Article thumbnail

A new approach to comparing anti-CD20 antibodies: importance of the lipid rafts in their lytic efficiency

By Mariam Hammadi, Jacques-Olivier Pers, Christian Berthou, Pierre Youinou and Anne Bordron


The view that B lymphocytes are pathogenic in diverse pathological settings is supported by the efficacy of B-cell-ablative therapy in lymphoproliferative disorders, autoimmune diseases and graft rejection. Anti-B-cell antibodies (Abs) directed against CD20 have therefore been generated, and of these, rituximab was the first anti-CD20 monoclonal Ab (mAb) to be applied. Rituximab-mediated apoptosis, complement-dependent cytotoxicity and Ab-dependent cellular cytotoxicity differ from one disease to another, and, for the same disease, from one patient to another. This knowledge has prompted the development of new anti-CD20 mAbs in the hope of improving B-cell depletion. The inclusion of CD20/anti-CD20 complexes in large lipid rafts (LRs) enhances the results of some, but not all, anti-CD20 mAbs, and it may be possible to include smaller LRs. Lipid contents of membrane may be abnormal in malignant B-cells, and could explain resistance to treatment. The function of these mAbs and the importance of LRs warrant further investigation. A detailed understanding of them will increase results for B-cell depletion in lymphoproliferative diseases

Topics: Review
Publisher: Dove Medical Press
OAI identifier:
Provided by: PubMed Central

To submit an update or takedown request for this paper, please submit an Update/Correction/Removal Request.

