Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Immunogenicity of anti-TNF biologic therapies for rheumatoid arthritis

Nature Reviews Rheumatology volume 9, pages 164–172 (2013)Cite this article

Subjects

Abstract

Currently, five anti-TNF biologic agents are approved for the treatment of rheumatoid arthritis (RA): adalimumab, infliximab, etanercept, golimumab and certolizumab pegol. Formation of anti-drug antibodies (ADA) has been associated with all five agents. In the case of adalimumab and infliximab, immunogenicity is strongly linked to subtherapeutic serum drug levels and a lack of clinical response, but for the other three agents, data on immunogenicity are scarce, suggesting that further research would be valuable. Low ADA levels might not influence the efficacy of anti-TNF therapy, whereas high ADA levels impair treatment efficacy by considerably reducing unbound drug levels. Immunogenicity is not only an issue in patients treated with anti-TNF biologic agents; the immunogenicity of other therapeutic proteins, such as factor VIII and interferons, is well known and has been investigated for many years. The results of such studies suggest that investigations to determine the optimal treatment regimen (drug dosing, treatment schedule and co-medication) required to minimize the likelihood of ADA formation might be an effective and practical way to deal with the immunogenicity of anti-TNF biologic agents for RA.

Key Points

  • The anti-TNF agents currently approved for the treatment of rheumatoid arthritis are associated with the formation of anti-drug antibodies (ADA)

  • A substantial proportion of patients treated with adalimumab or infliximab develop detectable ADA, typically in the first 6 months of therapy

  • Low ADA levels do not impair the efficacy of anti-TNF therapy, since adequate drug levels remain, but high ADA levels impair treatment efficacy by considerably reducing unbound drug levels

  • Many factors influence the immunogenicity of anti-TNF biologic agents: the drug's characteristics; the patient's genotype and immune system activity; dose, duration, administration route and co-treatment with immunomodulatory agents

  • Insight into how and why anti-TNF therapeutic antibodies evoke an immune response could lead to the development of strategies to minimize the adverse effects of existing anti-TNF agents

  • Study of immune responses in patients receiving anti-TNF agents could lead to techniques for preclinical identification and elimination of problematic epitopes during development of new drugs

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: The five anti-TNF agents approved for the treatment of rheumatoid arthritis.
Figure 2: Detection of ADA.
Figure 3: The three main types of assays for detecting ADA.

Similar content being viewed by others

References

  1. Elliott, M. J. et al. Randomised double-blind comparison of chimeric monoclonal antibody to tumour necrosis factor α (cA2) versus placebo in rheumatoid arthritis. Lancet 344, 1105–1110 (1994).

    Article  CAS  PubMed  Google Scholar 

  2. Weinblatt, M. E. et al. Adalimumab, a fully human anti-tumor necrosis factor α monoclonal antibody, for the treatment of rheumatoid arthritis in patients taking concomitant methotrexate: the ARMADA trial. Arthritis Rheum. 48, 35–45 (2003).

    Article  CAS  PubMed  Google Scholar 

  3. Moreland, L. W. et al. Treatment of rheumatoid arthritis with a recombinant human tumor necrosis factor receptor (p75)–Fc fusion protein. N. Engl. J. Med. 337, 141–147 (1997).

    Article  CAS  PubMed  Google Scholar 

  4. Zhou, H. et al. Pharmacokinetics and safety of golimumab, a fully human anti-TNF-α monoclonal antibody, in subjects with rheumatoid arthritis. J. Clin. Pharmacol. 47, 383–396 (2007).

    Article  CAS  PubMed  Google Scholar 

  5. Choy, E. H. et al. Efficacy of a novel PEGylated humanized anti-TNF fragment (CDP870) in patients with rheumatoid arthritis: a phase II double-blinded, randomized, dose-escalating trial. Rheumatology (Oxford) 41, 1133–1137 (2002).

    Article  CAS  Google Scholar 

  6. Chinol, M. et al. Biochemical modifications of avidin improve pharmacokinetics and biodistribution, and reduce immunogenicity. Br. J. Cancer 78, 189–197 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Baert, F. et al. Influence of immunogenicity on the long-term efficacy of infliximab in Crohn's disease. N. Engl. J. Med. 348, 601–608 (2003).

