Biosimilars pp 489-542 | Cite as

Immunogenicity Assessment of Biosimilars: A Multidisciplinary Perspective

  • Paul ChamberlainEmail author
  • Pekka Kurki
Part of the AAPS Advances in the Pharmaceutical Sciences Series book series (AAPS, volume 34)


Evaluation of the relative immunogenicity of a biosimilar candidate in direct comparison to the reference product is a general regulatory requirement, with the main weight of evidence deriving from head-to-head clinical studies in populations that are adequately sensitive to reveal clinically meaningful differences across the proposed conditions of use.

This chapter provides case examples to illustrate the multi-disciplinary nature of the exercise, which involves interpretation of bioanalytical measures of the immune response in relation to differences detected in the product quality profile, as well as potential biases in bioanalytical methodology and confounding patient-related factors. Most importantly, the design of the clinical immunogenicity evaluation needs to reflect the risk profile established for the reference product, allied to uncertainty about possible impact of minor heterogeneity in product-related variants and process-derived impurities, and limitations of the methodology for detection of clinically meaningful consequences. Thus, a difference in the measured anti-drug antibody incidence may not necessarily preclude a conclusion of biosimilarity if this does not translate into a negative impact on efficacy or safety: examples of authorized biosimilar products are discussed to show how regulators have applied a “totality of evidence” approach to deal with apparent numerical differences in immune response parameters.

Validity of extrapolating conclusions about relative immunogenicity in one therapeutic setting to other indications is reviewed based on actual clinical results obtained for products associated with clinically impactful immunogenicity. Then, experience gained from transitioning between product versions is discussed in the context of interchangeability considerations. Finally, reflection is given to longer-term management of potential immunogenicity-related risks associated with manufacturing changes during the independent post-authorization life-cycles of different product versions.


Immunogenicity Biosimilars Aggregates Extrapolation Switching Interchangeability Substitution 


  1. Ahmadi M, etal. Small amounts of sub-visible aggregates enhance the immunogenic potential of monoclonal antibody therapeutics. Pharm Res. 2015;32(4):1383–94.PubMedCrossRefGoogle Scholar
  2. Amgen. Neupogen prescribing information, revised 06/2016. 2016a. Available at Last Accessed 16 April 2018.
  3. Amgen. Amgen Briefing Document for Arthritis Advisory Committee meeting for ABP 501 held on 12 July 2016. 2016b. Available at Last Accessed 10 May 2018.
  4. Amgen. Neulasta prescribing information revised 12/2017. 2017. Available at Last Accessed 16 April 2018.
  5. Amgen. Aranesp prescribing information revised 01/2018. 2018. Available at Last Accessed 16 April 2018.
  6. Apostolopoulos V, Thalhammer T, Tzakos AG, Stojanovska L. Targeting antigens to dendritic cell receptors for vaccine development. J Drug Deliv. 2013;2013:869718. Scholar
  7. Armstrong JK, Hempel G, Koling S, Chan LS, Fisher T, Meiselman HJ, Garratty G. Antibody against poly(ethylene glycol) adversely affects PEG-asparaginase therapy in acute lymphoblastic leukemia patients. Cancer. 2007;110(1):103–11.PubMedCrossRefGoogle Scholar
  8. Ataca P, Atilla E, Kendir R, Bavbek S, Ozcan M. Successful desensitization of rituximab hypersensitivity. Case Rep Immunol. 2015;2015:524507.Google Scholar
  9. Baker MP, Jones TD, Chamberlain P. Immunogenicity of biologics. In: Vaughan T, Osbourn J, Jallal B, editors. Protein therapeutics. Weinheim: Wiley; 2017. Scholar
  10. Barger TE, Wrona D, Goletz TJ, Mytych DT. A detailed examination of the antibody prevalence and characteristics of anti-ESA antibodies. Nephrol Dial Transplant. 2012;27(10):3892–9. Scholar
  11. Bartelds GM, Wijbrandts CA, Nurmohamed MT, Stapel S, Lems WF, Aarden L, Dijkmans BA, Tak PP, Wolbink GJ. Clinical response to adalimumab: relationship to anti-adalimumab antibodies and serum adalimumab concentrations in rheumatoid arthritis. Ann Rheum Dis. 2007;66(7):921–6.PubMedPubMedCentralCrossRefGoogle Scholar
  12. Bartelds GM, Krieckaert CL, Nurmohamed MT, van Schouwenburg PA, Lems WF, Twisk JW, Dijkmans BA, Aarden L, Wolbink GJ. Development of antidrug antibodies against adalimumab and association with disease activity and treatment failure during long-term follow-up. JAMA. 2011;305(14):1460–8. Scholar
  13. Beart F, Noman M, Vermeire S, Van Assche G, D’Haens G, Carbonez A, Rutgeerts P. Influence of immunogenicity on the long-term efficacy of infliximab in Crohn’s disease. N Engl J Med. 2003;348:601–8.CrossRefGoogle Scholar
  14. Bendtzen K, Geborek P, Svenson M, Larsson L, Kapetanovic MC, Saxne T. Individualized monitoring of drug bioavailability and immunogenicity in rheumatoid arthritis patients treated with the tumor necrosis factor α inhibitor infliximab. Arthritis Rheum. 2006;54(12):3782–9.PubMedCrossRefGoogle Scholar
  15. Ben-Horin S, Yavzori M, Benhar I, etal. Cross-immunogenicity: antibodies to infliximab in Remicade-treated patients with IBD similarly recognise the biosimilar Remsima. Gut. 2015;65:1132–8.PubMedCrossRefGoogle Scholar
  16. Bennett CL, Luminari S, Nissenson AR, Tallman MS, Klinge SA, McWilliams N, McKoy JM, Kim B, Lyons EA, Trifilio SM, Raisch DW, Evens AM, Kuzel TM, Schumock GT, Belknap SM, Locatelli F, Rossert J, Casadevall N. Pure red-cell aplasia and epoetin therapy. N Engl J Med. 2004;351(14):1403–8.PubMedCrossRefGoogle Scholar
  17. Bloem K, van Leeuwen A, Verbeek G, Nurmohamed MT, Wolbink GJ, van der Kleij D, Rispens T. Systematic comparison of drug-tolerant assays for anti-drug antibodies in a cohort of adalimumab-treated rheumatoid arthritis patients. J Immunol Methods. 2015;418:29–38. Scholar
