Biologic response of B lymphoma cells to anti-CD20 monoclonal antibody rituximab in vitro: CD55 and CD59 regulate complement-mediated cell lysis

The chimeric anti-CD20 mAb rituximab has recently become a treatment of cho ice for low-grade or follicular non-Hodgkin's lymphomas (FL) with a respons e rate of about 50%, In this report, we have investigated the mechanism of action of rituximab on 4 FL and 1 Burkitt's lymphoma (Bt) cell lines, 3 fre sh FL samples and normal B cells in vitro. Rituximab efficiently blocks the proliferation of normal B cells, but not that of the lymphoma lines. We di d not detect significant apoptosis of the cell lines in response to rituxim ab alone. All cell lines were targets of antibody-dependent cellular cytoto xicity (ADCC), On the other hand, human complement-mediated lysis was highl y variable between cell lines, ranging from 100% lysis to complete resistan ce, Investigation of the role of the complement inhibitors CD35, CD46, CD55 , and CD59 showed that CD55, and to a lesser extent CD59, are important reg ulators of complement-mediated cytotoxicity (CDC) in FL cell lines as well as in fresh cases of FL: Blocking CD55 and/or CD59 function with specific a ntibodies significantly increased CDC in FL cells. We conclude that CDC and ADCC are major mechanisms of action of rituximab on B-cell lymphomas and t hat a heterogeneous susceptibility of different lymphoma cells to complemen t may be at least in part responsible for the heterogeneity of the response of different patients to rituximab in vivo. Furthermore, we suggest that t he relative levels of CD55 and CD59 may become useful markers to predict th e clinical response. (C) 2000 by The American Society of nematology.