    Article  CAS  PubMed  Google Scholar 

  8. Pascual-Salcedo, D. et al. Influence of immunogenicity on the efficacy of long-term treatment with infliximab in rheumatoid arthritis. Rheumatology (Oxford) 50, 1445–1452 (2011).

    Article  CAS  Google Scholar 

  9. Wolbink, G. J. et al. Development of antiinfliximab antibodies and relationship to clinical response in patients with rheumatoid arthritis. Arthritis Rheum. 54, 711–715 (2006).

    Article  CAS  PubMed  Google Scholar 

  10. Bendtzen, K. et al. Individualized monitoring of drug bioavailability and immunogenicity in rheumatoid arthritis patients treated with the tumor necrosis factor α inhibitor infliximab. Arthritis Rheum. 54, 3782–3789 (2006).

    Article  CAS  PubMed  Google Scholar 

  11. Svenson, M., Geborek, P., Saxne, T. & Bendtzen, K. Monitoring patients treated with anti-TNF-α biopharmaceuticals: assessing serum infliximab and anti-infliximab antibodies. Rheumatology (Oxford) 46, 1828–1834 (2007).

    Article  CAS  Google Scholar 

  12. Jamnitski, A. et al. The presence or absence of antibodies to infliximab or adalimumab determines the outcome of switching to etanercept. Ann. Rheum. Dis. 70, 284–288 (2011).

    Article  CAS  PubMed  Google Scholar 

  13. van De Putte, L. B. et al. Efficacy and safety of adalimumab as monotherapy in patients with rheumatoid arthritis for whom previous disease modifying antirheumatic drug treatment has failed. Ann. Rheum. Dis. 63, 508–516 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Miyasaka, N. Clinical investigation in highly disease-affected rheumatoid arthritis patients in Japan with adalimumab applying standard and general evaluation: the CHANGE study. Mod. Rheumatol. 18, 252–262 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Rathanaswami, P. et al. Demonstration of an in vivo generated sub-picomolar affinity fully human monoclonal antibody to interleukin-8. Biochem. Biophys. Res. Commun. 334, 1004–1013 (2005).

    Article  CAS  PubMed  Google Scholar 

  16. Bray, G. L. et al. A multicenter study of recombinant factor VIII (recombinate): safety, efficacy, and inhibitor risk in previously untreated patients with hemophilia A. The Recombinate Study Group. Blood 83, 2428–2435 (1994).

    CAS  PubMed  Google Scholar 

  17. Lusher, J. M., Arkin, S., Abildgaard, C. F. & Schwartz, R. S. Recombinant factor VIII for the treatment of previously untreated patients with hemophilia A. Safety, efficacy, and development of inhibitors. Kogenate Previously Untreated Patient Study Group. N. Engl. J. Med. 328, 453–459 (1993).

    Article  CAS  PubMed  Google Scholar 

  18. Antonelli, G. et al. Antibodies to interferon (IFN) in hepatitis C patients relapsing while continuing recombinant IFN-α2 therapy. Clin. Exp. Immunol. 104, 384–387 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Antonelli, G. Neutralising antibodies against interferon β in multiple sclerosis. Lancet 363, 168–169 (2004).

    Article  PubMed  Google Scholar 

  20. Giannelli, G. et al. Biological and clinical significance of neutralizing and binding antibodies to interferon-α (IFN-α) during therapy for chronic hepatitis C. Clin. Exp. Immunol. 97, 4–9 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Ross, C. et al. Immunogenicity of interferon-β in multiple sclerosis patients: influence of preparation, dosage, dose frequency, and route of administration. Danish Multiple Sclerosis Study Group. Ann. Neurol. 48, 706–712 (2000).

    Article  CAS  PubMed  Google Scholar 

  22. Weinblatt, M. E. et al. Adalimumab, a fully human anti-tumor necrosis factor α monoclonal antibody, for the treatment of rheumatoid arthritis in patients taking concomitant methotrexate: the ARMADA trial. Arthritis Rheum. 48, 35–45 (2003).