Suggested articles


  1. A novel polymorphism of FcgammaRIIIa (CD16) alters receptor function and predisposes to autoimmune disease.
  2. A phase 2 study of yttrium-90 ibritumomab tiuxetan (Zevalin) in patients with chronic lymphocytic leukemia.
  3. A pilot study of the anti-CD20 monoclonal antibody rituximab in patients with refractory immune thrombocytopenia. Semin Oncol.
  4. A polymorphism in the complement component C1qA correlates with prolonged response following rituximab therapy of follicular lymphoma.
  5. (2003). Anti-CD20 therapeutic antibody rituximab modifies the functional organization of rafts/ microdomains of B lymphoma cells. Cancer Res.
  6. (2008). Antibody therapy for chronic lymphocytic leukemia. Semin Hematol.
  7. B cell lipid rafts regulate both peptide-dependent and peptide-independent APC-T cell interaction.
  8. B cells are required for lupus nephritis in the polygenic, Fas-intact MRL model of systemic autoimmunity.
  9. (2005). B-cell depletion in the treatment of patients with systemic lupus erythematosus: a longitudinal analysis of 24 patients. Rheumatology
  10. (2007). BAFF-modulated repopulation of B lymphocytes in the blood and salivary glands of rituximab-treated patients with Sjögren’s syndrome. Arthritis Rheum.
  11. BAFF-modulated repopulation of B lymphocytes in the blood and salivary glands of rituximabtreated patients with Sjögren’s syndrome.
  12. (2002). Bexxar (Corixa/GlaxoSmithKline). Curr Opin Investig Drugs.
  13. Binding of submaximal C1q promotes complement-dependent cytotoxicity (CDC) of B cells opsonized with anti-CD20 mAbs ofatumumab (OFA) or rituximab (RTX): considerably higher levels of CDC are induced by OFA than by RTX.
  14. (2000). Biologic response of B lymphoma cells to anti-CD20 monoclonal antibody rituximab in vitro: CD55 and CD59 regulate complement-mediated cell lysis.
  15. CD20-induced lymphoma cell death is independent of both caspases and its redistribution into triton X-100 insoluble membrane rafts. Cancer Res.
  16. CD45 modulates phosphorylation of both autophosphorylation and negative regulatory tyrosines of Lyn in B cells.
  17. Chronic lymphocytic leukaemia cells are efficiently killed by an antiCD20 monoclonal antibody selected for improved engagement of FcgammaRIIIA/CD16.
  18. Colocalization of the B cell receptor and CD20 followed by activation-dependent dissociation in distinct lipid rafts.
  19. Complement activation on B lymphocytes opsonized with rituximab or ofatumumab produces substantial changes in membrane structure preceding cell lysis.
  20. Complement activation plays a key role in the side-effects of rituximab treatment.
  21. Crystal structure of chimeric antibody C2H7 Fab in complex with a CD20 peptide. Mol Immunol.
  22. Cytokine-release syndrome in patients with B-cell chronic lymphocytic leukemia and high lymphocyte counts after treatment with an anti-CD20 monoclonal antibody (rituximab,
  23. (2005). Decreased Lyn expression and translocation to lipid raft signaling domains in B lymphocytes from patients with systemic lupus erythematosus. Arthritis Rheum.
  24. Depletion of B cells in murine lupus: efficacy and resistance.
  25. (2009). Development of a new fully human anti-CD20 monoclonal antibody for the treatment of B-cell malignancies. Invest New Drugs.
  26. Development of novel tetravalent antiCD20 antibodies with potent antitumor activity. Cancer Res.
  27. (2007). Development of psoriasis after B cell depletion with rituximab. Arthritis Rheum.
  28. Effects of anti-CD20 monoclonal antibody as a rescue treatment for ANCA-associated idiopathic systemic vasculitis with or without overt renal involvement. Clin Exp Rheumatol. 2008;26(3 Suppl 49):S67–S71.
  29. Enhancing the action of rituximab in chronic lymphocytic leukemia by adding fresh frozen plasma: complement/rituximab interactions and clinical results in refractory CLL.
  30. (1989). Expression of proliferation and differentiation antigens in response to modulation of membrane fluidity in chronic lymphocytic leukemia lymphocytes. Anticancer Res.
  31. Favorable response to therapy with the anti-CD20 monoclonal antibody rituximab in primary chronic cold agglutinin disease.
  32. FcgammaRIIB Ile232Thr transmembrane polymorphism associated with human systemic lupus erythematosus decreases affinity to lipid rafts and attenuates inhibitory effects on B cell receptor signaling. Hum Mol Genet.
  33. First clinical use of ofatumumab, a novel fully human anti-CD20 monoclonal antibody in relapsed or refractory follicular lymphoma: results of a phase 1/2 trial.
