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

Rituximab: Mechanism of Action

  • George J. Weiner

      Affiliations

    • Corresponding Author InformationAddress correspondence to George Weiner, MD, Holden Comprehensive Cancer Center, University of Iowa, 200 Hawkins Dr, 5970 JPP, Iowa City, IA 52242-1002

References 

  1. Maloney DG, Grillo-Lopez AJ, Bodkin DJ, et al. IDEC-C2B8: results of a phase I multiple-dose trial in patients with relapsed non-Hodgkin's lymphoma. J Clin Oncol. 1997;15:3266–3274
  2. McLaughlin P, Grillo-Lopez AJ, Link BK, et al. Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: half of patients respond to a four-dose treatment program. J Clin Oncol. 1998;16:2825–2833
  3. Habermann TM, Weller EA, Morrison VA, et al. Rituximab-CHOP versus CHOP alone or with maintenance rituximab in older patients with diffuse large B-cell lymphoma. J Clin Oncol. 2006;24:3121–3127
  4. Coiffier B, Lepage E, Briere J, et al. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med. 2002;346:235–242
  5. Maloney DG, Grillolopez AJ, White CA, et al. Idec-C2b8 (rituximab) anti-CD20 monoclonal antibody therapy patients with relapsed low-grade non-Hodgkins lymphoma. Blood. 1997;90:2188–2195
  6. Egeblad M, Ewald AJ, Askautrud HA, et al. Visualizing stromal cell dynamics in different tumor microenvironments by spinning disk confocal microscopy. Dis Model Mech. 2008;1:155–167
  7. Shan D, Ledbetter JA, Press OW. Signaling events involved in anti-CD20-induced apoptosis of malignant human B cells. Cancer Immunol Immunother. 2000;48:673–683
  8. Semac I, Palomba C, Kulangara K, et al. Anti-CD20 therapeutic antibody rituximab modifies the functional organization of rafts/microdomains of B lymphoma cells. Cancer Res. 2003;63:534–540
  9. Jazirehi AR, Gan XH, De Vos S, Emmanouilides C, Bonavida B. 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. 2003;2:1183–1193
  10. Bonavida B. Rituximab-induced inhibition of antiapoptotic cell survival pathways: implications in chemo/immunoresistance, rituximab unresponsiveness, prognostic and novel therapeutic interventions. Oncogene. 2007;26:3629–3636
  11. Czuczman MS, Olejniczak S, Gowda A, et al. 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. 2008;14:1561–1570
  12. Pedersen IM, Buhl AM, Klausen P, Geisler CH, Jurlander J. 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;99:1314–1319
  13. Emmanouilides C, Jazirehi AR, Bonavida B. Rituximab-mediated sensitization of B-non-Hodgkin's lymphoma (NHL) to cytotoxicity induced by paclitaxel, gemcitabine, and vinorelbine. Cancer Biother Radiopharm. 2002;17:621–630
  14. Jazirehi AR, Vega MI, Bonavida B. Development of rituximab-resistant lymphoma clones with altered cell signaling and cross-resistance to chemotherapy. Cancer Res. 2007;67:1270–1281
  15. Vega MI, Huerta-Yepez S, Martinez-Paniagua M, et al. Rituximab-mediated cell signaling and chemo/immuno-sensitization of drug-resistant B-NHL is independent of its Fc functions. Clin Cancer Res. 2009;15:6582–6594
  16. Schliemann C, Palumbo A, Zuberbuhler K, et al. Complete eradication of human B-cell lymphoma xenografts using rituximab in combination with the immunocytokine L19-IL2. Blood. 2009;113:2275–2283
  17. Mohammad RM, Aboukameel A, Nabha S, Ibrahim D, Al-Katib A. Rituximab, cyclophosphamide, dexamethasone (RCD) regimen induces cure in WSU-WM xenograft model and a partial remission in previously treated Waldenstrom's macroglobulinemia patient. J Drug Target. 2002;10:405–410
  18. Kaminski MS, Zasadny KR, Francis IR, et al. Radioimmunotherapy of B-cell lymphoma with [131I]anti-B1 (anti-CD20) antibody. N Engl J Med. 1993;329:459–465
  19. Rubenstein JL, Fridlyand J, Abrey L, et al. Phase I study of intraventricular administration of rituximab in patients with recurrent CNS and intraocular lymphoma. J Clin Oncol. 2007;25:1350–1356
  20. Takami A, Hayashi T, Kita D, Nishimura R, Asakura H, Nakao S. Treatment of primary central nervous system lymphoma with induction of complement-dependent cytotoxicity by intraventricular administration of autologous-serum-supplemented rituximab. Cancer Sci. 2006;97:80–83
  21. Czuczman MS, Grillo-Lopez AJ, White CA, et al. Treatment of patients with low-grade B-cell lymphoma with the combination of chimeric anti-CD20 monoclonal antibody and CHOP chemotherapy. J Clin Oncol. 1999;17:268–276
