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Superior Activity of Fusion Protein scFvRit:sFasL over Cotreatment with Rituximab and Fas Agonists

¹ Groningen University Institute for Drug Exploration, Department of Pathology and Laboratory Medicine, Section Medical Biology, Laboratory for Tumor Immunology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands; ² Department of Molecular Internal Medicine, Medical Clinic and Polyclinic II, University of Wuerzburg, Wuerzburg, Germany; ³ Department of Hematology, VU Institute for Cancer and Immunology, VU Medical Center, Amsterdam, the Netherlands; and ⁴ Chair of Genetics, University of Erlangen-Nuremberg, Erlangen, Germany

Requests for reprints: Wijnand Helfrich, University Medical Center Groningen, Department of Pathology and Laboratory Medicine, Section Medical Biology, Laboratory for Tumor Immunology, Hanzeplein 1, 9713 GZ Groningen, the Netherlands. Phone: 31-50-3613733; Fax: 31-50-3619911; E-mail: w.helfrich{at}med.umcg.nl.

The clinical efficacy of the CD20-specific chimeric monoclonal antibody rituximab is significantly hampered by intrinsic or acquired resistance to therapy. Rituximab activates antibody-dependent cellular cytotoxicity/complement-dependent cytotoxicity–dependent lysis but also induces apoptosis by cross-linking of its target antigen CD20. Recent reports indicate that this apoptotic activity of rituximab can be synergized by cotreatment with Fas agonists. Here, we report on a strategy designed to exploit and optimize the synergy between rituximab and Fas signaling by genetically fusing a rituximab-derived antibody fragment to soluble Fas ligand (sFasL). The resultant fusion protein, designated scFvRit:sFasL, potently induced CD20-restricted apoptosis in a panel of malignant B-cell lines (10 of 11) and primary patient-derived malignant B cells (two of two non–Hodgkin lymphoma and five of six B cell chronic lymphocytic leukemia). ScFvRit:sFasL efficiently activated CD20 and Fas apoptotic signaling, resulting in a far superior proapoptotic activity compared with cotreatment with rituximab and Fas agonists. ScFvRit:sFasL lacked activity toward normal human B cells and also lacked systemic toxicity in nude mice with no elevation of aspartate aminotransferase and alanine aminotransferase levels or liver caspase-3 activity. In conclusion, scFvRit:sFasL efficiently activates CD20 and Fas-apoptotic signaling and may be useful for the elimination of malignant B cells. [Cancer Res 2008;68(2):597–604]

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