The role of complement in the mechanism of action of rituximab for B-cell lymphoma: implications for therapy.
Rituximab, a genetically engineered chimeric monoclonal antibody specifically binding to CD20, was the first antibody approved by the U.S. Food and Drug Administration for the treatment of cancer. Rituximab significantly improves treatment outcome in relapsed or refractory, low-grade or follicular B-cell non-Hodgkin's lymphoma (NHL). However, there are also some challenges for us to overcome: why approximately 50% of patients are unresponsive to rituximab in spite of the expression of CD20, and why some responsive patients develop resistance to further treatment. Although the antitumor mechanisms of rituximab are not completely understood, several distinct antitumor activities of rituximab have been suspected, including complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC), apoptosis, and direct growth arrest. To counteract resistance to rituximab therapy, several strategies have been developed to: (a) augment the CDC effect by increasing CD20 expression, heteroconjugating rituximab to cobra venom factor and C3b, and inhibiting membrane complement regulatory protein, especially CD59, function; (b) enhance the ADCC effect through some immunomodulatory cytokines and CR3-binding beta-glucan; and (c) reduce the apoptotic threshold or induce apoptotic signaling on the tumor. Extensive studies indicate that rituximab combined with these approaches is more effective than a single rituximab approach. Herein, the mechanism of action of and resistance to rituximab therapy in B-cell NHL, in particular, the involvement of the complement system, are extensively reviewed.
Zhou
Xuhui
X
Changzheng Hospital, Second Military Medical University, Shanghai, China.
Hu
Weiguo
W
Qin
Xuebin
X
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D058846:Antibodies, Monoclonal, Murine-Derived; D018951:Antigens, CD20 / Q000276:immunology; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D003165:Complement System Proteins / Q000276:immunology*; D006801:Humans; D016393:Lymphoma, B-Cell / Q000188:drug therapy* / Q000276:immunology*; D000069283:Rituximab
D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D018951:Antigens, CD20; D000970:Antineoplastic Agents; D000069283:Rituximab; D003165:Complement System Proteins