title: 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.
abstract: 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.
authors.affiliation: Laboratory for Tumor Immunology, Department of Pathology and Laboratory Medicine, Section Medical Biology, University Hospital Groningen, Groningen University Institute for Drug Exploration, 9713 GZ Groningen, the Netherlands.
authors.forename: Edwin
authors.initials: E
authors.lastname: Bremer
authors.forename: Douwe F
authors.initials: DF
authors.lastname: Samplonius
authors.forename: Matthias
authors.initials: M
authors.lastname: Peipp
authors.forename: Linda
authors.initials: L
authors.lastname: van Genne
authors.forename: Bart-Jan
authors.initials: BJ
authors.lastname: Kroesen
authors.forename: Georg H
authors.initials: GH
authors.lastname: Fey
authors.forename: Martin
authors.initials: M
authors.lastname: Gramatzki
authors.forename: Lou F M H
authors.initials: LF
authors.lastname: de Leij
authors.forename: Wijnand
authors.initials: W
authors.lastname: Helfrich
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000235:genetics / Q000276:immunology / Q000494:pharmacology; D019011:Antigens, CD7 / Q000235:genetics / Q000276:immunology*; D017209:Apoptosis / Q000187:drug effects* / Q000276:immunology; D051017:Apoptosis Regulatory Proteins; D016466:CHO Cells; D045744:Cell Line, Tumor; D006224:Cricetinae; D004357:Drug Synergism; D000939:Epitopes; D006801:Humans; D007128:Immunoglobulin Fragments / Q000235:genetics / Q000276:immunology / Q000494:pharmacology; D000922:Immunotoxins / Q000235:genetics / Q000276:immunology / Q000494:pharmacology*; D019169:Jurkat Cells / Q000166:cytology / Q000187:drug effects; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D008562:Membrane Glycoproteins / Q000235:genetics / Q000494:pharmacology*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000494:pharmacology*; D014750:Vincristine / Q000494:pharmacology
chemical_list: D000911:Antibodies, Monoclonal; D019011:Antigens, CD7; D051017:Apoptosis Regulatory Proteins; D000939:Epitopes; D007128:Immunoglobulin Fragments; D000922:Immunotoxins; D008562:Membrane Glycoproteins; D011993:Recombinant Fusion Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha; D014750:Vincristine