Concepts in radiotherapy and immunotherapy: anti-CD20 mechanisms of action and targets.
Immunotherapy became a feasible therapeutic approach following the development of monoclonal antibody technology. Despite many small clinical trials using a wide variety of antibodies, in hematologic malignancies, success has largely been restricted to a few antibodies generated against antigens expressed on the tumor cell surface: rituximab (anti-CD20) and alemtuzumab (anti-CD52) are the most widely used monoclonal antibodies. CD20 is expressed on B cells, and rituximab has been widely used in the treatment of various histologies of B-cell non-Hodgkin's lymphoma. The mode of action of rituximab is discussed in this article. Despite extensive empiric clinical trial experience, the critical factors important in the mechanism of tumor cell kill by monoclonal antibodies continue to be elusive and the subject of debate. The major immune mechanisms of action of rituximab include complement-dependent cytotoxicity and antibody-dependent cellular cytotoxicity. While some investigations have suggested that the complement system is essential to tumor cell kill with rituximab; most lines of evidence point to the importance of antibody-dependent cellular cytotoxicity. Fc receptor binding appears to be critical in determining efficacy. Observations from several studies have shown that the response rate to single-agent rituximab is better in patients who have higher affinity polymorphisms in their Fc receptors. The other mechanisms that may play a role in rituximab therapy include direct anti-tumor effects mediated by the antibody binding to cell-surface CD20 antigen. Although this is more controversial, observations in tumor cell lines following CD20 ligation suggest that direct effects may be important.
Maloney
David G
DG
Fred Hutchinson Cancer Research Center, Seattle, WA 98109-1024, USA. dmaloney@fhcrc.org
D000911:Antibodies, Monoclonal / Q000494:pharmacology* / Q000627:therapeutic use*; D058846:Antibodies, Monoclonal, Murine-Derived; D018951:Antigens, CD20 / Q000276:immunology*; D003602:Cytotoxicity, Immunologic; D006801:Humans; D016393:Lymphoma, B-Cell / Q000188:drug therapy* / Q000532:radiotherapy; D016499:Radioimmunotherapy; D011961:Receptors, Fc; D000069283:Rituximab
D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D018951:Antigens, CD20; D011961:Receptors, Fc; D000069283:Rituximab