  34. Fractionated subcutaneous Rituximab is well tolerated and preserves CD20 expression on tumor cells in patients with chronic lymphocytic leukemia.
  35. (1989). Functions of sphingolipids and sphingolipid breakdown products in cellular regulation.
  36. G.B-cell-targeted therapy for systemic lupus erythematosus: an update.
  37. (2009). GA-101, a third-generation, humanized and glyco-engineered anti-CD20 mAb for the treatment of B-cell lymphoid malignancies. Curr Opin Investig Drugs.
  38. (2002). GD3 ganglioside and apoptosis. Biochim Biophys Acta.
  39. Glucosylceramide synthase inhibitors sensitize CLL cells to cytotoxic agents without reversing P-gp functional activity.
  40. Glycosphingolipid (GSL) microdomains as attachment platforms for host pathogens and their toxins on intestinal epithelial cells: activation of signal transduction pathways and perturbations of intestinal absorption and secretion.
  41. Glycosphingolipids and drug resistance.
  42. (2008). GM1 expression of non-Hodgkin’s lymphoma determines susceptibility to rituximab treatment. Cancer Res.
  43. Humanized anti-CD20 antibody, veltuzumab, in refractory/recurrent non-Hodgkin’s lymphoma: phase I/II results.
  44. IDEC-C2B8 (Rituximab) anti-CD20 monoclonal antibody therapy in patients with relapsed low-grade non-Hodgkin’s lymphoma.
  45. (2005). Importance of cellular microenvironment and circulatory dynamics in B cell immunotherapy. J Immunol.
  46. Improvement of rituximab efficiency in chronic lymphocytic leukemia by CpG-mediated up-regulation of CD20 expression independently of PU.1.
  47. (2007). Improvement of Sjögren’s syndrome after two infusions of rituximab (anti-CD20). Arthritis Rheum.
  48. In vitro mechanisms of action of rituximab on primary non-Hodgkin lymphomas.
  49. Insertion of ganglioside GM1 into rat glioma C6 cells renders them susceptible to growth inhibition by the B subunit of cholera toxin.
  50. Lack of dynamic lipid changes after binding of interleukin 2 in chronic lymphatic leukemia lymphocytes indicates defective transmembrane signaling. Anticancer Res.
  51. (2005). Lipid rafts and membrane dynamics.
  52. Lipid rafts and membrane traffic.
  53. Lipid rafts are enriched in arachidonic acid and plasmenylethanolamine and their composition is independent of caveolin-1 expression: a quantitative electrospray ionization/mass spectrometric analysis.
  54. Lipid rafts as a membrane-organizing principle.
  55. Lipid rafts regulate cellular CD40 receptor localization in vascular endothelial cells.
  56. Long-term results of the R-CHOP study in the treatment of elderly patients with diffuse large B-cell lymphoma: a study by the Groupe d’Etude des Lymphomes de l’Adulte.
  57. (2009). Low-grade B-cell proliferation progressing to high-grade B-cell lymphoma.
  58. Mechanisms of killing by anti-CD20 monoclonal antibodies.
  59. Membrane heterogeneities in the formation of B cell receptor-Lyn kinase microclusters and the immune synapse.
  60. (2006). Mimotope vaccination for epitopespecific induction of anti-CD20 antibodies. Cell Immunol.
  61. Modulation of complement lysis of human erythrocytes by the membrane lipid viscosity. Vox Sang.
  62. (2009). Molecular mechanisms of resistance to Rituximab and pharmacologic strategies for its circumvention. Leuk Lymphoma.
  63. Multidrug resistance mechanisms in chronic lymphocytic leukaemia.
  64. Natural antibodies and cancer.
  65. (2007). New treatments for acute humoral rejection of kidney allografts. Expert Opin Investig Drugs.
  66. Novel designs of multivalent anti-CD20 humanized antibodies as improved lymphoma therapeutics. Cancer Res.
  67. Ocrelizumab, a humanized anti-CD20 monoclonal antibody, in the treatment of patients with rheumatoid arthritis: A phase I/II randomized, blinded, placebo- controlled, dose-ranging study.
  68. (2008). Ofatumumab, a human monoclonal antibody for lymphoid malignancies and autoimmune disorders. Curr Opin Mol Ther.
  69. On behalf of the GRAGIL Study Group. Evidence for Humoral Rejection of a Pancreatic Islet Graft and Rescue with Rituximab and IV Immunoglobulin Therapy.
  70. (2008). Onset of psoriasis with psoriatic arthropathy during rituximab treatment of non-Hodgkin lymphoma. Ann Rheum Dis.
  71. Properties and structurefunction relationships of veltuzumab (hA20), a humanized anti-CD20 monoclonal antibody.
  72. Protein profiling of plasma membranes defines aberrant signaling pathways in mantle cell lymphoma. Mol Cell Proteomics.