  18. BMS. Orencia® Prescribing Information, June 2017, BMS. 2017. Sourced on 10 May 2018.
  19. Bourdage JS, Cook CA, Farrington DL, Chain JS, Konrad RJ. An affinity capture elution (ACE) assay for detection of anti-drug antibody to monoclonal antibody therapeutics in the presence of high levels of drug. J Immunol Methods. 2007;327(1-2):10–7.PubMedCrossRefGoogle Scholar
  20. Braun J, Kudrin A. Switching to biosimilar infliximab (CT-P13): evidence of clinical safety, effectiveness and impact on public health. Biologicals. 2016;44(4):257–66. Scholar
  21. Brezski RJ, Knight DM, Jordan RE. The origins, specificity, and potential biological relevance of human anti-IgG hinge autoantibodies. Sci World J. 2011;11:1153–67. Scholar
  22. Carpenter JF, Randolph TW, Jiskoot W, Crommelin DJ, Middaugh CR, Winter G, Fan YX, Kirshner S, Verthelyi D, Kozlowski S, Clouse KA, Swann PG, Rosenberg A, Cherney B. Overlooking subvisible particles in therapeutic protein products: gaps that may compromise product quality. J Pharm Sci. 2009;98(4):1201–5. Scholar
  23. Casadevall N, Dupuy E, Molho-Sabatier P, Tobelem G, Varet B, Mayeux P. Brief report: autoantibodies against erythropoietin in a patient with pure red-cell aplasia. N Engl J Med. 1996;334(10):630–3.PubMedCrossRefGoogle Scholar
  24. Casadevall N, Eckhardt K-U, Rossert J. Epoetin-induced autoimmune pure red cell aplasia. J Am Soc Nephrol. 2005;16:S67–9.PubMedCrossRefGoogle Scholar
  25. Celltrion. Briefing for FDA AC for CT-P13. 2016. Available at Last Accessed 16 April 2018.
  26. Chamberlain PD. Multidisciplinary approach to evaluating immunogenicity of biosimilars: lessons learnt and open questions based on 10 years’ experience of the European Union regulatory pathway. Biosimilars. 2014;4:23–43.CrossRefGoogle Scholar
  27. Cho IH, Lee N, Song D, Jung SY, Bou-Assaf G, Sosic Z, Zhang W, Lyubarskaya Y. Evaluation of the structural, physicochemical, and biological characteristics of SB4, a biosimilar of etanercept. MAbs. 2016;8(6):1136–55. Scholar
  28. Chung CH, Mirakhur B, Chan E, Le QT, Berlin J, Morse M, Murphy BA, Satinover SM, Hosen J, Mauro D, Slebos RJ, Zhou Q, Gold D, Hatley T, Hicklin DJ, Platts-Mills TA. Cetuximab-induced anaphylaxis and IgE specific for galactose-alpha-1,3-galactose. N Engl J Med. 2008;358(11):1109–17. Scholar
  29. Cohen HP, Blauvelt A, Rifkin RM, Danese S, Gokhale SB, Woollett G. Switching Reference Medicines to Biosimilars: A Systematic Literature Review of Clinical Outcomes. Drugs. 2018 Mar;78(4):463-478. doi: 10.1007/s40265-018-0881-y.PubMedPubMedCentralCrossRefGoogle Scholar
  30. Cohen HP, Blauvelt A, Rifkin RM, Danese S, Gokhale SB, Woollett G. Switching reference medicines to biosimilars: a systematic literature review of clinical outcomes. Drugs. 2018;78(4):463–78. Scholar
  31. Cohen SB, Alonso-Ruiz A, Klimiuk PA, Lee EC, Peter N, Sonderegger I, Assudani D. Similar efficacy, safety and immunogenicity of adalimumab biosimilar BI 695501 and Humira reference product in patients with moderately to severely active rheumatoid arthritis: results from the phase III randomised VOLTAIRE-RA equivalence study. Ann Rheum Dis. 2018b;77(6):914–21.PubMedPubMedCentralGoogle Scholar
  32. De Groot AS, Scott DW. Immunogenicity of protein therapeutics. Trends Immunol. 2007;28(11):482–90.PubMedCrossRefGoogle Scholar
  33. Dellanna F, Goldsmith D, Krendyukov A, Seidl A, Höbel N, Combe C. HX575: established biosimilarity in the treatment of renal anemia and 10 years of clinical experience. Drug Des Devel Ther. 2017;12:9–14. Scholar
  34. Delluc S, Ravot G, Maillere B. Quantification of the preexisting CD4 T-cell repertoire specific for human erythropoietin reveals its immunogenicity potential. Blood. 2010;116(22):4542–5.PubMedCrossRefGoogle Scholar
  35. Ebbers HC, Chamberlain P. Interchangeability: an insurmountable 5th hurdle? GaBI J. 2014;3(2):88–92.CrossRefGoogle Scholar
  36. Ebbers HC, Chamberlain P. Controversies in establishing biosimilarity: extrapolation of indications and global labelling practices. BioDrugs. 2016;30(1):1–8.PubMedPubMedCentralCrossRefGoogle Scholar
