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• W2593977422 abstract "Abstract The CD20-specific monoclonal antibody rituximab (RTX) has significantly enhanced the overall survival of B-cell non-Hodgkin’s lymphoma but not of chronic lymphocytic leukemia. The level of CD20 expression on tumors has been related to response, but results of several studies are contradictory and no clear relationship could be established. The main effector mechanisms of RTX are thought to be complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC), but the exact mechanism is still unknown. Part of the lack of a clear relationship may be explained by the absence of data on the combined contribution of CDC and ADCC. To study the impact of CD20-expression level on CDC, ADCC and their relative contribution, we developed a system to manipulate CD20-expression levels on cells by transducing the CD20-negative CEM T cell line and developed a new assay to investigate the combined contribution of RTX-mediated CDC and ADCC. By limiting dilution of the transduced and selected cells, clonally-related CEM-CD20 cells were obtained with the number of CD20 molecules as the only variable parameter (mean fluorescence intensity range: 256–693, N=90). These were then subjected to RTX and human serum as a complement source. The results show that the CDC activity clearly depends on CD20-expression level and there is a linear correlation of CD20-expression level to RTX-mediated killing by CDC (p<0.001, r2=0.9125). To further strengthen the importance of CD20-expression level to RTX-mediated CDC, we transduced the already CD20-postive Raji Burkitt’s lymphoma cell line with the CD20-encoding retrovirus. The extra CD20 molecules thus obtained made the cells significantly more sensitive to human serum and RTX (p<0.001). For ADCC, the CEM-CD20 clones were subjected to effector cells and RTX, which, in contrast to CDC, showed no correlation between CD20-expression level and cell kill via ADCC (p=0.1402, r2=0.1869). For the combination of CDC and ADCC, as with CDC alone, results showed a correlation between CD20 expression and cell kill (p<0.0201, r2=0.6214). Importantly, CDC-resistant cells were sensitive to ADCC and vice versa. These findings indicate that CDC and ADCC act complementary. In summary, these data show the importance of CD20-expression level for RTX-mediated cell kill and give new insights into the development of novel strategies to increase RTX-efficacy and the possibility to predict tumor response." @default.
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• W2593977422 date "2005-11-16" @default.
• W2593977422 modified "2023-09-29" @default.
• W2593977422 title "Complement-Induced Cell Death by Rituximab Depends on CD20-Expression Level and Acts Complementary to Antibody-Dependent Cell-Mediated Cytotoxicity." @default.
• W2593977422 doi "https://doi.org/10.1182/blood.v106.11.775.775" @default.
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