    Article  CAS  PubMed  Google Scholar 

  23. Bartelds, G. M. et al. Development of antidrug antibodies against adalimumab and association with disease activity and treatment failure during long-term follow-up. JAMA 305, 1460–1468 (2011).

    Article  CAS  PubMed  Google Scholar 

  24. Krieckaert, C., Rispens, T. & Wolbink, G. Immunogenicity of biological therapeutics: from assay to patient. Curr. Opin. Rheumatol. 24, 306–311 (2012).

    Article  PubMed  Google Scholar 

  25. Petitpain, N. et al. Arterial and venous thromboembolic events during anti-TNF therapy: a study of 85 spontaneous reports in the period 2000–2006. Biomed. Mater. Eng. 19, 355–364 (2009).

    PubMed  Google Scholar 

  26. Makol, A., Grover, M., Guggenheim, C. & Hassouna, H. Etanercept and venous thromboembolism: a case series. J. Med. Case Rep. 4, 12 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  27. Korswagen, L. A. et al. Venous and arterial thromboembolic events in adalimumab-treated patients with antiadalimumab antibodies: a case series and cohort study. Arthritis Rheum. 63, 877–883 (2011).

    Article  CAS  PubMed  Google Scholar 

  28. Dore, R. K. et al. The immunogenicity, safety, and efficacy of etanercept liquid administered once weekly in patients with rheumatoid arthritis. Clin. Exp. Rheumatol. 25, 40–46 (2007).

    CAS  PubMed  Google Scholar 

  29. Jamnitski, A. et al. Patients non-responding to etanercept obtain lower etanercept concentrations compared with responding patients. Ann. Rheum. Dis. 71, 88–91 (2012).

    Article  CAS  PubMed  Google Scholar 

  30. Anderson, P. J. Tumor necrosis factor inhibitors: clinical implications of their different immunogenicity profiles. Semin. Arthritis Rheum. 34, 19–22 (2005).

    Article  CAS  PubMed  Google Scholar 

  31. Jacobi, A. M. et al. Activated memory B cell subsets correlate with disease activity in systemic lupus erythematosus: delineation by expression of CD27, IgD, and CD95. Arthritis Rheum. 58, 1762–1773 (2008).

    Article  CAS  PubMed  Google Scholar 

  32. Fleischmann, R. et al. Efficacy and safety of certolizumab pegol monotherapy every 4 weeks in patients with rheumatoid arthritis failing previous disease-modifying antirheumatic therapy: the FAST4WARD study. Ann. Rheum. Dis. 68, 805–811 (2009).

    Article  CAS  PubMed  Google Scholar 

  33. Smolen, J. et al. Efficacy and safety of certolizumab pegol plus methotrexate in active rheumatoid arthritis: the RAPID 2 study. A randomised controlled trial. Ann. Rheum. Dis. 68, 797–804 (2009).

    Article  CAS  PubMed  Google Scholar 

  34. Vennegoor, A. et al. Clinical relevance of serum natalizumab concentration and anti-natalizumab antibodies in multiple sclerosis. Mult. Scler. http://dx.doi.org/10.1177/1352458512460604.

  35. Aarden, L., Ruuls, S. R. & Wolbink, G. Immunogenicity of anti-tumor necrosis factor antibodies—toward improved methods of anti-antibody measurement. Curr. Opin. Immunol. 20, 431–435 (2008).

    Article  CAS  PubMed  Google Scholar 

  36. Chirmule, N., Jawa, V. & Meibohm, B. Immunogenicity to therapeutic proteins: impact on PK/PD and efficacy. AAPS J. 14, 296–302 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Koren, E. et al. Recommendations on risk-based strategies for detection and characterization of antibodies against biotechnology products. J. Immunol. Methods 333, 1–9 (2008).

    Article  CAS  PubMed  Google Scholar 

  38. Hart, M. H. et al. Differential effect of drug interference in immunogenicity assays. J. Immunol. Methods 372, 196–203 (2011).

