gene therapy ; PV701 ; STRAINS ; VIROTHERAPY
    Abstract: Previously we have demonstrated that a recombinant Newcastle disease virus (NDV) carrying the transgene EGFP can be retargeted to IL-2 receptor positive tumor cells by a bispecific fusion protein alpha HN-IL-2 in vitro. The purpose of the present study was to investigate the specificity and efficiency of gene delivery to tumor cells in vivo via this modified RNA virus. Prior ex vivo infection of murine lymphoma cells by the modified virus resulted in selective EGFP expression in IL-2R(+) target tumor cells in vivo. Direct fluorescence microscopy and immunohistology showed viral replication in target positive tumor tissue resulting, in much more EGFP expression than in target negative tumor tissue, 24 It after intraturnoral injection of the aHN-IL-2 modified NDV. A quantitative real-time RT-PCR for EGFP mRNA. confirmed the selective gene expression in IL-2R(+) tumor cells. Biodistribution Studies showed that EGFP transgene delivery was reduced by 35-100% in liver, spleen, kidney, lung and thymus by the modified virus, while 98% of the transgene was delivered to IL-2R(+) tumors. In conclusion, the modification of NDV by the bispecific protein does not compromise severely the efficiency of gene delivery into IL-2R-positive tumors, but greatly reduces viral gene expression in IL-2R-negative tumors and in normal tissues
    Type of Publication: Journal article published
    PubMed ID: 16010418
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  • 4
    Keywords: CELLS ; tumor ; TUMOR-CELLS ; CELL ; Germany ; IN-VIVO ; LUNG ; PHASE-I ; THERAPY ; TOXICITY ; VIVO ; SYSTEM ; DISEASE ; liver ; SITE ; GENE ; GENES ; PROTEIN ; RNA ; EFFICIENCY ; TISSUE ; gene therapy ; MICE ; INFECTION ; kidney ; BINDING ; virus ; PATTERNS ; ASSAY ; VECTOR ; DELIVERY ; BIODISTRIBUTION ; REPLICATION ; real-time PCR ; TUMOR CELLS ; FUSION PROTEIN ; INTERLEUKIN-2 RECEPTOR ; RE ; cancer therapy ; oncolytic virus ; NEWCASTLE-DISEASE-VIRUS ; TUMOR TISSUE ; TUMOR-CELL ; BLOCKS ; Newcastle disease virus ; VIROTHERAPY ; GLIOBLASTOMA-MULTIFORME ; BINDING-SITE ; uptake ; in vivo ; ANTITUMOR ; ANTITUMOR VACCINATION ; AUGMENTATION ; bispecific protein ; hemadsorption ; SELECTIVE GENE-TRANSFER ; spleen
    Abstract: 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
    Type of Publication: Journal article published
    PubMed ID: 17088973
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