CD7-restricted activation of Fas-mediated apoptosis: a novel therapeutic approach for acute T-cell leukemia.
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.
Bremer
Edwin
E
University Medical Center Groningen, Department of Pathology & Laboratory Medicine, Medical Biology Section, Laboratory for Tumor Immunology, Hanzeplein 1, 9713 GZ Groningen, The Netherlands.
ten Cate
Bram
B
Samplonius
Douwe F
DF
de Leij
Lou F M H
LF
Helfrich
Wijnand
W
D019011:Antigens, CD7 / Q000235:genetics / Q000276:immunology* / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology*; D024201:Bystander Effect; D045744:Cell Line, Tumor; D017931:DNA Primers; D053222:Fas Ligand Protein; D006801:Humans; D019169:Jurkat Cells; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000276:immunology / Q000628:therapy*; D008562:Membrane Glycoproteins / Q000235:genetics / Q000276:immunology* / Q000627:therapeutic use; D048069:Tumor Necrosis Factors / Q000235:genetics / Q000276:immunology* / Q000627:therapeutic use
D019011:Antigens, CD7; D000970:Antineoplastic Agents; D017931:DNA Primers; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D008562:Membrane Glycoproteins; D048069:Tumor Necrosis Factors