  37. EMA. European Public Assessment Report (EPAR) for Avastin®. 2005a. Available at Last Accessed 16 April 2018.
  38. EMA. EPAR for Herceptin®. 2005b. Available at Last Accessed 16 April 2018.
  39. EMA. Guidance on similar medicinal products containing recombinant granulocyte-colony stimulating factor, EMEA/CHMP/BMWP/31329/2005. 2006. Available at Last Accessed 16 April 2018.
  40. EMA. Assessment Report for ARANESP, Doc. Ref No. EMEA/478499/2008. 2008. Available at Accessed 15 April 2018.
  41. EMA. Guideline on non-clinical and clinical development of similar biological medicinal products containing recombinant erythropoietins (Revision), EMEA/CHMP/BMWP/301636/2008 Corr. 2010. Available at Last Accessed 16 April 2018.
  42. EMA. EPAR for REMSIMA, June 2013, EMA/CHMP/589317/2013. 2013. Last Accessed 16 April 2018.
  43. EMA. Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: non-clinical and clinical issues. EMEA/CHMP/BMWP/42832/2005 Rev1. Committee for Medicinal Products for Human Use (CHMP). 2014. Last Accessed 8 January 2018.
  44. EMA. EPAR for BENEPALI, EMA/CHMP/819219/2015. 2015. Available at Last Accessed 16 April 2018.
  45. EMA. EPAR for FLIXABI, April 2016, EMA/CHMP/272283/2016. 2016a. Available at Last Accessed 16 April 2018.
  46. EMA. EPAR for MOVYMIA, EMA/88527/2017. 2016b. Available at Last Accessed 16 April 2018.
  47. EMA. Guideline on Immunogenicity assessment of therapeutic proteins (EMEA/CHMP/BMWP/14327/2006 Rev 1) Committee for Medicinal Products for Human Use (CHMP). 2017a. Last Accessed 8 January 2018.
  48. EMA. EPAR for IMRALDI, June 2017, EMA/CHMP/559383/2017. 2017b. Available at Last Accessed 16 April 2018.
  49. EMA. Variation Assessment Report for IV Orencia, June 2017, EMA/455579/2017. 2017c. Available at Last Accessed 16 April 2018.
  50. EMA. EPARs for RIXATHON EMA/303207/2017. 2017d. Available at Last Accessed 16 April 2018.
  51. EMA. EPAR for TRUXIMA; EMA/CHMP/75695/2017. 2017e. Last Accessed 16 April 2018.
  52. EMA. EPAR for GP2015 ERELZI; April 2017, EMA/CHMP/302222/2017. 2017f. Available at Last Accessed 16 April 2018.
  53. Emery P, Vencovský J, Sylwestrzak A, Leszczyński P, Porawska W, Stasiuk B, Hilt J, Mosterova Z, Cheong SY, Ghil J. Long-term efficacy and safety in patients with rheumatoid arthritis continuing on SB4 or switching from reference etanercept to SB4. Ann Rheum Dis. 2017. Scholar
  54. FDA. Guidance for industry: immunogenicity assessment for therapeutic protein products. 2014. Available at Last Accessed 16 April 2018.
  55. FDA. Guidance for industry: scientific considerations in demonstrating biosimilarity to a reference product. FDA, April 2015. 2015b. Last Accessed 16 April 2018.
  56. FDA. FDA summary review for supplementary BLA (Humira 100mg/mL). 2015c. Available at Last Accessed 16 April 2018.
  57. FDA. Guidance for industry: clinical pharmacology data to support a demonstration of biosimilarity to a reference product, FDA. 2016a. Last Accessed 8 January 2018.
  58. FDA. FDA Briefing Document for Arthritis Advisory Committee meeting held on 9 February 2016 (Table 16) CT-P13. 2016b. Available at Last Accessed 16 April 2018.
  59. FDA. Cross discipline team leader review for CT-P13 review. 2016c. Available at Last Accessed 16 April 2018.
  60. FDA. FDA summary review for CT-P13 review. 2016d. Available at Last Accessed 16 April 2018.
  61. FDA. FDA addendum to primary clinical review for CT-P13 review. 2016e. Available at Last Accessed 16 April 2018.
  62. FDA. FDA Backgrounder for GP2015 AC, 13 July 2016, Page 23. 2016f. Available at Last Accessed 16 April 2018.
  63. FDA. FDA Briefing Document for Arthritis Advisory Committee meeting for ABP 501 dated 12 July 2016. 2016g. Available at Last Accessed 10 May 2018.
  64. FDA. Draft Guidance for industry: considerations in demonstrating interchangeability with a reference product. 2017a.
  65. FDA. FDA clinical review for Samsung 351(k) BLA submission for SB2 (RENFLEXIS). 2017b. Available at Last Accessed 18 April 2018.
