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Comparability of Antibody-Mediated Cell Killing Activity Between a Proposed Biosimilar RTXM83 and the Originator Rituximab

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Abstract

Background

Biosimilars are described as biological products that resemble the structure of original biologic therapeutic products, with no clinically meaningful differences in terms of safety and effectiveness from the original. A wide range of biosimilars are under development or are already licensed in many countries. Biosimilars are earning acceptance and becoming a reality for immunotherapy treatments mainly based on the alternatives for the commercial anti-CD20 monoclonal antibody rituximab. The most important mechanism of action reported for this antibody is the induction of antibody-dependent cell cytotoxicity (ADCC), which is associated with the polymorphisms present at the 158 position in the IgG receptor FcγRIIIa.

Objective

The aim of the study was to validate the functional comparability between the proposed rituximab biosimilar RTXM83 and the original product. To achieve this we assessed the binding capacity and ADCC induction of this biosimilar, taking into account the different FcγRIIIa-158 polymorphisms.

Methods

Binding capacity was evaluated by flow cytometry using CD20 positive cells and a wide range of antibody concentrations. The FcγRIIIa-158 polymorphisms were analyzed by polymerase chain reaction (PCR) followed by allele-specific restriction enzyme digestion. ADCC was measured by a colorimetric lactate dehydrogenase-release assay, using effector cells from donors with different FcγRIIIa-158 polymorphisms.

Results

Binding capacity assay showed no differences between both products. Regarding ADCC, a similar relative potency was obtained between both antibodies, showing a higher response for the FcγRIIIa-158 valine/valine (V/V) polymorphism compared to the phenylalanine/phenylalanine (F/F), for both rituximab and RTXM83.

Conclusion

Our data strongly suggest the biocomparability between the proposed biosimilar and the originator rituximab, in antibody recognition and ADCC activity. Additionally, our results suggest that donors with the FcγRIIIa-158V/V polymorphism induce a higher ADCC response, as has been reported.

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References

  1. Blackstone EA, Joseph PF. The economics of biosimilars. Am Health Drug Benefits. 2013;6(8):469–78 (Epub 2014/07/06).

    PubMed  PubMed Central  Google Scholar 

  2. King S. First word lists: the best selling drugs in 2014. In: First Word Pharma. 2015. http://www.firstwordpharma.com/node/1263906?tsid=17#axzz42Dj7T1GI. Accessed 31 May 2015.

  3. Scheinberg MA, Kay J. The advent of biosimilar therapies in rheumatology—”O brave new world”. Nat Rev Rheumatol. 2012;8(7):430–6 (Epub 2012/06/06).

    Article  CAS  PubMed  Google Scholar 

  4. Rioufol C, Salles G. Biosimilar monoclonal antibodies in lymphoma: a critical appraisal. Expert Rev Anticancer Ther. 2015;15(5):569–78 (Epub 2015/03/31).

    Article  CAS  PubMed  Google Scholar 

  5. European Medicines Agency, Committee for Medicinal Products for Human Use (CHMP). Guideline on similar biological medicinal products containing monoclonal antibodies—non-clinical and clinical issues. London: European Medicines Agency; 2012. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific.

  6. Food and Drug Administration, Center for Drug Evaluation and Research (CDER). Guidance for Industry. Scientific considerations in demonstrating biosimilarity to a reference product. Rockville: Food and Drug Administration; 2012. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM291128.pdf.

  7. Reff ME, Carner K, Chambers KS, Chinn PC, Leonard JE, Raab R, et al. Depletion of B cells in vivo by a chimeric mouse human monoclonal antibody to CD20. Blood. 1994;83(2):435–45 (Epub 1994/01/15).

    CAS  PubMed  Google Scholar 

  8. Leveille C, Chandad F, Al-Daccak R, Mourad W. CD40 associates with the MHC class II molecules on human B cells. Eur J Immunol. 1999;29(11):3516–26 (Epub 1999/11/11).

    Article  CAS  PubMed  Google Scholar 

  9. Petrie RJ, Deans JP. Colocalization of the B cell receptor and CD20 followed by activation-dependent dissociation in distinct lipid rafts. J Immunol. 2002;169(6):2886–91 (Epub 2002/09/10).

    Article  CAS  PubMed  Google Scholar 

  10. Szollosi J, Horejsi V, Bene L, Angelisova P, Damjanovich S. Supramolecular complexes of MHC class I, MHC class II, CD20, and tetraspan molecules (CD53, CD81, and CD82) at the surface of a B cell line JY. J Immunol. 1996;157(7):2939–46 (Epub 1996/10/01).

    CAS  PubMed  Google Scholar 

  11. Li H, Ayer LM, Lytton J, Deans JP. Store-operated cation entry mediated by CD20 in membrane rafts. J Biol Chem. 2003;278(43):42427–34 (Epub 2003/08/16).

    Article  CAS  PubMed  Google Scholar 

  12. Uchida J, Lee Y, Hasegawa M, Liang Y, Bradney A, Oliver JA, et al. Mouse CD20 expression and function. Int Immunol. 2004;16(1):119–29 (Epub 2003/12/23).