    Article  CAS  PubMed  Google Scholar 

  39. Wang, Y. M. et al. A survey of applications of biological products for drug interference of immunogenicity assays. Pharm. Res. http://dx.doi.org/10.1007/s11095-012-0833–2.

  40. van Schouwenburg, P. A. et al. A novel method for the detection of antibodies to adalimumab in the presence of drug reveals “hidden” immunogenicity in rheumatoid arthritis patients. J. Immunol. Methods 362, 82–88 (2010).

    Article  CAS  PubMed  Google Scholar 

  41. Kosmac, M. et al. Exploring the binding sites of anti-infliximab antibodies in pediatric patients with rheumatic diseases treated with infliximab. Pediatr. Res. 69, 243–248 (2011).

    Article  CAS  PubMed  Google Scholar 

  42. Candon, S. et al. Clinical and biological consequences of immunization to infliximab in pediatric Crohn's disease. Clin. Immunol. 118, 11–19 (2006).

    Article  CAS  PubMed  Google Scholar 

  43. Vultaggio, A. et al. Anti-infliximab IgE and non-IgE antibodies and induction of infusion-related severe anaphylactic reactions. Allergy 65, 657–661 (2010).

    Article  CAS  PubMed  Google Scholar 

  44. van Schouwenburg, P. A. et al. IgG4 production against adalimumab during long term treatment of RA patients. J. Clin. Immunol. 32, 1000–1006 (2012).

    Article  CAS  PubMed  Google Scholar 

  45. Aalberse, R. C., van der Gaag, R. & van, L. J. Serologic aspects of IgG4 antibodies. I. Prolonged immunization results in an IgG4-restricted response. J. Immunol. 130, 722–726 (1983).

    CAS  PubMed  Google Scholar 

  46. Baker, M. P., Reynolds, H. M., Lumicisi, B. & Bryson, C. J. Immunogenicity of protein therapeutics: the key causes, consequences and challenges. Self Nonself 1, 314–322 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  47. Ben-Horin, S. et al. The immunogenic part of infliximab is the F(ab')2, but measuring antibodies to the intact infliximab molecule is more clinically useful. Gut 60, 41–48 (2011).

    Article  CAS  PubMed  Google Scholar 

  48. van Schouwenburg, P. A. et al. Adalimumab elicits a restricted anti-idiotypic antibody response in autoimmune patients resulting in functional neutralisation. Ann. Rheum. Dis. http://dx.doi.org/10.1136/annrheumdis-2012-201445.

  49. Lobo, E. D., Hansen, R. J. & Balthasar, J. P. Antibody pharmacokinetics and pharmacodynamics. J. Pharm. Sci. 93, 2645–2668 (2004).

    Article  CAS  PubMed  Google Scholar 

  50. Moreland, L. W. et al. Etanercept therapy in rheumatoid arthritis. A randomized, controlled trial. Ann. Intern. Med. 130, 478–486 (1999).

    Article  CAS  PubMed  Google Scholar 

  51. Weinblatt, M. E. et al. A trial of etanercept, a recombinant tumor necrosis factor receptor:Fc fusion protein, in patients with rheumatoid arthritis receiving methotrexate. N. Engl. J. Med. 340, 253–259 (1999).

    Article  CAS  PubMed  Google Scholar 

  52. Lacroix-Desmazes, S. et al. Pathophysiology of inhibitors to factor VIII in patients with haemophilia A. Haemophilia 8, 273–279 (2002).

    Article  CAS  PubMed  Google Scholar 

  53. Rojas, J. R. et al. Formation, distribution, and elimination of infliximab and anti-infliximab immune complexes in cynomolgus monkeys. J. Pharmacol. Exp. Ther. 313, 578–585 (2005).

    Article  CAS  PubMed  Google Scholar 

  54. van der Laken, C. J. et al. Imaging and serum analysis of immune complex formation of radiolabelled infliximab and anti-infliximab in responders and non-responders to therapy for rheumatoid arthritis. Ann. Rheum. Dis. 66, 253–256 (2007).

