The mechanisms of action of rituximab in the elimination of tumor cells.
The anti-CD20 chimeric monoclonal antibody rituximab kills B cells by multiple mechanisms, including complement-dependent cytoxicity, antibody-dependent cellular cytotoxicity, and induction of apoptosis. Rituximab can also sensitize cells to the effects of chemotherapy. To optimize treatment of non-Hodgkin's lymphoma and improve response rates, a fuller understanding of these mechanisms and their relative contributions to clinical efficacy is required. Therefore, this has been an area of active research in recent years. Preclinical studies have established that the human Fc region of rituximab is important in mobilizing antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity effector mechanisms. In addition, molecular consequences of CD20 binding, including redistribution of membrane lipid "rafts," activation of src kinases, phospholipases and caspases, and down-regulation of interleukin-10, have been identified. Clinical studies have also identified differences in patients' responses to rituximab associated with Fc receptor polymorphisms, and increases in enzymes involved in apoptotic pathways have been seen in the lymphocytes of patients following rituximab treatment. This article reviews the current understanding of the mechanisms of rituximab cell killing in the light of the latest clinical and preclinical data.
Johnson
Peter
P
Cancer Sciences Division, Southampton University School of Medicine, Southampton, UK.
Glennie
Martin
M
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D058846:Antibodies, Monoclonal, Murine-Derived; D000920:Antibody-Dependent Cell Cytotoxicity / Q000276:immunology*; D018951:Antigens, CD20 / Q000276:immunology* / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology; D004357:Drug Synergism; D006801:Humans; D011485:Protein Binding; D000069283:Rituximab
D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D018951:Antigens, CD20; D000970:Antineoplastic Agents; D000069283:Rituximab