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Impact of Polymorphisms on the Clinical Outcomes of Monoclonal Antibody Therapy Against Hematologic Malignancies

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Genomics and Pharmacogenomics in Anticancer Drug Development and Clinical Response

Part of the book series: Cancer Drug Discovery and Development™ ((CDD&D))

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Summary

Monoclonal antibodies that target various specific antigens can be used to kill the tumor cells expressing specific antigens, especially in hematologic cancers. Rituximab, one of the commonly used monoclonal antibodies, was suggested to mediate its action mechanism via antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), or a direct pro-apoptotic effect. It has been proposed that the inter-individual variation of gene expression is a consequence of single nucleotide polymorphisms (SNPs) and that the response to a monoclonal antibody can be affected by the SNPs in the host genes corresponding to the drug binding to the target cells or the metabolism of the drug.

This chapter reviews the current understanding of the mechanism of action of monoclonal antibodies (especially rituximab), the role of Fcγ receptor and Fcγ receptor gene polymorphisms, and their impact on treatment outcomes in hematologic malignancies including follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), Waldenstrom’s macroglobulinemia (WM), and chronic lymphocytic leukemia (CLL). In addition, we discuss the approaches augmenting its clinical activity, especially focusing on Fcγ receptor re-engineered monoclonal antibody.

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References

  1. McLaughlin P, Grillo-Lopez JA, 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 Oncol1998;16:2825–2833.

    CAS  PubMed  Google Scholar 

  2. Habermann TM, Weller E, Morrison VA et al. Rituximab-CHOP versus CHOP with or without maintenance rituximab in patients 60 years of age or older with diffuse large B-cell lymphoma (DLBCL): an update. Blood2004;104:127.

    Google Scholar 

  3. Cartron G, Watier H, Golay J et al. From the bench to the bedside: ways to improve rituximab efficacy. Blood2004;104:2635–2642.

    Article  CAS  PubMed  Google Scholar 

  4. Smith MR. Rituximab (monoclonal anti-CD20 antibody): mechanisms of action and resistance. Oncogene2003;22:7359–7368.

    Article  CAS  PubMed  Google Scholar 

  5. Binstadt BA, Geha RS, Bonilla FA. IgG Fc receptor polymorphisms in human disease: implications for intravenous immunoglobulin therapy. J Allergy Clin Immunol2003;697–703.

    Google Scholar 

  6. van Sorge NM, van der Pol WL, van de Winkel JG. FcgammaR polymorphisms: Implications for function, disease susceptibility and immunotherapy. Tissue Antigens2003;6:189–202.

    Article  Google Scholar 

  7. Golay J, Zaffaroni L, Vaccari T et al. Biologic response of B lymphoma cells to anti-CD20 monoclonal antibody rituximab in vitro: CD55 and CD59 regulate complement-mediated cell lysis. Blood2000;95:3900–3908.

    CAS  PubMed  Google Scholar 

  8. Shan D, Ledbetter JA, Press OW. Apoptosis of malignant human B-cells by ligation of CD20 with monoclonal antibodies. Blood1998;91:1644–1652.

    CAS  PubMed  Google Scholar 

  9. Hofmeister JK, Cooney D, Coggeshall KM. Clustered CD20 induced apoptosis: src-family kinase, the proximal regulator of tyrosine phosphorylation, calcium influx, and caspase 3-dependent apoptosis. Blood Cells Mol Dis2000;26:133–143.

    Article  CAS  PubMed  Google Scholar 

  10. Villamor N, Montserrat E, Colomer D. Mechanism of action and resistance to monoclonal antibody therapy. Semin Oncol2003;30:424–433.

    Article  CAS  PubMed  Google Scholar 

  11. Jazirehi AR, Gan XH, De Vos S et al. 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 Ther2003;2:1183–1193.

    CAS  PubMed  Google Scholar 

  12. Jazirehi AR, Vega MI, Chatterjee D et al. Inhibition of the Raf-MEK1/2-ERK1/2 signaling pathway, Bcl-xL down-regulation, and chemosensitization of non-Hodgkin's lymphoma B-cells by Rituximab. Cancer Res2004;64:7117–7126.

    Article  CAS  PubMed  Google Scholar 

  13. Shan D, Ledbetter JA, Press OW. Signaling events involved in anti-CD20-induced apoptosis of malignant human B-cells. Cancer Immunol Immunother2000;48:673–683.

