Abstract
Rituximab [chimeric anti-CD20 monoclonal antibody], alone or combined with chemotherapy, is used in the treatment of non-Hodgkin's lymphoma (NHL). Rituximab binds to CD20 and inhibits intracellular survival/growth pathways leading to chemo/immunosensitization of tumor cells in vitro. The contribution of rituximab Fc-FcR interaction in signaling is not known. This study examined the role of Fc-FcR interactions in rituximab-induced signaling using rituximab (Fab')(2) fragments as well as rituximab devoid of the CH2 Fc-binding domain (CH2(-)). Rituximab (CH2(-)) and rituximab (Fab')(2) were tested for their activity on B-NHL cell lines. Cell signaling and sensitization to chemotherapy and immunotherapy were examined. The in vitro studies were validated in mice bearing tumor xenografts. Although the modified antibodies were defective in antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity functions, they retained all other biological activities such as inhibition of cell proliferation, induction of cell aggregation, and apoptosis induction. In addition, similar to rituximab, the modified antibodies inhibited the activity of cell survival/growth pathways and their associated transcription factors (e.g., NF-kappaB, YY1, SP-1), and signal transducers and activators of transcription 3 (STAT-3), and downregulated the expression of antiapoptotic gene products, such as Bcl-2/Bcl(xl), which regulate drug resistance. The modified antibodies, similar to rituximab, sensitized resistant B-NHL cells to both CDDP and Fas ligand-induced apoptosis. Furthermore, treatment of nude mice bearing Raji tumor cell xenografts with the combination of rituximab (Fab')(2) or rituximab and CDDP resulted in similar and significant inhibition of tumor growth. These findings reveal that rituximab-mediated inhibition of intracellular signaling pathways and leading to chemo/immuno-sensitization of resistant B-NHL is Fc independent.
Highlights
Rituximab [chimeric anti-CD20 monoclonal antibody], alone or combined with chemotherapy, is used in the treatment of non–Hodgkin's lymphoma (NHL)
We have reported that rituximab triggers CD20+ B-NHL cells and results in the inhibition of several intracellular survival pathways leading to chemo/immunosensitization [11,12,13]
We have reported that rituximab can trigger B-NHL cell lines in vitro and modify several intracellular signaling pathways that result in reversing the chemoresistant and immunoresistant phenotypes to sensitive phenotypes
Summary
Rituximab [chimeric anti-CD20 monoclonal antibody], alone or combined with chemotherapy, is used in the treatment of non–Hodgkin's lymphoma (NHL). Treatment of nude mice bearing Raji tumor cell xenografts with the combination of rituximab (Fab') or rituximab and CDDP resulted in similar and significant inhibition of tumor growth. Reported studies showed that rituximab mediates cell signaling and inhibits several survival pathways, and sensitizes resistant tumors to apoptosis by chemotherapeutic drugs. The role of the Fc fragment of rituximab in mediating cell signaling and chemosensitization was examined and was found to be Fc independent These studies suggest that the chemosensitizing effect of rituximab should occur in patients with Fc polymorphism. Modulation of the signaling pathways upon treatment of BNHL cells with rituximab might be the direct result of triggering the CD20 receptor by rituximab (Supplementary Fig. S1) or, conceivably, through cross-linking of the Fc fragment of rituximab with FcRs expressed on the tumor cells or on host-effector cells. It is conceivable to postulate that rituximab-mediated cell signaling may be dependent, in part, on the rituximab Fc fragments triggering FcR-bearing cells
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