Blood, 1 February 2003, Vol. 101, No. 3, pp. 788-788
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.
George J. Weiner
Holden Comprehensive Cancer Center at The University of
Iowa