  66. FDA. Cross-discipline team leader review/division director summary for Samsung 351(k) BLA submission for SB2. 2017c. Available at
  67. Federici M, Lubiniecki A, Manikwar P, Volkin DB. Analytical lessons learned from selected therapeutic protein drug comparability studies. Biologicals. 2013;41(3):131–47. Scholar
  68. Fineberg SE, Kawabata TT, Finco-Kent D, Fountaine RJ, Finch GL, Krasner AS. Immunological responses to exogenous insulin. Endocr Rev. 2007;28(6):625–52.PubMedCrossRefGoogle Scholar
  69. Fiorino G, Ruiz-Argüello MB, Maguregui A, Nagore D, Correale C, Radice S, Gilardi D, Allocca M, Furfaro F, Martínez A, Danese S. Full interchangeability in regard to immunogenicity between the infliximab reference biologic and biosimilars CT-P13 and SB2 in inflammatory bowel disease. Inflamm Bowel Dis. 2018;24(3):601–6. Scholar
  70. Glintborg B, Kringelbach T, Bolstad N, Warren DJ, Eng G, Sørensen IJ, Loft AG, Hendricks O, Hansen I, Linauskas A, Nordin H, Kristensen S, Lindegaard H, Jensen DV, Goll GL, Høgdall E, Gehin J, Enevold C, Nielsen CH, Krogh NS, Johansen JS, Hetland ML. Drug concentrations and anti-drug antibodies during treatment with biosimilar infliximab (CT-P13) in routine care. Scand J Rheumatol. 2018;9:1–4. Scholar
  71. Haile LA, Puig M, Kelley-Baker L, Verthelyi D. Detection of innate immune response modulating impurities in therapeutic proteins. PLoS One. 2015;10(4):e0125078.PubMedPubMedCentralCrossRefGoogle Scholar
  72. Haile LA, etal. Cell based assay identifies TLR2 and TLR4 stimulating impurities in interferon beta. Sci Rep. 2017;7(1):10490.PubMedPubMedCentralCrossRefGoogle Scholar
  73. Harding FA, Stickler MM, Razo J, DuBridge RB. The immunogenicity of humanized and fully human antibodies: residual immunogenicity resides in the CDR regions. MAbs. 2010;2(3):256–65.PubMedPubMedCentralCrossRefGoogle Scholar
  74. Hassett B, Singh E, Mahgoub E, O'Brien J, Vicik SM, Fitzpatrick B. Manufacturing history of etanercept (Enbrel®): consistency of product quality through major process revisions. MAbs. 2018;10(1):159–65. Scholar
  75. Hawe A, Romeijn S, Filipe V, Jiskoot W. Asymmetrical flow field-flow fractionation method for the analysis of submicron protein aggregates. J Pharm Sci. 2012;101(11):4129–39. Scholar
  76. Homann A, Röckendorf N, Kromminga A, Frey A, Platts-Mills TA, Jappe U. Glycan and peptide IgE epitopes of the TNF-alpha blockers infliximab and adalimumab - precision diagnostics by cross-reactivity immune profiling of patient sera. Theranostics. 2017;7(19):4699–709. Scholar
  77. ICH. ICH comparability of biotechnological/biological products subject to changes in their manufacturing process. Q5E. ICH, June 2005. CPMP/ICH/5721/03. 2005. Last Accessed 8 January.
  78. Inotai A, Prins CPJ, Csanádi M, Vitezic D, Codreanu C, Kaló Z. Is there a reason for concern or is it just hype? A systematic literature review of the clinical consequences of switching from originator biologics to biosimilars. Expert Opin Biol Ther. 2017;17(8):915–26.PubMedCrossRefGoogle Scholar
  79. Jawa V, Cousens LP, Awwad M, Wakshull E, Kropshofer H, De Groot AS. T-cell dependent immunogenicity of protein therapeutics: preclinical assessment and mitigation. Clin Immunol. 2013;149(3):534–55. Scholar
  80. Jørgensen KK, Olsen IC, Goll GL, Lorentzen M, Bolstad N, Haavardsholm EA, Lundin KEA, Mørk C, Jahnsen J. Kvien TK; NOR-SWITCH study group. Switching from originator infliximab to biosimilar CT-P13 compared with maintained treatment with originator infliximab (NOR-SWITCH): a 52-week, randomised, double-blind, non-inferiority trial. Lancet. 2017;389(10086):2304–16.PubMedCrossRefGoogle Scholar
  81. Joubert MK, Deshpande M, Yang J, Reynolds H, Bryson C, Fogg M, Baker MP, Herskovitz J, Goletz TJ, Zhou L, Moxness M, Flynn GC, Narhi LO, Jawa V. Use of in vitro assays to assess immunogenicity risk of antibody-based biotherapeutics. PLoS One. 2016;11(8):e0159328. Scholar
  82. Jung SK, Lee KH, Jeon JW, Lee JW, Kwon BO, Kim YJ, Bae JS, Kim DI, Lee SY, Chang SJ. Physicochemical characterization of Remsima. MAbs. 2014;6(5):1163–77. Scholar
  83. Karsten Roth NM, Wessels H, Hoefler J, Jankowsky R. Comparability of pharmacodynamics and immunogenicity of B12019, a proposed pegfilgrastim biosimilar to neulasta. Blood. 2017;130(Suppl 1):1002.Google Scholar
  84. Kim JS, Kim SH, Kwon B, Hong S. Comparison of immunogenicity test methods used in clinical studies of infliximab and its biosimilar (CT-P13). Expert Rev Clin Immunol. 2015;11(Suppl 1):S33–41. Scholar
