Rituximab (monoclonal anti-CD20 antibody): mechanisms of action and resistance.
Rituximab, a chimeric monoclonal antibody targeted against the pan-B-cell marker CD20, was the first monoclonal antibody to be approved for therapeutic use. Treatment with rituximab at standard weekly dosing is effective in more than 50% of patients with relapsed or refractory CD20-positive follicular non-Hodgkin's lymphoma, but is not curative. It is less effective in other subtypes of CD20-positive lymphoma and for retreatment, even with CD20 still expressed. Thus, binding of rituximab to CD20 is not sufficient to kill many lymphoma cells, indicating that there are mechanisms of resistance. Mechanisms of cell destruction that have been demonstrated to be activated by rituximab binding to CD20 include direct signaling of apoptosis, complement activation and cell-mediated cytotoxicity. The relative importance of each of these mechanisms in determining clinical response to rituximab treatment remains a matter of conjecture. Thus, the role of various resistance pathways, some documented in experimental systems and others still hypothetical, remains uncertain. Resistance could potentially be mediated by alterations in CD20 expression or signaling, elevated apoptotic threshold, modulation of complement activity or diminished cellular cytotoxicity. As the first of an expanding class of anticancer agents, lessons learned regarding the mechanism of rituximab action and resistance will be of increasing importance.
Smith
Mitchell R
MR
Lymphoma Service, Fox Chase Cancer Center, 7701 Burholme Avenue, Philadelphia, PA 19111, USA. M_smith@fccc.edu
D000911:Antibodies, Monoclonal / Q000276:immunology / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D058846:Antibodies, Monoclonal, Murine-Derived; D000937:Antigen-Antibody Reactions; D018951:Antigens, CD20 / Q000276:immunology / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D006801:Humans; D016499:Radioimmunotherapy; D000069283:Rituximab; D016896:Treatment Outcome
D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D018951:Antigens, CD20; D000069283:Rituximab