Cytolytic and cytotoxic activity of a human natural killer cell line genetically modified to specifically recognize HER-2/neu overexpressing tumor cells.
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.
Demirtzoglou
F J
FJ
Cancer Immunology and Immunotherapy Center, Saint Savas Cancer Hospital, Athens, Greece. fdemi@humofert.gr
Papadopoulos
S
S
Zografos
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D000818:Animals; D000911:Antibodies, Monoclonal / Q000096:biosynthesis / Q000235:genetics; D015153:Blotting, Western; D017252:CD3 Complex / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D005098:Exotoxins / Q000235:genetics; D005260:Female; D005455:Fluorescent Antibody Technique; D006801:Humans; D007694:Killer Cells, Natural / Q000502:physiology*; D051379:Mice; D016513:Mice, SCID; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology; D030781:Organisms, Genetically Modified; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis* / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000235:genetics; D057127:Single-Chain Antibodies; D013602:T-Lymphocytes, Cytotoxic / Q000502:physiology*; D014161:Transduction, Genetic
D000911:Antibodies, Monoclonal; D017252:CD3 Complex; D005098:Exotoxins; D018719:Erb-b2 Receptor Tyrosine Kinases; D011993:Recombinant Fusion Proteins; D057127:Single-Chain Antibodies; C508054:scFv(FRP5)-ETA antibody toxin