  85. Kim HS, Kim I, Zheng L, Vernes JM, Meng YG, Spiess C. Evading pre-existing anti-hinge antibody binding by hinge engineering. MAbs. 2016;8(8):1536–47.PubMedPubMedCentralCrossRefGoogle Scholar
  86. Krieckaert CL, Nurmohamed MT, Wolbink GJ. Methotrexate reduces immunogenicity in adalimumab treated rheumatoid arthritis patients in a dose dependent manner. Ann Rheum Dis. 2012;71(11):1914–5. Scholar
  87. Kurki P, van Aerts L, Wolff-Holz E, Giezen T, Skibeli V, Weise M. Interchangeability of biosimilars: a European perspective. BioDrugs. 2017;31(2):83–91.PubMedPubMedCentralCrossRefGoogle Scholar
  88. Lee KH, Lee J, Bae JS, Kim YJ, Kang HA, Kim SH, Lee SJ, Lim KJ, Lee JW, Jung SK, Chang SJ. Analytical similarity assessment of rituximab biosimilar CT-P10 to reference medicinal product. MAbs. 2018;10(3):380–96. Scholar
  89. Li J, Yang C, Xia Y, Bertino A, Glaspy J, Roberts M, Kuter DJ. Thrombocytopenia caused by the development of antibodies to thrombopoietin. Blood. 2001;98(12):3241–8.PubMedCrossRefGoogle Scholar
  90. Liu YD, van Erik JZ, Flynn GC. Human antibody Fc deamidation in vivo. Biologicals. 2009;37(5):313–22.PubMedPubMedCentralCrossRefGoogle Scholar
  91. Liu J, Eris T, Li C, Cao S, Kuhns S. Assessing analytical similarity of proposed amgen biosimilar ABP 501 to adalimumab. BioDrugs. 2016;30(4):321–38. Scholar
  92. London G, Mann J, Goldsmith D, Combe C, Dellanna F, Zaoui P, Hoebel N, Krendyukov A, MacDonald K, Abraham I. Long-term treatment with biosimilar epoetin-α (HX575) in hemodialysis patients with renal anemia: real-world effectiveness and safety in the MONITOR-CKD5 study. Clin Nephrol. 2018;89(1):1–9. Scholar
  93. Loumaye E, Dreano M, Galazka A, Howles C, Ham L, Munafo A. Recombinant human FSH product development group, Ares-Serono. Recombinant follicle stimulating hormone: development of the first biotechnology product for the treatment of fertility. Hum Reprod Update. 1998;4(6):862–81.CrossRefGoogle Scholar
  94. Luo Y, Lu Z, Raso SW, Entrican C, Tangarone B. Dimers and multimers of monoclonal IgG1 exhibit higher in vitro binding affinities to Fc γ receptors. MAbs. 2009;1(5):491–504.PubMedPubMedCentralCrossRefGoogle Scholar
  95. Macdougall IC, Casadevall N, Locatelli F, Combe C, London GM, Di Paolo S, Kribben A, Fliser D, Messner H, McNeil J, Stevens P, Santoro A, De Francisco AL, Percheson P, Potamianou A, Foucher A, Fife D, Mérit V. Vercammen E; PRIMS study group. Incidence of erythropoietin antibody-mediated pure red cell aplasia: the Prospective Immunogenicity Surveillance Registry (PRIMS). Nephrol Dial Transplant. 2015;30(3):451–60. Scholar
  96. Manivannan V, Decker WW, Stead LG, Li JT, Campbell RL. Visual representation of National Institute of Allergy and Infectious Disease and Food Allergy and Anaphylaxis Network criteria for anaphylaxis. Int J Emerg Med. 2009;2:3–5.PubMedPubMedCentralCrossRefGoogle Scholar
  97. McKinnon RA, Cook M, Liauw W, Marabani M, Marschner IC, Packer NH, Prins JB. Biosimilarity and Interchangeability: principles and evidence: a systematic review. BioDrugs. 2018;32(1):27–52. PubMedPubMedCentralCrossRefGoogle Scholar
  98. Minghetti P, Rocco P, Schellekens H. The constrained prescription, interchangeability and substitution of biosimilars. Nat Biotechnol. 2015;33(7):688–9. Scholar
  99. Moots R, Azevedo V, Coindreau JL, Dörner T, Mahgoub E, Mysler E, Scheinberg M, Marshall L. Switching between reference biologics and biosimilars for the treatment of rheumatology, gastroenterology, and dermatology inflammatory conditions: considerations for the clinician. Curr Rheumatol Rep. 2017;19(6):37. Scholar
  100. Murdaca G, Spanò F, Contatore M, Guastalla A, Penza E, Magnani O, Puppo F. Immunogenicity of infliximab and adalimumab: what is its role in hypersensitivity and modulation of therapeutic efficacy and safety? Expert Opin Drug Saf. 2016;15(1):43–52. Scholar
  101. Nimmerjahn F, Ravetch JV. Fcgamma receptors as regulators of immune responses. Nat Rev Immunol. 2008;8(1):34–47.PubMedCrossRefGoogle Scholar
  102. Park W, Yoo DH, Miranda P, Brzosko M, Wiland P, Gutierrez-Ureña S, etal. Efficacy and safety of switching from reference infliximab to CT-P13 compared with maintenance of CT-P13 in ankylosing spondylitis: 102-week data from the PLANETAS extension study. Ann Rheum Dis. 2017;76:346–54. Scholar
