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

  • Dong Hwan Kim
Part of the Cancer Drug Discovery and Development™ book series (CDD&D)

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.

Key Words

Polymorphisms monoclonal antibody hematologic malignancies rituximab 

References

  1. 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.PubMedGoogle Scholar
  2. 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. 3.
    Cartron G, Watier H, Golay J et al. From the bench to the bedside: ways to improve rituximab efficacy. Blood2004;104:2635–2642.CrossRefPubMedGoogle Scholar
  4. 4.
    Smith MR. Rituximab (monoclonal anti-CD20 antibody): mechanisms of action and resistance. Oncogene2003;22:7359–7368.CrossRefPubMedGoogle Scholar
  5. 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. 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.CrossRefGoogle Scholar
  7. 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.PubMedGoogle Scholar
  8. 8.
    Shan D, Ledbetter JA, Press OW. Apoptosis of malignant human B-cells by ligation of CD20 with monoclonal antibodies. Blood1998;91:1644–1652.PubMedGoogle Scholar
  9. 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.CrossRefPubMedGoogle Scholar
  10. 10.
    Villamor N, Montserrat E, Colomer D. Mechanism of action and resistance to monoclonal antibody therapy. Semin Oncol2003;30:424–433.CrossRefPubMedGoogle Scholar
  11. 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.PubMedGoogle Scholar
  12. 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.CrossRefPubMedGoogle Scholar
  13. 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.CrossRefPubMedGoogle Scholar
  14. 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.PubMedGoogle Scholar
  15. 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.CrossRefPubMedGoogle Scholar
  16. 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.CrossRefPubMedGoogle Scholar
  17. 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.CrossRefPubMedGoogle Scholar
  18. 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.CrossRefPubMedGoogle Scholar
  19. 19.
    Cortes J, Kurzrock R. Interleukin-10 in non-Hodgkin's lymphoma. Leuk Lymphoma1997;26: 251–259.PubMedGoogle Scholar
  20. 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.CrossRefPubMedGoogle Scholar
  21. 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.PubMedGoogle Scholar
  22. 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.Google Scholar
  23. 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.CrossRefPubMedGoogle Scholar
  24. 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.CrossRefPubMedGoogle Scholar
  25. 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.PubMedGoogle Scholar
  26. 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.CrossRefPubMedGoogle Scholar
  27. 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.CrossRefPubMedGoogle Scholar
  28. 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.PubMedGoogle Scholar
  29. 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.PubMedGoogle Scholar
  30. 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.PubMedGoogle Scholar
  31. 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.PubMedGoogle Scholar
  32. 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.PubMedGoogle Scholar
  33. 33.
    Treumann A, Lifely MR, Schneider P et al. Primary structure of CD52. J Biol Chem1995;270: 6088–6099.CrossRefPubMedGoogle Scholar
  34. 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.CrossRefPubMedGoogle Scholar
  35. 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.CrossRefPubMedGoogle Scholar
  36. 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.CrossRefPubMedGoogle Scholar
  37. 37.
    Hernandez MC, Knox SJ. Radiobiology of radioimmunotherapy with 90Y ibritumomab tiuxetan (Zevalin). Semin Oncol2003;30:6–10.CrossRefPubMedGoogle Scholar
  38. 38.
    Witzig TE. Efficacy and safety of 90Y ibritumomab tiuxetan (Zevalin) radioimmunotherapy for non-Hodgkin's lymphoma. Semin Oncol2003;30:11–16.CrossRefPubMedGoogle Scholar
  39. 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.CrossRefPubMedGoogle Scholar
  40. 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.CrossRefPubMedGoogle Scholar
  41. 41.
    van der Pol W, van de Winkel G. IgG receptor polymorphisms: risk factors for disease. Immunogenetics1998;48:222–232.CrossRefPubMedGoogle Scholar
  42. 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.CrossRefPubMedGoogle Scholar
  43. 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.CrossRefPubMedGoogle Scholar
  44. 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.CrossRefPubMedGoogle Scholar
  45. 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. 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.CrossRefPubMedGoogle Scholar
  47. 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. 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.CrossRefPubMedGoogle Scholar
  49. 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.CrossRefGoogle Scholar
  50. 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. 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.CrossRefGoogle Scholar
  52. 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. 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. 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.CrossRefPubMedGoogle Scholar
  55. 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. 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.CrossRefPubMedGoogle Scholar
  57. 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.CrossRefPubMedGoogle Scholar
  58. 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.CrossRefPubMedGoogle Scholar
  59. 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.PubMedGoogle Scholar
  60. 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.CrossRefPubMedGoogle Scholar
  61. 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.CrossRefPubMedGoogle Scholar
  62. 62.
    Johnson SA, Birchall J, Luckie C et al. Guidelines on the management of Waldenstrom macroglobulinaemia. Br J Haematol2006;132:683–697.CrossRefPubMedGoogle Scholar
  63. 63.
    Johnson SA. Advances in the treatment of Waldenstrom's macroglobulinemia. Expert Rev Anticancer Ther2006;6:329–334.CrossRefPubMedGoogle Scholar
  64. 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.CrossRefPubMedGoogle Scholar
  65. 65.
    Ferrajoli A, Keating MJ. Current guidelines in defining therapeutic strategies. Hematol Oncol Clin North Am2004;18:881–983, ix.CrossRefPubMedGoogle Scholar
  66. 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. ReviewCrossRefPubMedGoogle Scholar
  67. 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.CrossRefPubMedGoogle Scholar
  68. 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.PubMedGoogle Scholar
  69. 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.CrossRefPubMedGoogle Scholar
  70. 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.CrossRefPubMedGoogle Scholar
  71. 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. 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. 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.CrossRefPubMedGoogle Scholar
  74. 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.CrossRefPubMedGoogle Scholar
  75. 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.CrossRefPubMedGoogle Scholar
  76. 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.CrossRefPubMedGoogle Scholar
  77. 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.CrossRefPubMedGoogle Scholar
  78. 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

Copyright information

© Humana Press, a part of Springer Science+Business Media, LLC 2008

Authors and Affiliations

  • Dong Hwan Kim
    • 1
  1. 1.Dept. of Hematology/OncologySamsung Medical Center, Sungkyunkwan University School of MedicineSeoulKorea

Personalised recommendations