Rituximab: mechanism of action and resistance.
Rituximab (Rituxan; Genentech, Inc, South San Francisco, CA, and IDEC Pharmaceuticals, San Diego, CA)-mediated killing of CD20-positive tumor cells is likely caused by a combination of immune-mediated effects including complement-mediated lysis and antibody-dependent cell-mediated cytotoxicity and direct effects induced by CD20 ligation. In vivo, the clearance of damaged or preapoptotic cells through specific receptors for phosphatidylserine translocated to the outer cell membrane may also be important. Direct effects, including growth inhibition and apoptosis, have been shown in vitro; however, their contribution to the clinical effect is not known. Currently, most data suggest that the predominant effector mechanism is antibody-dependent cell-mediated cytotoxicity, with a minor role of complement. With treatment, resistance to rituximab-mediated killing may emerge. Little is known regarding the molecular pathogenesis of this resistance. In rare cases, the CD20 antigen may be lost. Complement-resistance proteins may also increase, but it is not clear that this is the reason for loss of sensitivity. A better understanding of these mechanisms should allow combination therapy with agents capable of augmenting antibody-based killing.
Maloney
David G
DG
Clinical Research Division of the Fred Hutchinson Cancer Research Center, Seattle, WA 98019-1024, USA.
Smith
Barbara
B
Rose
Andrea
A
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology* / Q000627:therapeutic use; D058846:Antibodies, Monoclonal, Murine-Derived; D000920:Antibody-Dependent Cell Cytotoxicity; D018951:Antigens, CD20; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D002986:Clinical Trials as Topic; D019008:Drug Resistance, Neoplasm; D006801:Humans; D008024:Ligands; D016393:Lymphoma, B-Cell / Q000188:drug therapy; D010587:Phagocytosis / Q000187:drug effects; D000069283:Rituximab; D015398:Signal Transduction / Q000187:drug effects
D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D018951:Antigens, CD20; D000970:Antineoplastic Agents; D008024:Ligands; D000069283:Rituximab