  103. Pfizer. Genotropin® prescribing information, December 2016, Pfizer. Sourced on 10 May 2018. 2016.
  104. Pisupati K, Benet A, Tian Y, Okbazghi S, Kang J, Ford M, Saveliev S, Sen KI, Carlson E, Tolbert TJ, Ruotolo BT, Schwendeman SP, Schwendeman A. Biosimilarity under stress: a forced degradation study of Remicade® and Remsima™. MAbs. 2017;9(7):1197–209. Scholar
  105. Pulsipher MA, etal. Lower risk for serious adverse events and no increased risk for cancer after PBSC vs BM donation. Blood. 2014;123(23):3655–63.PubMedPubMedCentralCrossRefGoogle Scholar
  106. Radstake TR, Svenson M, Eijsbouts AM, van den Hoogen FH, Enevold C, van Riel PL, Bendtzen K. Formation of antibodies against infliximab and adalimumab strongly correlates with functional drug levels and clinical responses in rheumatoid arthritis. Ann Rheum Dis. 2009;68(11):1739–45. Scholar
  107. Reinisch W, Jahnsen J, Schreiber S, Danese S, Panés J, Balsa A, Park W, Kim J, Lee JU, Yoo DH. Evaluation of the cross-reactivity of antidrug antibodies to CT-P13 and infliximab reference product (remicade): an analysis using immunoassays tagged with both agents. BioDrugs. 2017;31(3):223–37. Scholar
  108. Reinivuori T, Kurki P, Chamberlain P. Immunogenicity assessment of biosimilars. Pharm Med. 2018;32:103. Scholar
  109. Rombach-Riegraf V, Karle AC, Wolf B, Sordé L, Koepke S, Gottlieb S, Krieg J, Djidja MC, Baban A, Spindeldreher S, Koulov AV, Kiessling A. Aggregation of human recombinant monoclonal antibodies influences the capacity of dendritic cells to stimulate adaptive T-cell responses in vitro. PLoS One. 2014;9(1):e86322. Scholar
  110. Rosenberg AS. Immunogenicity of biological therapeutics: a hierarchy of concerns. Dev Biol. 2003;112:15–21.Google Scholar
  111. Rubic-Schneider T, Kuwana M, Christen B, Aßenmacher M, Hainzl O, Zimmermann F, Fischer R, Koppenburg V, Chibout SD, Wright TM, Seidl A, Kammüller M. T-cell assays confirm immunogenicity of tungsten-induced erythropoietin aggregates associated with pure red cell aplasia. Blood Adv. 2017;1(6):367–79. Scholar
  112. Rup B, Pallardy M, Sikkema D, Albert T, Allez M, Broet P, Carini C, Creeke P, Davidson J, De Vries N, Finco D, Fogdell-Hahn A, Havrdova E, Hincelin-Mery A, Holland MC, Jensen PEH, Jury EC, Kirby H, Kramer D, Lacroix-Desmazes S, Legrand J, Maggi E, Maillère B, Mariette X, Mauri C, Mikol V, Mulleman D, Oldenburg J, Paintaud G, Pedersen CR, Ruperto N, Seitz R, Spindeldreher S, Deisenhammer F, ABIRISK Consortium. Standardizing terms, definitions and concepts for describing and interpreting unwanted immunogenicity of biopharmaceuticals: recommendations of the Innovative Medicines Initiative ABIRISK consortium. Clin Exp Immunol. 2015;181(3):385–400.PubMedPubMedCentralCrossRefGoogle Scholar
  113. Ryding J, Stahl M, Ullmann M. Demonstrating biosimilar and originator antidrug antibody binding comparability in antidrug antibody assays: a practical approach. Bioanalysis. 2017;9(18):1395–406. Scholar
  114. Sandoz. Sandoz backgrounder for FDA Advisory Committee for GP2015 AC, 13 July 2016, Page 23. 2016. Available at Last Accessed 16 April 2018.