    Article  CAS  PubMed  Google Scholar 

  14. Deans JP, Schieven GL, Shu GL et al. Association of tyrosine and serine kinases with the B-cell surface antigen CD20: induction via CD20 of tyrosine phosphorylation and activation of phospholipase C-gamma 1 and PLC phospholipase C-gamma 2. J Immunol1993;151:4494–4504.

    CAS  PubMed  Google Scholar 

  15. Pedersen IM, Buhl AM, Klausen P 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. Blood2002;99:1314–1319.

    Article  CAS  PubMed  Google Scholar 

  16. Janas E, Priest R, Wilde JI et al. Rituxan (anti-CD20 antibody)-induced translocation of CD20 into lipid rafts is crucial for calcium influx and apoptosis. Clin Exp Immunol2005;139:439–446.

    Article  CAS  PubMed  Google Scholar 

  17. Aydin F, Yilmaz M, Ozdemir F et al. Correlation of serum IL-2, IL-6 and IL-10 levels with International Prognostic Index in patients with aggressive non-Hodgkin's lymphoma. Am J Clin Oncol2002;25:570–572.

    Article  PubMed  Google Scholar 

  18. Bohlen H, Kessler M, Sextro M et al. Poor clinical outcome of patients with Hodgkin's disease and elevated interleukin-10 serum levels: clinical significance of interleukin-10 serum levels for Hodgkin's disease. Ann Hematol2000;79:110–113.

    Article  CAS  PubMed  Google Scholar 

  19. Cortes J, Kurzrock R. Interleukin-10 in non-Hodgkin's lymphoma. Leuk Lymphoma1997;26: 251–259.

    CAS  PubMed  Google Scholar 

  20. el-Far M, Fouda M, Yahya R et al. Serum IL-10 and IL-6 levels at diagnosis as independent predictors of outcome in non-Hodgkin's lymphoma. J Physiol Biochem2004;60(4):253–258.

    Article  CAS  PubMed  Google Scholar 

  21. Ozdemir F, Aydin F, Yilmaz M et al. The effects of IL-2, IL-6, and IL-10 levels on prognosis in patients with aggressive non-Hodgkin's lymphoma (NHL). J Exp Clin Cancer Res2004;23:485–488.

    CAS  PubMed  Google Scholar 

  22. Salgami EV, Efstathiou SP, Vlachakis V et al. High pretreatment interleukin-10 is an independent predictor of poor failure-free survival in patients with Hodgkin's lymphoma. Haematologia (Budap)2002;32:377–387.

    CAS  Google Scholar 

  23. Sarris AH, Kliche KO, Pethambaram P et al. Interleukin-10 levels are often elevated in serum of adults with Hodgkin's disease and are associated with inferior failure-free survival. Ann Oncol1999;10: 433–440.

    Article  CAS  PubMed  Google Scholar 

  24. Stasi R, Zinzani PL, Galieni P et al. Prognostic value of serum IL-10 and soluble IL-2 receptor levels in aggressive non-Hodgkin's lymphoma. Br J Haematol1994;88:770–777.

    Article  CAS  PubMed  Google Scholar 

  25. Vassilakopoulos TP, Nadali G, Angelopoulou MK et al. Serum interleukin-10 levels are an independent prognostic factor for patients with Hodgkin's lymphoma. Haematologica2001;86:274–281.

    CAS  PubMed  Google Scholar 

  26. Visco C, Vassilakopoulos TP, Kliche KO et al. Elevated serum levels of IL-10 are associated with inferior progression-free survival in patients with Hodgkin's disease treated with radiotherapy. Leuk Lymphoma2004;45:2085–2092.

    Article  CAS  PubMed  Google Scholar 

  27. Viviani S, Notti P, Bonfante V et al. Elevated pretreatment serum levels of Il-10 are associated with a poor prognosis in Hodgkin's disease, the Milan cancer institute experience. Med Oncol2000;17: 59–63.

    Article  CAS  PubMed  Google Scholar 

  28. Voorzanger N, Touitou R, Garcia E et al. Interleukin (IL)-10 and IL-6 are produced in vivo by non-Hodgkin's lymphoma cells and act as cooperative growth factors. Cancer Res1996;56:5499–5505.

    CAS  PubMed  Google Scholar 

  29. Weber-Nordt RM, Henschler R, Schott E et al. Interleukin-10 increases bcl-2 expression and survival in primary human CD34+ hematopoietic progenitor cells. Blood1996;88:2549–2558.

    CAS  PubMed  Google Scholar 

  30. Alas S, Bonavida B. Rituximab inactivates signal transducer and activation of transcription 3 (STAT3) activity in B-non-Hodgkin's lymphoma through inhibition of the interleukin 10 autocrine/paracrine loop and results in down-regulation of Bcl-2 and sensitization to cytotoxic drugs. Cancer Res2001;61:5137–5144.

