Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:O76050 (neu)
 3,969 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The continuously growing natural killer (NK) cell line NK-92 is highly cytotoxic against malignant cells of various origins without affecting normal human cells. Based on this selectivity, the potential of NK-92 cells for adoptive therapy is currently being investigated in phase I clinical studies. To further enhance the antitumoral activity of NK-92 cells and expand the range of tumor entities suitable for NK-92-based therapies, here by transduction with a retroviral vector we have generated genetically modified NK-92 cells expressing a chimeric antigen receptor specific for the tumor-associated ErbB2 (HER2/neu) antigen, which is overexpressed by many tumors of epithelial origin. The chimeric antigen receptor consists of the ErbB2-specific scFv(FRP5) antibody fragment, a flexible hinge region derived from CD8, and transmembrane and intracellular regions of the CD3 zeta chain. Transduced NK-92-scFv(FRP5)-zeta cells express high levels of the fusion protein on the cell surface as determined by fluorescence-activated cell-scanning (FACS) analysis. In europium release assays, no difference in cytotoxic activity of NK-92 and NK-92-scFv(FRP5)-zeta cells toward ErbB2-negative targets was found. However, even at low effector-to-target ratios, NK-92-scFv(FRP5)-zeta cells specifically and efficiently lysed established and primary ErbB2-expressing tumor cells that were completely resistant to cytolytic activity of parental NK-92 cells. These results demonstrate that efficient retargeting of NK-92 cytotoxicity can be achieved and might allow the generation of potent cell-based therapeutics for the treatment of ErbB2-expressing malignancies.
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PMID:Retargeting of natural killer-cell cytolytic activity to ErbB2-expressing cancer cells results in efficient and selective tumor cell destruction. 1214 7

NK92 cells genetically engineered to recognize the HER-2/neu oncoprotein have been previously reported to lyse HER-2/neu positive tumor cell lines through direct cell to cell contact. In the present study we have transduced NK92 cells with a chimeric receptor gene composed of the HER-/neu specific scFv (FRP5) antibody fragment, joined to the peptide CD8 hinge region and the signaling CD3 zeta chain. NK92 cells expressing this chimeric receptor (NK92.HER-2/neu/zeta) specifically recognized and lysed HER-2/neu overexpressing tumor cell lines both in vitro and in preclinical tumor models in vivo. More important we demonstrate that NK92.HER-2/neu/zeta cells constitutively secrete high levels of soluble scFv which mediate strong tumor cytostatic effects by directly binding on cell surface HER-2/neu. Our data uncover an additional mechanism through which NK92.HER-2/neu/zeta cells mediate antitumor effects and further support their use in cell based therapeutics for the treatment of HER-2/neu expressing cancers.
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PMID:Cytolytic and cytotoxic activity of a human natural killer cell line genetically modified to specifically recognize HER-2/neu overexpressing tumor cells. 1719 Jul 35