  115. Sauerborn M, Brinks V, Jiskoot W, Schellekens H. Immunological mechanism underlying the immune response to recombinant human protein therapeutics. Trends Pharmacol Sci. 2010;31(2):53–9. Scholar
  116. Scherlinger M, Schaeverbeke T, Truchetet ME. Serum sickness-like disease after switching to biosimilar infliximab. Rheumatology. 2017;56(11):2032–4. Scholar
  117. Schiestl M, Stangler T, Torella C, Cepeljnik T, Toll H, Grau R. Acceptable changes in quality attributes of glycosylated biopharmaceuticals. Nat Biotechnol. 2011;29(4):310–2. Scholar
  118. Schmidt E, Hennig K, Mengede C, Zillikens D, Kromminga A. Immunogenicity of rituximab in patients with severe pemphigus. Clin Immunol. 2009;132(3):334–41.PubMedCrossRefGoogle Scholar
  119. Schultz HS, Reedtz-Runge SL, Bäckström BT, Lamberth K, Pedersen CR, Kvarnhammar AM, ABIRISK Consortium. Quantitative analysis of the CD4+ T cell response to therapeutic antibodies in healthy donors using a novel T cell:PBMC assay. PLoS One. 2017;12(5):e0178544. Scholar
  120. Seidl A, Hainzl O, Richter M, Fischer R, Böhm S, Deutel B, Hartinger M, Windisch J, Casadevall N, London GM, Macdougall I. Tungsten-induced denaturation and aggregation of epoetin alfa during primary packaging as a cause of immunogenicity. Pharm Res. 2012;29(6):1454–67. Scholar
  121. Seo N, Polozova A, Zhang M, Yates Z, Cao S, Li H, Kuhns S, Maher G, McBride HJ, Liu J. Analytical and functional similarity of Amgen biosimilar ABP 215 to bevacizumab. MAbs. 2018;10(4):678–91. Scholar
  122. Shankar G, Arkin S, Cocea L, Devanarayan V, Kirshner S, Kromminga A, Quarmby V, Richards S, Schneider CK, Subramanyam M, Swanson S, Verthelyi D, Yim S, American Association of Pharmaceutical Scientists. Assessment and reporting of the clinical immunogenicity of therapeutic proteins and peptides-harmonized terminology and tactical recommendations. AAPS J. 2014;16(4):658–73.PubMedPubMedCentralCrossRefGoogle Scholar
  123. Sherman MR, Williams LD, Sobczyk MA, Michaels SJ, Saifer MG. Role of the methoxy group in immune responses to mPEG-protein conjugates. Bioconjug Chem. 2012;23(3):485–99. Scholar
  124. Smith HW, Butterfield A, Sun D. Detection of antibodies against therapeutic proteins in the presence of residual therapeutic protein using a solid-phase extraction with acid dissociation (SPEAD) sample treatment prior to ELISA. Regul Toxicol Pharmacol. 2007;49(3):230–7.PubMedCrossRefGoogle Scholar
  125. Smolen JS, Choe J-Y, Prodanovic N, Niebrzydowski J, Staykov I, Dokoupilova E, Rho YH. Safety, immunogenicity and efficacy after switching from reference infliximab to biosimilar SB2 compared with continuing reference infliximab and SB2 in patients with rheumatoid arthritis: results of a randomised, double-blind, phase III transition study. Ann Rheum Dis. 2018;77(2):234–40. Scholar
  126. Somerville L, Bardelas J, Viegas A, D’Andrea P, Blogg M, Peachey G. Immunogenicity and safety of omalizumab in pre-filled syringes in patients with allergic (IgE-mediated) asthma. Curr Med Res Opin. 2014;30(1):59–66.PubMedCrossRefGoogle Scholar
  127. Stickler M, Valdes AM, Gebel W, Razo OJ, Faravashi N, Chin R, etal. The HLA-DR2 haplotype is associated with an increased proliferative response to the immunodominant CD4(+) T-cell epitope in human interferon-beta. Genes Immun. 2004;5(1):1–7.PubMedCrossRefGoogle Scholar
  128. Strik AS, van de Vrie W, Bloemsaat-Minekus JPJ, Nurmohamed M, Bossuyt PJJ, Bodelier A, Rispens T, van Megen YJB, D’Haens GR, SECURE Study Group. Serum concentrations after switching from originator infliximab to the biosimilar CT-P13 in patients with quiescent inflammatory bowel disease (SECURE): an open-label, multicentre, phase 4 non-inferiority trial. Lancet Gastroenterol Hepatol. 2018;3(6):404–12.PubMedCrossRefGoogle Scholar
  129. Subramanyam M. Case study: immunogenicity of natalizumab. In: Weert M, Møller EH, editors. Immunogenicity of biopharmaceuticals. Biotechnology: pharmaceutical aspects, vol. VIII. New York: Springer; 2008.Google Scholar
  130. Talotta R, Berzi A, Doria A, Batticciotto A, Ditto MC, Atzeni F, Sarzi-Puttini P, Trabattoni D. The immunogenicity of branded and biosimilar infliximab in rheumatoid arthritis according to Th9-related responses. Int J Mol Sci. 2017;18(10):E2127. Scholar
  131. Tangri S, Mothé BR, Eisenbraun J, Sidney J, Southwood S, Briggs K, Zinckgraf J, Bilsel P, Newman M, Chesnut R, Licalsi C, Sette A. Rationally engineered therapeutic proteins with reduced immunogenicity. J Immunol. 2005;174(6):3187–96.PubMedCrossRefGoogle Scholar
  132. Tebbey PW, Varga A, Naill M, Clewell J, Venema J. Consistency of quality attributes for the glycosylated monoclonal antibody Humira® (adalimumab). MAbs. 2015;7(5):805–11. Scholar
  133. Torosantucci R, Schöneich C, Jiskoot W. Oxidation of therapeutic proteins and peptides: structural and biological consequences. Pharm Res. 2014;31(3):541–53.PubMedCrossRefGoogle Scholar
  134. Van Aerts LA, De Smet K, Reichmann G, van der Laan JW, Schneider CK. Biosimilars entering the clinic without animal studies. A paradigm shift in Europe. MAbs. 2014;6(5):1155–62.PubMedPubMedCentralCrossRefGoogle Scholar