  22. Keating MJ, O'Brien S, Albitar M, et al. Early results of a chemoimmunotherapy regimen of fludarabine, cyclophosphamide, and rituximab as initial therapy for chronic lymphocytic leukemia. J Clin Oncol. 2005;23:4079–4088
  23. Carlotti E, Palumbo GA, Oldani E, et al. FcgammaRIIIA and FcgammaRIIA polymorphisms do not predict clinical outcome of follicular non-Hodgkin's lymphoma patients treated with sequential CHOP and rituximab. Haematologica. 2007;92:1127–1130
  24. Reff ME, Carner K, Chambers KS, et al. Depletion of B cells in vivo by a chimeric mouse human monoclonal antibody to CD20. Blood. 1994;83:435–445
  25. Flieger D, Renoth S, Beier I, Sauerbruch T, Schmidt-Wolf I. Mechanism of cytotoxicity induced by chimeric mouse human monoclonal antibody IDEC-C2B8 in CD20-expressing lymphoma cell lines. Cell Immunol. 2000;204:55–63
  26. Golay J, Lazzari M, Facchinetti V, 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;98:3383–3389
  27. Harjunpaa A, Junnikkala S, Meri S. Rituximab (anti-CD20) therapy of B-cell lymphomas: direct complement killing is superior to cellular effector mechanisms. Scand J Immunol. 2000;51:634–641
  28. Bellosillo B, Villamor N, Lopez-Guillermo A, 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;98:2771–2777
  29. Weng WK, Levy R. 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;98:1352–1357
  30. Manches O, Lui G, Chaperot L, et al. In vitro mechanisms of action of rituximab on primary non-Hodgkin lymphomas. Blood. 2003;101:949–954
  31. Wang S-Y, Veeramani S, Racila E, 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;114:5322–5330
  32. Di Gaetano N, Cittera E, Nota R, et al. Complement activation determines the therapeutic activity of rituximab in vivo. J Immunol. 2003;171:1581–1587
  33. Golay J, Cittera E, Di Gaetano N, et al. The role of complement in the therapeutic activity of rituximab in a murine B lymphoma model homing in lymph nodes. Haematologica. 2006;91:176–183
  34. Tawara T, Hasegawa K, Sugiura Y, et al. Complement activation plays a key role in antibody-induced infusion toxicity in monkeys and rats. J Immunol. 2008;180:2294–2298
  35. Zhou X, Hu W, Qin X. The role of complement in the mechanism of action of rituximab for B-cell lymphoma: implications for therapy. Oncologist. 2008;13:954–966
  36. van der Kolk LE, Grillo-Lopez AJ, Baars JW, Hack CE, van Oers MH. Complement activation plays a key role in the side-effects of rituximab treatment. Br J Haematol. 2001;115:807–811
  37. Bannerji R, Kitada S, Flinn IW, et al. Apoptotic-regulatory and complement-protecting protein expression in chronic lymphocytic leukemia: relationship to in vivo rituximab resistance. J Clin Oncol. 2003;21:1466–1471
  38. Treon SP, Mitsiades C, Mitsiades N, et al. Tumor cell expression of CD59 is associated with resistance to CD20 serotherapy in patients with B-cell malignancies. J Immunother. 2001;24:263–271
  39. Pawluczkowycz AW, Beurskens FJ, Beum PV, et al. 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. J Immunol. 2009;183:749–758
  40. Klepfish A, Schattner A, Ghoti H, Rachmilewitz EA. Addition of fresh frozen plasma as a source of complement to rituximab in advanced chronic lymphocytic leukaemia. Lancet Oncol. 2007;8:361–362
  41. Dall'Ozzo S, Tartas S, Paintaud G, et al. Rituximab-dependent cytotoxicity by natural killer cells: influence of FCGR3A polymorphism on the concentration-effect relationship. Cancer Res. 2004;64:4664–4669
  42. Lefebvre ML, Krause SW, Salcedo M, Nardin A. Ex vivo-activated human macrophages kill chronic lymphocytic leukemia cells in the presence of rituximab: mechanism of antibody-dependent cellular cytotoxicity and impact of human serum. J Immunother. 2006;29:388–397
  43. Bowles JA, Wang SY, Link BK, et al. Anti-CD20 monoclonal antibody with enhanced affinity for CD16 activates NK cells at lower concentrations and more effectively than rituximab. Blood. 2006;108:2648–2654
  44. Hernandez-Ilizaliturri FJ, Jupudy V, Ostberg J, et al. Neutrophils contribute to the biological antitumor activity of rituximab in a non-Hodgkin's lymphoma severe combined immunodeficiency mouse model. Clin Cancer Res. 2003;9:5866–5873
  45. Stockmeyer B, Dechant M, van Egmond M, et al. Triggering Fc alpha-receptor I (CD89) recruits neutrophils as effector cells for CD20-directed antibody therapy. J Immunol. 2000;165:5954–5961
  46. Wooldridge JE, Ballas Z, Krieg AM, Weiner GJ. Immunostimulatory oligodeoxynucleotides containing CpG motifs enhance the efficacy of monoclonal antibody therapy of lymphoma. Blood. 1997;89:2994–2998