    CAS  PubMed  Google Scholar 

  31. Alas S, Bonavida B. Inhibition of constitutive STAT3 activity sensitizes resistant non-Hodgkin's lymphoma and multiple myeloma to chemotherapeutic drug-mediated apoptosis.Clin Cancer Res2003;9:316–326.

    CAS  PubMed  Google Scholar 

  32. Alas S, Emmanouilides C, Bonavida B. Inhibition of interleukin-10 by rituximab results in down-regulation of bcl-2 and sensitization of B-cell non-Hodgkin's lymphoma to apoptosis. Clin Cancer Res2001;7:709–723.

    CAS  PubMed  Google Scholar 

  33. Treumann A, Lifely MR, Schneider P et al. Primary structure of CD52. J Biol Chem1995;270: 6088–6099.

    Article  CAS  PubMed  Google Scholar 

  34. Mone AP, Cheney C, Banks AL et al. Alemtuzumab induces caspase-independent cell death in human chronic lymphocytic leukemia cells through a lipid raft-dependent mechanism. Leukemia2006;20:272–279.

    Article  CAS  PubMed  Google Scholar 

  35. Keating M, Coutre S, Rai K et al. Management guidelines for use of alemtuzumab in B-cell chronic lymphocytic leukemia. Clin Lymphoma2004;4:220–227.

    Article  CAS  PubMed  Google Scholar 

  36. Montillo M, Schinkoethe T, Elter T. Eradication of minimal residual disease with alemtuzumab in B-cell chronic lymphocytic leukemia (B-CLL) patients: the need for a standard method of detection and the potential impact of bone marrow clearance on disease outcome. Cancer Invest2005;23:488–496.

    Article  CAS  PubMed  Google Scholar 

  37. Hernandez MC, Knox SJ. Radiobiology of radioimmunotherapy with 90Y ibritumomab tiuxetan (Zevalin). Semin Oncol2003;30:6–10.

    Article  CAS  PubMed  Google Scholar 

  38. Witzig TE. Efficacy and safety of 90Y ibritumomab tiuxetan (Zevalin) radioimmunotherapy for non-Hodgkin's lymphoma. Semin Oncol2003;30:11–16.

    Article  CAS  PubMed  Google Scholar 

  39. Weigert O, Illidge T, Hiddemann W et al. Recommendations for the use of Yttrium-90 ibritumomab tiuxetan in malignant lymphoma. Cancer2006;107:686–695.

    Article  CAS  PubMed  Google Scholar 

  40. Wiseman GA, Witzig TE. Yttrium-90 (90Y) ibritumomab tiuxetan (Zevalin) induces long-term durable responses in patients with relapsed or refractory B-cell non-Hodgkin's lymphoma. Cancer Biother Radiopharm2005;20:185–188.

    Article  CAS  PubMed  Google Scholar 

  41. van der Pol W, van de Winkel G. IgG receptor polymorphisms: risk factors for disease. Immunogenetics1998;48:222–232.

    Article  PubMed  Google Scholar 

  42. Wu J., Edberg JC, Redecha PB et al. A novel polymorphism of FcgammaRIIIa (CD16) alters receptor function and predisposes to autoimmune disease. J Clin Invest1997;100:1059–1070.

    Article  CAS  PubMed  Google Scholar 

  43. Shields RL, Lai J, Keck R et al. Lack of fucose on human IgG1 N-linked oligosaccharide improves binding to human Fcgamma RIII and antibody-dependent cellular toxicity. J Biol Chem2002;277:26733–26740.

    Article  CAS  PubMed  Google Scholar 

  44. 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 Res2004;64: 4664–4669.

    Article  PubMed  Google Scholar 

  45. Hatjiharissi E, Santo DD, Xu L et al. Individuals expressing Fcgamma-RIIIA-158 V/V and V/F show increased NK cell surface expression of FcgRIIIA (CD16), rituximab binding, and demonstrate higher levels of ADCC activity in response to rituximab. Blood2005;106:776.

    Google Scholar 

  46. Weng WK, Levy R. Two immunoglobulin G fragment C receptor polymorphisms independently predict response to rituximab in patients with follicular lymphoma. J Clin Oncol2003;21:3940–3947.

    Article  CAS  PubMed  Google Scholar 

  47. Hatjiharissi E, Hansen M, Verselis S et al. Polymorphisms in Fcgamma-RIIIA are genetically linked to Fcgamma-RIIA and may account for the primary predictive role ascribed to polymorphisms in Fcgamma-RIIIA-158 in determining rituximab responses. Blood2005;106:684a.

