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 choice for low-grade or follicular non-Hodgkin's lymphomas (FL) with a response rate of about 50%. In this report, we have investigated the mechanism of action of rituximab on 4 FL and 1 Burkitt's lymphoma (BL) cell lines, 3 fresh 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 did not detect significant apoptosis of the cell lines in response to rituximab alone. All cell lines were targets of antibody-dependent cellular cytotoxicity (ADCC). On the other hand, human complement-mediated lysis was highly variable between cell lines, ranging from 100% lysis to complete resistance. Investigation of the role of the complement inhibitors CD35, CD46, CD55, and CD59 showed that CD55, and to a lesser extent CD59, are important regulators 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 antibodies significantly increased CDC in FL cells. We conclude that CDC and ADCC are major mechanisms of action of rituximab on B-cell lymphomas and that a heterogeneous susceptibility of different lymphoma cells to complement may be at least in part responsible for the heterogeneity of the response of different patients to rituximab in vivo. Furthermore, we suggest that the relative levels of CD55 and CD59 may become useful markers to predict the clinical response. (Blood. 2000;95:3900-3908)
Golay
J
J
Istituto Ricerche Farmacologiche "Mario Negri," Milan; the Hematology Division, Ospedali Riuniti, Bergamo, Italy.
Zaffaroni
L
L
Vaccari
T
T
Lazzari
M
M
Borleri
G M
GM
Bernasconi
S
S
Tedesco
F
F
Rambaldi
A
A
Introna
M
M
D000911:Antibodies, Monoclonal / Q000633:toxicity*; D058846:Antibodies, Monoclonal, Murine-Derived; D018951:Antigens, CD20 / Q000276:immunology*; D000970:Antineoplastic Agents / Q000633:toxicity*; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D002051:Burkitt Lymphoma / Q000276:immunology* / Q000473:pathology; D018958:CD55 Antigens / Q000276:immunology*; D018957:CD59 Antigens / Q000276:immunology*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003165:Complement System Proteins / Q000494:pharmacology*; D003602:Cytotoxicity, Immunologic; D006801:Humans; D008213:Lymphocyte Activation; D016393:Lymphoma, B-Cell / Q000276:immunology* / Q000473:pathology; D014066:Palatine Tonsil / Q000276:immunology; D000069283:Rituximab; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D018951:Antigens, CD20; D000970:Antineoplastic Agents; D018958:CD55 Antigens; D018957:CD59 Antigens; D000069283:Rituximab; D003165:Complement System Proteins