  47. Clynes R, Takechi Y, Moroi Y, Houghton A, Ravetch JV. Fc receptors are required in passive and active immunity to melanoma. Proc Natl Acad Sci U S A. 1998;95:652–656
  48. Clynes RA, Towers TL, Presta LG, Ravetch JV. Inhibitory Fc receptors modulate in vivo cytoxicity against tumor targets. Nat Med. 2000;6:443–446
  49. Koene HR, Kleijer M, Algra J, Roos D, von dem Borne AE, de Haas M. 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. 1997;90:1109–1114
  50. Cartron G, Dacheux L, Salles G, et al. Therapeutic activity of humanized anti-CD20 monoclonal antibody and polymorphism in IgG Fc receptor FcgammaRIIIa gene. Blood. 2002;99:754–758
  51. Weng WK, Levy R. Two immunoglobulin G fragment C receptor polymorphisms independently predict response to rituximab in patients with follicular lymphoma. J Clin Oncol. 2003;21:3940–3947
  52. Treon SP, Hansen M, Branagan AR, et al. Polymorphisms in FcgammaRIIIA (CD16) receptor expression are associated with clinical response to rituximab in Waldenstrom's macroglobulinemia. J Clin Oncol. 2005;23:474–481
  53. Farag SS, Flinn IW, Modali R, Lehman TA, Young D, Byrd JC. Fc gamma RIIIa and Fc gamma RIIa polymorphisms do not predict response to rituximab in B-cell chronic lymphocytic leukemia. Blood. 2004;103:1472–1474
  54. Friedberg JW, Neuberg D, Gribben JG, et al. Combination immunotherapy with rituximab and interleukin 2 in patients with relapsed or refractory follicular non-Hodgkin's lymphoma. Br J Haematol. 2002;117:828–834
  55. Leonard JP, Link BK, Emmanouilides C, et al. Phase I trial of Toll-like receptor 9 agonist PF-3512676 with and following rituximab in patients with recurrent indolent and aggressive non Hodgkin's lymphoma. Clin Cancer Res. 2007;13:6168–6174
  56. Robak T. GA-101, a third-generation, humanized and glyco-engineered anti-CD20 mAb for the treatment of B-cell lymphoid malignancies. Curr Opin Invest Drugs. 2009;10:588–596
  57. Bowles JA, Weiner GJ. CD16 polymorphisms and NK activation induced by monoclonal antibody-coated target cells. J Immunol Meth. 2005;304:88–99
  58. Hoffmeyer F, Witte K, Schmidt RE. The high-affinity Fc gamma RI on PMN: regulation of expression and signal transduction. Immunology. 1997;92:544–552
  59. Dalle S, Dupire S, Brunet-Manquat S, Reslan L, Plesa A, Dumontet C. In vivo model of follicular lymphoma resistant to rituximab. Clin Cancer Res. 2009;15:851–857
  60. Stolz C, Hess G, Hahnel PS, et al. Targeting Bcl-2 family proteins modulates the sensitivity of B-cell lymphoma to rituximab-induced apoptosis. Blood. 2008;112:3312–3321
  61. Carroll MC. The complement system in B cell regulation. Mol Immunol. 2004;41:141–146
  62. Charriaut C, Senik A, Kolb JP, Barel M, Frade R. Inhibition of in vitro natural killer activity by the third component of complement: role for the C3a fragment. Proc Natl Acad Sci U S A. 1982;79:6003–6007
  63. Boackle SA. Complement and autoimmunity. Biomed Pharmacother. 2003;57:269–273
  64. Botto M, Walport MJ. C1q, autoimmunity and apoptosis. Immunobiology. 2002;205:395–406
  65. Racila E, Link BK, Weng WK, et al. A polymorphism in the complement component C1qA correlates with prolonged response following rituximab therapy of follicular lymphoma. Clin Cancer Res. 2008;14:6697–6703
  66. Kennedy AD, Beum PV, Solga MD, et al. Rituximab infusion promotes rapid complement depletion and acute CD20 loss in chronic lymphocytic leukemia. J Immunol. 2004;172:3280–3288
  67. Beum PV, Lindorfer MA, Taylor RP. Within peripheral blood mononuclear cells, antibody-dependent cellular cytotoxicity of rituximab-opsonized Daudi cells is promoted by NK cells and inhibited by monocytes due to shaving. J Immunol. 2008;181:2916–2924
  68. Wang SY, Racila E, Taylor RP, Weiner GJ. NK-cell activation and antibody-dependent cellular cytotoxicity induced by rituximab-coated target cells is inhibited by the C3b component of complement. Blood. 2008;111:1456–1463
  69. Cragg MS, Glennie MJ. Antibody specificity controls in vivo effector mechanisms of anti-CD20 reagents. Blood. 2004;103:2738–2743
  70. Beers SA, Chan CH, James S, et al. Type II (tositumomab) anti-CD20 monoclonal antibody out performs type I (rituximab-like) reagents in B-cell depletion regardless of complement activation. Blood. 2008;112:4170–4177

PII: S0037-1963(10)00012-0

doi: 10.1053/j.seminhematol.2010.01.011

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