  135. van Schie KA, Wolbink GJ, Rispens T. Cross-reactive and pre-existing antibodies to therapeutic antibodies--Effects on treatment and immunogenicity. MAbs. 2015a;7(4):662–71. Scholar
  136. van Schie KA, Hart MH, de Groot ER, Kruithof S, Aarden LA, Wolbink GJ, Rispens T. The antibody response against human and chimeric anti-TNF therapeutic antibodies primarily targets the TNF binding region. Ann Rheum Dis. 2015b;74(1):311–4. Scholar
  137. van Schie KA, Kruithof S, van Schouwenburg PA, Vennegoor A, Killestein J, Wolbink G, Rispens T. Neutralizing capacity of monoclonal and polyclonal anti-natalizumab antibodies: the immune response to antibody therapeutics preferentially targets the antigen-binding site. J Allergy Clin Immunol. 2017;139(3):1035–1037.e6. Scholar
  138. van Schouwenburg PA, van de Stadt LA, de Jong RN, van Buren EE, Kruithof S, de Groot E, Hart M, van Ham SM, Rispens T, Aarden L, Wolbink GJ, Wouters D. Adalimumab elicits a restricted anti-idiotypic antibody response in autoimmune patients resulting in functional neutralisation. Ann Rheum Dis. 2013a;72(1):104–9. Scholar
  139. van Schouwenburg PA, Krieckaert CL, Rispens T, Aarden L, Wolbink GJ, Wouters D. Long-term measurement of anti-adalimumab using pH-shift-anti-idiotype antigen binding test shows predictive value and transient antibody formation. Ann Rheum Dis. 2013b;72(10):1680–6. Scholar
  140. van Schouwenburg PA, Kruithof S, Votsmeier C, van Schie K, Hart MH, de Jong RN, van Buren EE, van Ham M, Aarden L, Wolbink G, Wouters D, Rispens T. Functional analysis of the anti-adalimumab response using patient-derived monoclonal antibodies. J Biol Chem. 2014;289(50):34482–8. Scholar
  141. van Schouwenburg PA, Kruithof S, Wolbink G, Wouters D, Rispens T. Using monoclonal antibodies as an international standard for the measurement of anti-adalimumab antibodies. J Pharm Biomed Anal. 2016;120:198–201. Scholar
  142. Verma A, Ngundi MM, Burns DL. Mechanistic analysis of the effect of deamidation on the immunogenicity of anthrax protective antigen. Clin Vaccine Immunol. 2016;23(5):396–402.PubMedPubMedCentralCrossRefGoogle Scholar
  143. Verthelyi D, Wang V. Trace levels of innate immune response modulating impurities (IIRMIs) synergize to break tolerance to therapeutic proteins. PLoS One. 2010;5(12):e15252.PubMedPubMedCentralCrossRefGoogle Scholar
  144. Vezér B, Buzás Z, Sebeszta M, Zrubka Z. Authorized manufacturing changes for therapeutic monoclonal antibodies (mAbs) in European Public Assessment Report (EPAR) documents. Curr Med Res Opin. 2016;32(5):829–34. Scholar
  145. Visser J, Feuerstein I, Stangler T, Schmiederer T, Fritsch C, Schiestl M. Physicochemical and functional comparability between the proposed biosimilar rituximab GP2013 and originator rituximab. BioDrugs. 2013;27(5):495–507. PubMedPubMedCentralCrossRefGoogle Scholar
  146. Waller C, Ranganna GM, Pennella E, Mattano LA, Loa CC, Donnelly C, Liu MS, Watson H, St-Jean J, Chatterjee S, Nayak V, Sengupta N, Kothekar MA, Barve A. Comparison of immunogenicity between the proposed pegfilgrastim biosimilar MYL-1401H and reference pegfilgrastim. Blood. 2017;130(Suppl 1):3568.Google Scholar
  147. Wang YM, Fang L, Zhou L, Wang J, Ahn HY. A survey of applications of biological products for drug interference of immunogenicity assays. Pharm Res. 2012;29(12):3384–92.PubMedCrossRefGoogle Scholar
  148. Weber CA, Mehta PJ, Ardito M, Moise L, Martin B, De Groot AS. T cell epitope: friend or foe? Immunogenicity of biologics in context. Adv Drug Deliv Rev. 2009;61(11):965–76. Scholar
  149. Weinbuch D, Zölls S, Wiggenhorn M, Friess W, Winter G, Jiskoot W, Hawe A. Micro-flow imaging and resonant mass measurement (Archimedes)--complementary methods to quantitatively differentiate protein particles and silicone oil droplets. J Pharm Sci. 2013;102(7):2152–65. Scholar
  150. Weise M, Kurki P, Wolff-Holz E, Bielsky MC, Schneider CK. Biosimilars: the science of extrapolation. Blood. 2014;124(22):3191–6. Scholar
  151. Wolbink GJ, Voskuyl AE, Lems WF, de Groot E, Nurmohamed MT, Tak PP, etal. Relationship between serum trough infliximab levels, pretreatment C reactive protein levels, and clinical response to infliximab treatment in patients with rheumatoid arthritis. Ann Rheum Dis. 2005;64:704–7.PubMedCrossRefGoogle Scholar
  152. Wolbink GJ, Vis M, Lems W, de Groot E, Nurmohamed MT, Stapel S, etal. Development of antiinfliximab antibodies and relationship to clinical response in patients with rheumatoid arthritis. Arthritis Rheum. 2006;54:711–5.PubMedCrossRefGoogle Scholar
  153. Yoo DH, Prodanovic N, Jaworski J, Miranda P, Ramiterre E, Lanzon A, Park W. Efficacy and safety of CT-P13 (biosimilar infliximab) in patients with rheumatoid arthritis: comparison between switching from reference infliximab to CT-P13 and continuing CT-P13 in the PLANETRA extension study. Ann Rheum Dis. 2017;76(2):355–63. Scholar

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© American Association of Pharmaceutical Scientists 2018

Authors and Affiliations

  1. 1.NDA Advisory Services LtdLeatherheadUK
  2. 2.Clinical Immunology, University of HelsinkiHelsinkiFinland

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