Original article. Correlation of FcγRIIIa polymorphisms and responses to rituximab in Thai population

Open access

Abstract

Background: Rituximab is a chimeric IgG1 monoclonal antibody against CD20, approved for the treatment of B-cell non-Hodgkin’s lymphoma (NHL). Antibody dependent cellular cytotoxicity (ADCC) has been suggested to be an important mechanism of rituximab via binding to the Fc gamma IIIa receptor (FcγRIIIa) on natural killer (NK) cells. FcγRIIIa has two expressed alleles that differ at amino acid position 158 in the extracellular domain, valine (V158) and phenylalanine (F158). These allelic variants have been demonstrated to differ in IgG1 binding and ADCC. V/V homozygotes and V/F heterozygotes bind to IgG with higher affinity than F/F homozygotes.

Objectives: We identified the frequencies of FcγRIIIa polymorphism and investigate the correlation between FcγRIIIa polymorphism and rituximab responses, both in vitro and in vivo in Thai population.

Methods: The RFLP-Nested PCR and allele specific amplification was used to identify the FcγRIIIa polymorphism in the study. The correlation between FcγRIIIa polymorphism and rituximab responses, both in vitro and in vivo, was also studied.

Results: The distributions of FcγRIIIa-158 polymorphism in these subjects are V/V 40.26%, V/F 16.88%, and F/F 42.86%. Higher rituximab-induced Ramos cell cytotoxicity (mean 33.16%, 36.87%) was observed in the subjects with VV and VF genotypes, respectively. However, the lower cytotoxicity (mean 20.07%) was determined in subjects with FF genotype. As for the in vivo study, the NHL patients with V/V or V/F genotypes had a primary response as complete response; whereas, the NHL patients with F/F genotype had partial response.

Conclusion: FcγRIIIa polymorphism and the primary response in NHL patients tend to correlate. The higher number of patients is necessary for further study. These results provide useful information to understand beneficial response of rituximab as well as other IgG1 therapeutic antibody in Thai patients.

1. Zhong Y. Non-Hogkin’s lymphoma: what primary care professionals need to know. J Nurse Pract. 2006; 2:309-15.

2. Hennessy BT, Hanrahan EO, Daly PA. Non-Hodgkin lymphoma: an update. The Lancet Oncol. 2004; 5: 341-53.

3. Lu P. Staging and classification of lymphoma. Semin Nucl Med. 2005; 35:160-4.

4. Sacchi S, Federico M, Dastoli G, Fiorani C, Vinci G, Clo‘ V, et al. Treatment of B-cell non-Hodgkin’s lymphoma with anti CD 20 monoclonal antibody Rituximab. Crit Rev Oncol Hematol. 2001; 37: 13-25.

5. Chinn P, Braslawsky G, White C, Hanna N. Antibody therapy of non-Hodgkin’s B-cell lymphoma. Cancer Immunol Immunother. 2003; 52: 257-80.

6. Coiffier B. Monoclonal antibody as therapy for malignant lymphomas. C R Biol. 2006; 329: 241-54.

7. Perosa F, Favoino E, Caragnano MA, Prete M, Dammacco F. CD20: A target antigen for immunotherapy of autoimmune diseases. Autoimmun Rev. 2005; 4: 526-31.

8. Foran JM. Antibody-based therapy of Non-Hodgkin’s lymphoma. Best Pract Res Clin Haematol. 2002; 15: 449-65.

9. Marcus R, Hagenbeek A. The therapeutic use of rituximab in non-Hodgkin’s lymphoma. Hematol J. 2007; 67: 5-14.

10. Weiner GJ, Link BK. Antibody therapy of lymphoma. Adv Pharmacol. 2004; 51: 229-53.

11. Cheson BD, Leonard JP. Monoclonal antibody therapy for B-cell non-Hodgkin’s lymphoma. New Engl J Med. 2008; 359: 613-26.

12. Cohen-Solal JFG, Cassard L, Fridman WH, Sautès- Fridman C. Fcã receptors. Immunol Lett. 2004; 92: 199-205.

13. Nimmerjahn F, Ravetch JV. Antibodies, Fc receptors and cancer. Curr Opin Immunol. 2007; 19: 239-45.

14. Ravetch JV, Perussia B. Alternative membrane forms of FcγRIII (CD16) on human natural killer cells and neutropils. Journal Experimental Medicine. 1989; 170: 481-97

15. Bowles JA, Weiner GJ. CD16 polymorphisms and NK activation induced by monoclonal antibody-coated target cells. J Immunol Methods. 2005; 304: 88-99.

16. Bowles JA, Wang SY, Link BK, Allan B, Beuerlein G, Campbell M, 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: 2648-54.

17. Perosa F, Favoino E, Caragnano MA, Prete M, Dammacco F. CD20: A target antigen for immunotherapy of autoimmune diseases. Autoimmun Rev. 2005; 4: 526-31.