    Google Scholar 

  48. Cartron G, Dacheux L, Salles G et al. Therapeutic activity of humanized anti-CD20 monoclonal antibody and polymorphism in IgG Fc receptor FcgammaRIIIa gene. Blood2002;99:754–758.

    Article  CAS  PubMed  Google Scholar 

  49. Ghielmini M, Schmitz SFH, Leger-Falandry C et al. The genotype of the IgG Fc receptor is predictive of event-free survival after treatment with rituximab in patients with follicular lymphoma participating in study SAKK 35/98. Blood2003;102:409a.

    Article  Google Scholar 

  50. Weng WK, Levy R. Genetic polymorphism of the inhibitory IgG Fc receptor FcRIIb is not associated with clinical outcome of rituximab treated follicular lymphoma patients. Blood2005;106:683a.

    Google Scholar 

  51. Maloney DG, Pender-Smith B, Unger JM et al. Fc receptor polymorphisms do not influence progression-free survival (PFS) of follicular NHL patients treated with CHOP followed by rituximab (SWOG 9800). Blood2004;104:170a.

    Article  Google Scholar 

  52. Carlotti E, Palumbo GA, Oldani E et al. Bone marrow BCL2/IgH+ cells at diagnosis and not FCGRIIIA polymorphism predict response in follicular non-Hodgkin's lymphoma patients treated with sequential CHOP and rituximab. Blood2005;106:289–290a.

    Google Scholar 

  53. Weng WK, Rosenberg A, Levy R. Immunoglobulin G Fc receptor polymorphisms and clinical course in follicular lymphoma patients. Blood2004;104:887a.

    Google Scholar 

  54. Gluck WL, Hurst D, Yuen A et al. Phase I studies of interleukin (IL)-2 and rituximab in B-cell non-hodgkin's lymphoma: IL-2 mediated natural killer cell expansion correlations with clinical response. Clin Cancer Res2004;10:2253–2264.

    Article  CAS  PubMed  Google Scholar 

  55. Milan S, Wilson SE, Kahn KD et al. Investigation of FcgammaR polymorphisms and response to IL-2 (Proleukin®) and rituximab treatment in rituximab-resistant NHL patients: importance of the F/F polymorphism at position 158 of the Fcgamma. Blood2004;104:239b.

    Google Scholar 

  56. Weng WK, Czerwinski D, Timmerman J et al. Clinical outcome of lymphoma patients after idiotype vaccination is correlated with humoral immune response and immunoglobulin G Fc receptor genotype. J Clin Oncol2004;22:4717–4724.

    Article  CAS  PubMed  Google Scholar 

  57. Feugier, P, Van Hoof A, Sebban C et al. 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. J Clin Oncol2005;23:4117–4126.

    Article  CAS  PubMed  Google Scholar 

  58. Mounier N. Briere J, Gisselbrecht C et al. Rituximab plus CHOP (R-CHOP) overcomes bcl-2—associated resistance to chemotherapy in elderly patients with diffuse large B-cell lymphoma (DLBCL). Blood2003;101:4279–4284.

    Article  CAS  PubMed  Google Scholar 

  59. Chow KU, Sommerlad WD, Boehrer S et al. Anti-CD20 antibody (IDEC-C2B8, rituximab) enhances efficacy of cytotoxic drugs on neoplastic lymphocytes in vitro: role of cytokines, complement, and caspases. Haematologica2002;87:33–43.

    CAS  PubMed  Google Scholar 

  60. Ansell SM, Witzig TE, Kurtin PJ et al. Phase 1 study of interleukin-12 in combination with rituximab in patients with B-cell non-Hodgkin lymphoma. Blood2002;99:67–74.

    Article  CAS  PubMed  Google Scholar 

  61. Kim DH, Jung HD, Kim JG et al. FCGR3A gene polymorphisms may correlate with response to frontline R-CHOP therapy for diffuse large B-cell lymphoma. Blood2006;108:2720–2725.

    Article  CAS  PubMed  Google Scholar 

  62. Johnson SA, Birchall J, Luckie C et al. Guidelines on the management of Waldenstrom macroglobulinaemia. Br J Haematol2006;132:683–697.

    Article  CAS  PubMed  Google Scholar 

  63. Johnson SA. Advances in the treatment of Waldenstrom's macroglobulinemia. Expert Rev Anticancer Ther2006;6:329–334.

    Article  CAS  PubMed  Google Scholar 

  64. 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 Oncol2005;23:474–481.

