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Blood, 1 April 2006, Vol. 107, No. 7, pp. 2863-2870. Prepublished online as a Blood First Edition Paper on December 6, 2005; DOI 10.1182/blood-2005-07-2929. This Article Full Text Full Text (PDF) All Versions of this Article: 2005-07-2929v1 107/7/2863    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Bremer, E. Articles by Helfrich, W. Search for Related Content PubMed PubMed Citation Articles by Bremer, E. Articles by Helfrich, W. Related Collections Immunobiology Neoplasia Apoptosis Immunotherapy Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  IMMUNOBIOLOGY CD7-restricted activation of Fas-mediated apoptosis: a novel therapeutic approach for acute T-cell leukemia Edwin Bremer, Bram ten Cate, Douwe F. Samplonius, Lou F. M. H. de Leij, and Wijnand Helfrich From the Groningen University Institute for Drug Exploration (GUIDE), Department of Pathology & Laboratory Medicine, Medical Biology Section, Laboratory for Tumor Immunology, University Medical Center Groningen (UMCG), University of Groningen, The Netherlands. Agonistic anti-Fas antibodies and multimeric recombinant Fas ligand (FasL) preparations show high tumoricidal activity against leukemic cells, but are unsuitable for clinical application due to unacceptable systemic toxicity. Consequently, new antileukemia strategies based on Fas activation have to meet the criterion of strictly localized action at the tumor-cell surface. Recent insight into the FasL/Fas system has revealed that soluble homotrimeric FasL (sFasL) is in fact nontoxic to normal cells, but also lacks tumoricidal activity. We report on a novel fusion protein, designated scFvCD7:sFasL, that is designed to have leukemia-restricted activity. ScFvCD7:sFasL consists of sFasL genetically linked to a high-affinity single-chain fragment of variable regions (scFv) antibody fragment specific for the T-cell leukemia-associated antigen CD7. Soluble homotrimeric scFvCD7:sFasL is inactive and acquires tumoricidal activity only after specific binding to tumor cell-surface-expressed CD7. Treatment of T-cell acute lymphoblastic leukemia (T-ALL) cell lines and patient-derived T-ALL, peripheral T-cell lymphoma (PTCL), and CD7-positive acute myeloid leukemia (AML) cells with homotrimeric scFvCD7:sFasL revealed potent CD7-restricted induction of apoptosis that was augmented by conventional drugs, farnesyl transferase inhibitor L-744832, and the proteasome inhibitor bortezomib (Velcade; Millenium, Cambridge, MA). Importantly, identical treatment did not affect normal human peripheral-blood lymphocytes (PBLs) and endothelial cells, with only moderate apoptosis in interleukin-2 (IL-2)/CD3-activated T cells. CD7-restricted activation of Fas in T-cell leukemic cells by scFvCD7:sFasL revitalizes interest in the applicability of Fas signaling in leukemia therapy. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: E. Bremer, B. ten Cate, D. F. Samplonius, N. Mueller, H. Wajant, A. J. Stel, M. Chamuleau, A. A. van de Loosdrecht, J. Stieglmaier, G. H. Fey, et al. Superior Activity of Fusion Protein scFvRit:sFasL over Cotreatment with Rituximab and Fas Agonists Cancer Res., January 15, 2008; 68(2): 597 - 604. [Abstract] [Full Text] [PDF]

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