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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.
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Submitted July 21, 2005
Accepted November 28, 2005
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 de Leij, and Wijnand Helfrich*
Groningen University Institute for Drug Exploration (GUIDE), Department of Pathology & Laboratory Medicine, Section Medical Biology, Laboratory for Tumor Immunology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
* Corresponding author; email: w.helfrich{at}med.umcg.nl.
Agonistic anti-Fas antibodies and multimeric recombinant FasL preparations show high tumoricidal activity against leukemic cells, but are unsuitable for clinical application due to unacceptable systemic toxicity. Consequently, new anti-leukemia 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 non-toxic to normal cells, but also lacks tumoricidal activity. We report on a novel fusion protein, designated scFvCD7:sFasL, designed to have leukemia-restricted activity. ScFvCD7:sFasL consist of sFasL genetically linked to a high affinity 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-ALL cell lines and patient-derived T-ALL, PTCL, and CD7-positive AML cells with homotrimeric scFvCD7:sFasL revealed potent CD7-restricted induction of apoptosis that was augmented by conventional drugs, farnesyl transferase inhibitor L-744,832, and proteasome inhibitor Velcade. Importantly, identical treatment did not affect normal human PBLs and endothelial cells, with only moderate apoptosis in 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.
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