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Target Cell–Restricted Apoptosis Induction of Acute Leukemic T Cells by a Recombinant Tumor Necrosis Factor–Related Apoptosis-Inducing Ligand Fusion Protein with Specificity for Human CD7

¹ Laboratory for Tumor Immunology, Department of Pathology and Laboratory Medicine, Section Medical Biology, University Hospital Groningen, Groningen University Institute for Drug Exploration, Groningen, the Netherlands; ² Division of Nephrology, University Hospital Schleswig-Holstein, Campus Kiel; ³ Division of Stem Cell and Immunotherapy, 2nd Medical Department, University Clinic Schleswig-Holstein, Kiel, Germany; and ⁴ Chair of Genetics, University of Erlangen, Nuremberg, Erlangen, Germany

Requests for reprints: Wijnand Helfrich, Laboratory for Tumor Immunology, Department of Pathology and Laboratory Medicine, Section Medical Biology, University Hospital Groningen, Hanzeplein 1, 9713 GZ Groningen, the Netherlands. Phone: 31-503613851; Fax: 31-50-361-9911; E-mail: w.helfrich{at}med.rug.nl.

Current treatment of human T-cell leukemia and lymphoma is predominantly limited to conventional cytotoxic therapy and is associated with limited therapeutic response and significant morbidity. Therefore, more potent and leukemia-specific therapies with favorable toxicity profiles are urgently needed. Here, we report on the construction of a novel therapeutic fusion protein, scFvCD7:sTRAIL, designed to induce target antigen-restricted apoptosis in human T-cell tumors. ScFvCD7:sTRAIL consists of the death-inducing tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) genetically linked to an scFv antibody fragment specific for the T-cell surface antigen CD7. Treatment with scFvCD7:sTRAIL induced potent CD7-restricted apoptosis in a series of malignant T-cell lines, whereas normal resting leukocytes, activated T cells, and vascular endothelial cells (human umbilical vein endothelial cells) showed no detectable apoptosis. The apoptosis-inducing activity of scFvCD7:sTRAIL was stronger than that of the immunotoxin scFvCD7:ETA. In mixed culture experiments with CD7-positive and CD7-negative tumor cells, scFvCD7:sTRAIL induced very potent bystander apoptosis of CD7-negative tumor cells. In vitro treatment of blood cells freshly derived from T-acute lymphoblastic leukemia patients resulted in marked apoptosis of the malignant T cells that was strongly augmented by vincristin. In conclusion, scFvCD7:sTRAIL is a novel recombinant protein causing restricted apoptosis in human leukemic T cells with low toxicity for normal human blood and endothelial cells.

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