Rituximab: complementary mechanisms of action

Approximately 200 000 patients have been treated with rituximab, yet the debate over the relative importance of various potential mechanisms of action for this antibody continues. In this issue, Cragg and colleagues (page 1045) report on complement-mediated cytotoxicity induced by various anti-CD20 antibodies. They found that the ability of these antibodies to induce complement-mediated lysis is dependent not only on isotype and antigen binding, but also on the mobility of the resulting antibody-antigen complex in the plasma membrane. The anti-CD20 antibodies that fixed complement most effectively were those that translocated to lipid rafts in the cell membrane following CD20 binding. Lipid rafts are known to play a central role in the transmembrane signaling mediated by a variety of antigens. Thus the finding that anti-CD20 antibodies differ in their ability to segregate antigen-antibody complexes into lipid rafts has implications not only on complement-mediated cytotoxicity but also on apoptosis that can result directly from anti-CD20 binding to antigen.

Further, complement fixation can result in opsonization of the tumor cell, thereby leading to enhanced cellular cytotoxicity. Recent advances, including an understanding of differences between antibodies in their ability to alter membrane trafficking of antigen, will be useful in identifying approaches to selecting new antibodies for development or enhancing the efficacy of currently available antibodies. But one should not expect a rapid and clean conclusion to the debate about the relative clinical importance of transmembrane signaling, antibody-dependent cellular cytotoxicity, and complement-mediated cytotoxicity. In fact, the evidence is mounting that signaling, cellular cytotoxicity, and complement are interactive mechanisms that together are responsible for the antitumor activity of antitumor antibodies. Segregation into lipid rafts is a characteristic of the antigen-antibody complex that could impact on the efficacy of antibody therapy through all 3 major “complementary” antitumor antibody mechanisms of action.