    Article  CAS  PubMed  Google Scholar 

  13. Clynes RA, Towers TL, Presta LG, Ravetch JV. Inhibitory Fc receptors modulate in vivo cytotoxicity against tumor targets. Nat Med. 2000;6(4):443–6 (Epub 2000/03/31).

    Article  CAS  PubMed  Google Scholar 

  14. Seidel UJ, Schlegel P, Lang P. Natural killer cell mediated antibody-dependent cellular cytotoxicity in tumor immunotherapy with therapeutic antibodies. Front Immunol. 2013;4:76 (Epub 2013/04/02).

    Article  PubMed  PubMed Central  Google Scholar 

  15. Hatjiharissi E, Hansen M, Santos DD, Xu L, Leleu X, Dimmock EW, et al. Genetic linkage of Fc gamma RIIa and Fc gamma RIIIa and implications for their use in predicting clinical responses to CD20-directed monoclonal antibody therapy. Clin Lymphoma Myeloma. 2007;7(4):286–90 (Epub 2007/02/28).

    Article  CAS  PubMed  Google Scholar 

  16. 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 FcgammaRIIIa gene. Blood. 2002;99(3):754–8 (Epub 2002/01/25).

    Article  CAS  PubMed  Google Scholar 

  17. 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(21):3940–7 (Epub 2003/09/17).

    Article  CAS  PubMed  Google Scholar 

  18. Veeramani S, Wang SY, Dahle C, Blackwell S, Jacobus L, Knutson T, et al. Rituximab infusion induces NK activation in lymphoma patients with the high-affinity CD16 polymorphism. Blood. 2011;118(12):3347–9 (Epub 2011/07/20).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Kennedy AD, Beum PV, Solga MD, DiLillo DJ, Lindorfer MA, Hess CE, et al. Rituximab infusion promotes rapid complement depletion and acute CD20 loss in chronic lymphocytic leukemia. J Immunol. 2004;172(5):3280–8 (Epub 2004/02/24).

    Article  CAS  PubMed  Google Scholar 

  20. Seigelchifer MA, Corley E, Fresnillo G, Pesce A, Bes C, Elise M, Florez A, Millan S, Raha T. Development of RTXM83 (a potential rituximab biosimilar): In vitro and in vivo comparability with MabThera. J Clin Oncol. 2014;32(suppl):abstr e14020.

  21. Vital EM, Kay J, Emery P. Rituximab biosimilars. Expert Opin Biol Ther. 2013;13(7):1049–62 (Epub 2013/04/23).

    Article  CAS  PubMed  Google Scholar 

  22. Weiner GJ. Rituximab: mechanism of action. Semin Hematol. 2010;47(2):115–23 (Epub 2010/03/31).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Jeon HJ, Kim CW, Yoshino T, Akagi T. Establishment and characterization of a mantle cell lymphoma cell line. Br J Haematol. 1998;102(5):1323–6 (Epub 1998/09/30).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We would like to thank Ph.D. student Marina Pifano for the statistical support in this work.

Author contributions

All authors made substantial contributions to the conception or design of the work and/or the acquisition, analysis or interpretation of data. All authors were involved in developing and critically revising the content of the manuscript, and all provided final approval of the version submitted for publication. Mariano R. Gabri is the guarantor for the overall content.

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Authors and Affiliations

  1. Laboratory of Molecular Oncology, Department of Science and Technology, Quilmes National University, R. Saenz Peña 352, Bernal, B1876BXD, Buenos Aires, Argentina

    Hector A. Cuello, Valeria I. Segatori, Marina Alberto, Daniel F. Alonso & Mariano R. Gabri

  2. PharmADN, mAbxience Co., Buenos Aires, Argentina

    Analía Pesce

Authors
  1. Hector A. Cuello
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  2. Valeria I. Segatori
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  3. Marina Alberto
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  4. Analía Pesce
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  5. Daniel F. Alonso
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  6. Mariano R. Gabri
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Corresponding author

Correspondence to Mariano R. Gabri.

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Conflict of interest

Hector A. Cuello, Valeria I. Segatori, Marina Alberto, Daniel F. Alonso and Mariano R. Gabri have no conflicts of interest that are directly relevant to the content of this study. Analía Pesce is a full-time employee of PharmADN. The authors have no other conflicts of interest related to this work.

Funding

This work was supported by the National Institute of Cancer, Quilmes National University and the National Bureau of Science and Technology (Argentina). Hector A. Cuello is student fellow of the National Institute of Cancer. MRG and DFA are members of the National Research Council (CONICET, Argentina).

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Cuello, H.A., Segatori, V.I., Alberto, M. et al. Comparability of Antibody-Mediated Cell Killing Activity Between a Proposed Biosimilar RTXM83 and the Originator Rituximab. BioDrugs 30, 225–231 (2016). https://doi.org/10.1007/s40259-016-0171-8

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  • DOI: https://doi.org/10.1007/s40259-016-0171-8

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