Elsevier

Seminars in Hematology

Volume 47, Issue 2, April 2010, Pages 115-123
Seminars in Hematology

Rituximab: Mechanism of Action

https://doi.org/10.1053/j.seminhematol.2010.01.011Get rights and content

Rituximab is a mainstay in the therapy for a broad variety of B-cell malignancies. Despite its undeniable therapeutic value, we still do not fully understand the mechanisms of action responsible for rituximab's anti-tumor effects. Direct signaling, complement-mediated cytotoxicity (CMC), and antibody-dependent cellular cytotoxicity (ADCC) all appear to play a role in rituximab efficacy. In vitro, animal model and clinical data addressing each of these mechanisms of action are reviewed, as are data speaking to the complexity of interactions between these mechanisms. Taken together, these data suggest different mechanisms are likely important in different scenarios. Study of the complex mechanisms of action that contribute to the clinical efficacy of rituximab have led to novel clinical trials including novel combinations, schedules, and generation of additional antibodies designed to have even greater effect. Such studies need to be accompanied by rigorous correlative analysis if we are to understand the importance of various mechanisms of action of rituximab and use that information to improve on what is already an indispensable component of therapy.

Section snippets

In Vitro Studies

In the absence of immune effector mechanisms, rituximab can induce death of malignant B cell lines in vitro. The strength of this effect varies considerably between target cell lines.7, 8, 9, 10 Signaling mediated by cross-linking of CD20 appears to be related to functional reorganization of CD20 into lipid rafts. Changes that have been identified in response to rituximab in vitro include inhibition of p38 mitogen-activated protein kinase, nuclear factor-κB (NF-κB), extracellular

In Vitro Studies

Several studies have demonstrated in vitro that rituximab is highly efficient at mediating CMC of various B-cell lines, as well as fresh malignant B-cell samples. The expression of complement inhibitory molecules (CD55 and CD59) on malignant B cells correlates with the extent of in vitro lysis.24, 25, 26, 27, 28, 29 Follicular lymphoma is more sensitive to rituximab clinically, and follicular lymphoma cells are more effectively lysed by complement in vitro when compared to cells from subjects

In Vitro Studies

mAbs can induce ADCC mediated by a variety of effector cells, including natural killer (NK) cells, granulocytes, and macrophages.41, 42 These processes require that the Fc of the antibody bound to the target cell bind to Fcγ receptor (FcγRs) on the effector cells triggering immune cell activation and death of the target cell.43 Rituximab can induce ADCC of human lymphoma cell lines by human peripheral blood mononuclear cells.24 However, in vitro detection of ADCC with rituximab and other

Interacting Mechanisms

The discussion above addresses the major mechanisms of action of rituximab independently. In fact, results of a number of studies point to more than one mechanism playing a role sensitivity or resistance to therapy including an increase in complement inhibitory molecules, decreased expression of CD20, and enhanced expression of anti-apoptotic molecules.59, 60

There are also extensive interactions—both synergistic and antagonistic—between these mechanisms of action. A mechanism that may

Conclusion

The data presented here suggest that rituximab-mediated signaling, CMC, and ADCC all contribute to rituximab's anti-tumor activity. Given this complexity, where do we go from here? We are unable to say “This is it!” with respect to a single mechanism being central to clinical response to rituximab. However, the ongoing evaluation of mechanisms of action has led to new rituximab-based combinations, novel schedules, and the design of the next generation of antibodies discussed at length elsewhere

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