  73. (2008). Purine-rich box-1-mediated reduced expression of CD20 alters rituximab-induced lysis of chronic lymphocytic leukemia B cells. Cancer Res.
  74. (1999). Quantitative analysis of phospholipids in functionally important membrane domains from RBL-2H3 mast cells using tandem high-resolution mass spectrometry. Biochemistry.
  75. Rafts defined: a report on the Keystone Symposium on Lipid Rafts and Cell Function.
  76. Reduction of B cell turnover in chronic lymphocytic leukemia.
  77. Relation of P-glycoprotein expression with spontaneous in vitro apoptosis in B-cell chronic lymphocytic leukemia.
  78. (2005). Rituxan (anti-CD20 antibody)-induced translocation of CD20 into lipid rafts is crucial for calcium influx and apoptosis. Clin Exp Immunol.
  79. (2009). Rituximab and chemotherapy in diffuse large B-cell lymphoma. Expert Rev Anticancer Ther.
  80. Rituximab for steroid-refractory chronic graft-versus-host disease.
  81. Rituximab for the treatment of corticosteroid-refractory chronic graft-versus-host disease.
  82. Rituximab for the treatment of juvenile dermatomyositis: a report of four pediatric patients.
  83. Rituximab for the treatment of patients with very high-titre acquired factor VIII inhibitors refractory to conventional chemotherapy.
  84. (2009). Rituximab for the treatment of relapsed or refractory stage III or IV follicular non-Hodgkin’s lymphoma. Health Technol Assess.
  85. (2008). Rituximab immunotherapy in pemphigus: therapeutic effects beyond B-cell depletion. J Invest Dermatol.
  86. Rituximab in auto-immune haemolytic anaemia and immune thrombocytopenic purpura: a Belgian retrospective multicentric study.
  87. Rituximab infusion promotes rapid complement depletion and acute CD20 loss in chronic lymphocytic leukemia.
  88. Rituximab treatment of fibrillary glomerulonephritis.
  89. (2009). Rituximab-based treatments in Waldenström‘s macroglobulinemia. Clin Lymphoma Myeloma.
  90. Rituximab: an anti-CD20 antibody for the treatment of chronic refractory immune thrombocytopenic purpura.
  91. Safety and efficacy of ofatumumab, a fully human monoclonal anti-CD20 antibody, in patients with relapsed or refractory B-cell chronic lymphocytic leukemia: a phase 1–2 study.
  92. Serum BAFF predicts prognosis better than APRIL in diffuse large B-cell lymphoma patients treated with rituximab plus CHOP chemotherapy.
  93. Sorting of GPI-anchored proteins to glycolipid enriched membrane subdomains during transport to the apical cell surface.
  94. Sphingomyelinase and cellpermeable ceramide analogs stimulate cellular proliferation in quiescent Swiss 3T3 fibroblasts.
  95. Spotlight on rituximab in non-Hodgkin lymphoma and chronic lymphocytic leukemia.
  96. Successful long-term treatment of systemic lupus erythematosus with rituximab maintenance therapy.
  97. Successful treatment of chronic antibody-mediated rejection with IVIG and rituximab in pediatric renal transplant recipients.
  98. Systemic lupus erythematosus-associated defects in the inhibitory receptor FcgammaRIIb reduce susceptibility to malaria.
  99. (2005). The biology of CD20 and its potential as a target for mAb therapy. Curr Dir Autoimmun.
  100. The CD20 calcium channel is localized to microvilli and constitutively associated with membrane rafts: antibody binding increases the affinity of the association through an epitope-dependent cross-linking-independent mechanism.
  101. The chimeric anti-CD20 antibody rituximab induces apoptosis in B-cell chronic lymphocytic leukemia cells through a p38 mitogen activated protein-kinase-dependent mechanism.
  102. (2009). The expression of B-cell activating factor belonging to tumor necrosis factor super family (BAFF) significantly correlated with C4D in kidney allograft rejection. Transplant
  103. (2008). The lipid raft-anchored adaptor protein Cbp controls the oncogenic potential of c-Src. Mol Cell.
  104. (2004). The role of complement in the development of systemic lupus erythematosus. Annu Rev Immunol.
  105. Therapeutic activity of humanized anti-CD20 monoclonal antibody and polymorphism in IgG Fc receptor FcgammaRIIIa gene.
  106. (2006). Thrice-weekly low-dose rituximab decreases CD20 loss via shaving and promotes enhanced targeting in chronic lymphocytic leukemia. J Immunol.
  107. (2002). Treatment of humoral rejection with rituximab. Ann Thorac Surg.
  108. Tumor cell expression of CD59 is associated with resistance to CD20 serotherapy in patients with B-cell malignancies.
  109. (2009). Variable Contribution of Monoclonal Antibodies to ADCC in patients with chronic lymphocytic leukemia. Leuk Lymphoma.