18. Zhang M, Zhang Z, Garmestani K, Goldman CK, Ravetch JV, Brechbiel MW, et al. Activating Fc receptors are required for antitumor efficacy of the antibodies directed toward CD25 in a murine model of adult T-cell leukemia. Cancer Res. 2004; 64: 5825-29.

19. Hamaguchi Y, Xiu Y, Komura K, Nimmerjahn F, Tedder TF. Antibody isotype-specific engagement of Fcg receptors regulates B lymphocyte depletion during CD20 immunotherapy. J Exp Med. 2006; 203: 743-53.

20. Clynes RA, Towers TL, Presta LG, Ravetch JV. Inhibitory Fc receptors modulate in vivo cytoxicity against tumor targets. Nat Med. 2000; 6: 443-6.

21. Cartron G, Dacheux L, Salles G, Solal-Celigny P, Bardos P, Colombat P, et al. Therapeutic activity of humanized anti-CD20 monoclonal antibody and polymorphism in IgG Fc receptor FcãRIIIa gene. Blood. 2002; 99: 754-8.

22. Dall’Ozzo S, Tartas S, Paintaud G, Cartron G, Colombat P, Bardos P, et al. Rituximab-dependent cytotoxicity by natural killer cells: influence of FCGR3A polymorphism on the concentration-effect relationship. Cancer Res. 2004; 64:4664-9.

23. Weng WK, Levy R. Two immunoglobulin G fragment C receptor polymorphisms independently predict response to rituximab in patients with follicular lymphoma. Journal Clin Oncol. 2003; 21:3940-7.

24. Weng WK, Weng WK, Levy R. Immunoglobulin G Fc receptor polymorphisms do not correlate with response to chemotherapy or clinical course in patients with follicular lymphoma. Leuk lymphoma. 2009; 50:1494-500.

25. Mitrovic Z, Aurer I, Radman I, Ajdukovic R, Sertic J, Labar B. FcgammaRIIIA and FcgammaRIIA polymorphisms are not associated with response to rituximab and CHOP in patients with diffuse large B-cell lymphoma. Haematologica. 2007; 92:998-9.

26. Kim DH, Jung HD, Kim JG, Lee JJ, Yang DH, Park YH, et al. FCGR3A gene polymorphisms may correlate with response to frontline R-CHOP therapy for diffuse large B-cell lymphoma. Blood. 2006; 108: 2720-5.

27. Lin TS, Flinn IW, Modali R, Lehman TA, Webb J, Waymer S, et al. FCGR3A and FCGR2Apolymorphisms may not correlate with response to alemtuzumab in chronic lymphocytic leukemia. Blood. 2005; 105: 289-91.

28. Farag SS, Flinn IW, Modali R, Tibullo D, Salmoiraghi S, Rossi A, et.al. Fc gamma RIIIa and Fc gamma RIIa polymorphisms do not predict response to rituximab in B-cell chronic lymphocytic leukemia. Blood. 2004; 103:1472-4.

29. Leppers-van de Straat FG, van der Pol WL, Jansen MD, Sugita N, Yoshie H, Kobayashi T, et al. A novel PCR-based method for direct Fc gamma receptor IIIa (CD16) allotyping. J Immunol Methods. 2000; 242: 127-32.

30. Torkildsen O, Utsi E, Mellgren SI, Harbo HF, Vedeler CA, Myhr KM. Ethnic variation of Fcg receptor polymorphism in Sami and Norwegian populations. Immunology. 2005; 115:416-21.

31. Cheson BD, Pfistner B, Bruce D, Juweid MD, Gascoyne RD, Specht L, et al. Revised response criteria for malignant lymphoma. J Clin Oncol. 2007; 25: 579-86.

32. Wu J, Edberg JC, Radecha PB, Bansal V, Guyre PM, Coleman K, et al. A novel polymorphism of FcγRIIIa (CD16) alters receptorfunction and predisposes to autoimmune disease. J Clin Invest. 1997; 100:1059-70.

33. Koene HR, Kleijer M, Algra J, Roos D, von dem Borne AEG, de Haas M. FcRIIIa-158V/F polymorphism influences the binding of IgG by natural killer cell FcγRIIIa, independently of the FcRIIIa-48L/R/H phenotype. Blood. 1997; 90:1109-14.

Journal Information


IMPACT FACTOR 2017: 0.209
5-year IMPACT FACTOR: 0.243

CiteScore 2017: 0.24

SCImago Journal Rank (SJR) 2017: 0.162
Source Normalized Impact per Paper (SNIP) 2017: 0.173

Metrics

All Time Past Year Past 30 Days
Abstract Views 0 0 0
Full Text Views 91 91 8
PDF Downloads 43 43 1