    Article  CAS  PubMed  Google Scholar 

  65. Ferrajoli A, Keating MJ. Current guidelines in defining therapeutic strategies. Hematol Oncol Clin North Am2004;18:881–983, ix.

    Article  PubMed  Google Scholar 

  66. Oscier D, Fegan C, Hillmen P et al. Guidelines Working Group of the UK CLL Forum. British Committee for Standards in Haematology. Guidelines on the diagnosis and management of chronic lymphocytic leukaemia. Br J Haematol2004;125:294–317. Review

    Article  CAS  PubMed  Google Scholar 

  67. van Meerten T, van Rijn RS, Hol S et al. Complement-induced cell death by rituximab depends on CD20 expression level and acts complementary to antibody-dependent cellular cytotoxicity. Clin Cancer Res2006;12:4027–4035.

    Article  PubMed  Google Scholar 

  68. Kennedy AD, Beum PV, Solga MD et al. Rituximab infusion promotes rapid complement depletion and acute CD20 loss in chronic lymphocytic leukemia. J Immunol2004;172:3280–3288.

    CAS  PubMed  Google Scholar 

  69. Farag, SS, Flinn IW, Modali R et al. Fc gamma RIIIa and Fc gamma RIIa polymorphisms do not predict response to rituximab in B-cell chronic lymphocytic leukemia. Blood2004;103:1472–1474.

    Article  CAS  PubMed  Google Scholar 

  70. Lin TS, Flinn IW, Modali R et al. FCGR3A and FCGR2A polymorphisms may not correlate with response to alemtuzumab in chronic lymphocytic leukemia. Blood2005;105:289–291.

    Article  CAS  PubMed  Google Scholar 

  71. Weng WK., Horning SJ, Negrin RS et al. Immunoglobulin G Fc polymorphism is correlated with rituximab-induced neutropenia following autologous hematopoietic cell transplantation. Blood2004;104:129a.

    Google Scholar 

  72. Racila E, Weng WK, Wooldridge JE et al. A polymorphism in the C1qA component of complement correlates with prolonged complete remission following rituximab therapy of follicular lymphoma. Blood2005;106:229a.

    Google Scholar 

  73. Sashida G, Takaku TI, Honda S et al. Granulocyte colony-stimulating factor (G-CSF) could enhance Fcgamma receptor expression in neutrophils of patients with B-cell lymphoma treated with rituximab. Leuk Lymphoma2005;46:789–791.

    Article  CAS  PubMed  Google Scholar 

  74. Niitsu N, Hayama M, Okamoto M et al. Phase I study of Rituximab-CHOP regimen in combination with granulocyte colony-stimulating factor in patients with follicular lymphoma. Clin Cancer Res2004;10:4077–4082.

    Article  CAS  PubMed  Google Scholar 

  75. Niwa R, Hatanaka S, Shoji-Hosaka E et al. Enhancement of the antibody-dependent cellular cytotoxicity of low-fucose IgG1 Is independent of FcgammaRIIIa functional polymorphism. Clin Cancer Res2004;10:6248–6255.

    Article  CAS  PubMed  Google Scholar 

  76. Hodoniczky J, Zheng YZ, James DC. Control of recombinant monoclonal antibody effector functions by Fc N-glycan remodeling in vitro. Biotechnol Prog2005;21:1644–1652.

    Article  CAS  PubMed  Google Scholar 

  77. 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. Blood2006;108:2648–2654.

    Article  CAS  PubMed  Google Scholar 

  78. Weng WK, Stavenhagen J, Koenig S et al. Rituximab variants with re-engineered Fc with higher affinity to activating Fc R eliminate the functional difference between Fc R genotypes. Blood2005;106:105a.

    Google Scholar 

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Authors and Affiliations

  1. Dept. of Hematology/Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea

    Dong Hwan Kim MD, PhD

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  1. Dong Hwan Kim MD, PhD
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  1. Department of Medicine, Section of Hematology/Oncology, University of Chicago, 5841 South Maryland Avenue, Chicago, IL 60637-1470, USA

    Federico Innocenti

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Kim, D.H. (2008). Impact of Polymorphisms on the Clinical Outcomes of Monoclonal Antibody Therapy Against Hematologic Malignancies. In: Innocenti, F. (eds) Genomics and Pharmacogenomics in Anticancer Drug Development and Clinical Response. Cancer Drug Discovery and Development™. Humana Press. https://doi.org/10.1007/978-1-60327-088-5_12

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