Superior activity of fusion protein scFvRit: sFasL over cotreatment with rituximab and Fas agonistsBremer, E., ten Cate, B., Samplonius, D. F., Mueller, N., Wajant, H., Stel, A. J., Chamuleau, M., de Loosdrecht, A. A. V., Stieglmaier, J., Fey, G. H. & Helfrich, W., 15-Jan-2008, In : Cancer Research. 68, 2, p. 597-604 8 p.
Research output: Contribution to journal › Article › Academic › peer-review
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.
|Number of pages||8|
|Publication status||Published - 15-Jan-2008|
- APOPTOSIS INDUCTION, IN-VIVO, B-CELLS, RESTRICTED ACTIVATION, MEDIATED APOPTOSIS, DOWN-REGULATION, LIGAND, LYMPHOMA, CD20, EXPRESSION