Rituximab: Mechanism of Action
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
References (70)
- et al.
Idec-C2b8 (rituximab) anti-CD20 monoclonal antibody therapy patients with relapsed low-grade non-Hodgkins lymphoma
Blood
(1997) - et al.
The chimeric anti-CD20 antibody rituximab induces apoptosis in B-cell chronic lymphocytic leukemia cells through a p38 mitogen activated protein-kinase-dependent mechanism
Blood
(2002) - et al.
Complete eradication of human B-cell lymphoma xenografts using rituximab in combination with the immunocytokine L19-IL2
Blood
(2009) - et al.
Depletion of B cells in vivo by a chimeric mouse human monoclonal antibody to CD20
Blood
(1994) - et al.
Mechanism of cytotoxicity induced by chimeric mouse human monoclonal antibody IDEC-C2B8 in CD20-expressing lymphoma cell lines
Cell Immunol
(2000) - et al.
CD20 levels determine the in vitro susceptibility to rituximab and complement of B-cell chronic lymphocytic leukemia: further regulation by CD55 and CD59
Blood
(2001) - et al.
Complement-mediated cell death induced by rituximab in B-cell lymphoproliferative disorders is mediated in vitro by a caspase-independent mechanism involving the generation of reactive oxygen species
Blood
(2001) - et al.
Expression of complement inhibitors CD46, CD55, and CD59 on tumor cells does not predict clinical outcome after rituximab treatment in follicular non-Hodgkin lymphoma
Blood
(2001) - et al.
In vitro mechanisms of action of rituximab on primary non-Hodgkin lymphomas
Blood
(2003) - et al.
Depletion of the C3 component of complement enhances the ability of rituximab-coated target cells to activate human NK cells and improves the efficacy of monoclonal antibody therapy in an in vivo model
Blood
(2009)
Addition of fresh frozen plasma as a source of complement to rituximab in advanced chronic lymphocytic leukaemia
Lancet Oncol
Anti-CD20 monoclonal antibody with enhanced affinity for CD16 activates NK cells at lower concentrations and more effectively than rituximab
Blood
Immunostimulatory oligodeoxynucleotides containing CpG motifs enhance the efficacy of monoclonal antibody therapy of lymphoma
Blood
Fc gammaRIIIa-158V/F polymorphism influences the binding of IgG by natural killer cell Fc gammaRIIIa, independently of the Fc gammaRIIIa-48L/R/H phenotype
Blood
Therapeutic activity of humanized anti-CD20 monoclonal antibody and polymorphism in IgG Fc receptor FcgammaRIIIa gene
Blood
Fc gamma RIIIa and Fc gamma RIIa polymorphisms do not predict response to rituximab in B-cell chronic lymphocytic leukemia
Blood
CD16 polymorphisms and NK activation induced by monoclonal antibody-coated target cells
J Immunol Meth
Targeting Bcl-2 family proteins modulates the sensitivity of B-cell lymphoma to rituximab-induced apoptosis
Blood
The complement system in B cell regulation
Mol Immunol
Complement and autoimmunity
Biomed Pharmacother
C1q, autoimmunity and apoptosis
Immunobiology
NK-cell activation and antibody-dependent cellular cytotoxicity induced by rituximab-coated target cells is inhibited by the C3b component of complement
Blood
Antibody specificity controls in vivo effector mechanisms of anti-CD20 reagents
Blood
Type II (tositumomab) anti-CD20 monoclonal antibody out performs type I (rituximab-like) reagents in B-cell depletion regardless of complement activation
Blood
IDEC-C2B8: results of a phase I multiple-dose trial in patients with relapsed non-Hodgkin's lymphoma
J Clin Oncol
Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: half of patients respond to a four-dose treatment program
J Clin Oncol
Rituximab-CHOP versus CHOP alone or with maintenance rituximab in older patients with diffuse large B-cell lymphoma
J Clin Oncol
CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma
N Engl J Med
Visualizing stromal cell dynamics in different tumor microenvironments by spinning disk confocal microscopy
Dis Model Mech
Signaling events involved in anti-CD20-induced apoptosis of malignant human B cells
Cancer Immunol Immunother
Anti-CD20 therapeutic antibody rituximab modifies the functional organization of rafts/microdomains of B lymphoma cells
Cancer Res
Rituximab (anti-CD20) selectively modifies Bcl-xL and apoptosis protease activating factor-1 (Apaf-1) expression and sensitizes human non-Hodgkin's lymphoma B cell lines to paclitaxel-induced apoptosis
Mol Cancer Ther
Rituximab-induced inhibition of antiapoptotic cell survival pathways: implications in chemo/immunoresistance, rituximab unresponsiveness, prognostic and novel therapeutic interventions
Oncogene
Acquirement of rituximab resistance in lymphoma cell lines is associated with both global CD20 gene and protein down-regulation regulated at the pretranscriptional and posttranscriptional levels
Clin Cancer Res
Rituximab-mediated sensitization of B-non-Hodgkin's lymphoma (NHL) to cytotoxicity induced by paclitaxel, gemcitabine, and vinorelbine
Cancer Biother Radiopharm
Cited by (596)
B cell focused transient immune suppression protocol for efficient AAV readministration to the liver
2024, Molecular Therapy Methods and Clinical DevelopmentMyasthenia gravis: Molecular mechanisms and promising therapeutic strategies
2023, Biochemical PharmacologyCAR T-cell therapy in autoimmune diseases
2023, The LancetRole of Rituximab in Treatment of Patients With Primary Central Nervous System Lymphoma (PCNSL): A Systematic Review and Meta-Analysis
2023, Clinical Lymphoma, Myeloma and Leukemia