    Article  CAS  PubMed  Google Scholar 

  55. Korswagen, L. A. et al. Venous and arterial thromboembolic events in adalimumab-treated patients with antiadalimumab antibodies: a case series and cohort study. Arthritis Rheum. 63, 877–883 (2011).

    Article  CAS  PubMed  Google Scholar 

  56. Carter, P. Improving the efficacy of antibody-based cancer therapies. Nat. Rev. Cancer 1, 118–129 (2001).

    Article  CAS  PubMed  Google Scholar 

  57. Clark, M. Antibody humanization: a case of the 'Emperor's new clothes'? Immunol. Today 21, 397–402 (2000).

    Article  CAS  PubMed  Google Scholar 

  58. Schellekens, H. Immunogenicity of therapeutic proteins: clinical implications and future prospects. Clin. Ther. 24, 1720–1740 (2002).

    Article  CAS  PubMed  Google Scholar 

  59. Bartelds, G. M. et al. Surprising negative association between IgG1 allotype disparity and anti-adalimumab formation: a cohort study. Arthritis Res. Ther. 12, R221 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  60. Bartelds, G. M. et al. Anti-adalimumab antibodies in rheumatoid arthritis patients are associated with interleukin-10 gene polymorphisms. Arthritis Rheum. 60, 2541–2542 (2009).

    Article  CAS  PubMed  Google Scholar 

  61. Astermark, J. Prevention and prediction of inhibitor risk. Haemophilia 18 (Suppl. 4), 38–42 (2012).

    Article  PubMed  Google Scholar 

  62. Fakharzadeh, S. S. & Kazazian, H. H. Jr. Correlation between factor VIII genotype and inhibitor development in hemophilia A. Semin. Thromb. Hemost. 26, 167–171 (2000).

    Article  CAS  PubMed  Google Scholar 

  63. Maini, R. N. et al. Therapeutic efficacy of multiple intravenous infusions of anti-tumor necrosis factor α monoclonal antibody combined with low-dose weekly methotrexate in rheumatoid arthritis. Arthritis Rheum. 41, 1552–1563 (1998).

    Article  CAS  PubMed  Google Scholar 

  64. Oldenburg, J., Schwaab, R. & Brackmann, H. H. Induction of immune tolerance in haemophilia A inhibitor patients by the 'Bonn Protocol': predictive parameter for therapy duration and outcome. Vox Sang. 77 (Suppl. 1), 49–54 (1999).

    Article  CAS  PubMed  Google Scholar 

  65. Schellekens, H. Factors influencing the immunogenicity of therapeutic proteins. Nephrol. Dial. Transplant. 20 (Suppl. 6), vi3–vi9 (2005).

    Article  CAS  PubMed  Google Scholar 

  66. Porter, S. Human immune response to recombinant human proteins. J. Pharm. Sci. 90, 1–11 (2001).

    Article  CAS  PubMed  Google Scholar 

  67. Konrad, M. W., Childs, A. L., Merigan, T. C. & Borden, E. C. Assessment of the antigenic response in humans to a recombinant mutant interferon β. J. Clin. Immunol. 7, 365–375 (1987).

    Article  CAS  PubMed  Google Scholar 

  68. Genovese, M. C. et al. Subcutaneous abatacept versus intravenous abatacept: a phase IIIb noninferiority study in patients with an inadequate response to methotrexate. Arthritis Rheum. 63, 2854–2864 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Carpenter, J. et al. Meeting report on protein particles and immunogenicity of therapeutic proteins: filling in the gaps in risk evaluation and mitigation. Biologicals 38, 602–611 (2010).

    Article  PubMed  Google Scholar 

  70. Chirino, A. J. & Mire-Sluis, A. Characterizing biological products and assessing comparability following manufacturing changes. Nat. Biotechnol. 22, 1383–1391 (2004).

    Article  CAS  PubMed  Google Scholar 

  71. Hermeling, S. et al. Antibody response to aggregated human interferon α2b in wild-type and transgenic immune tolerant mice depends on type and level of aggregation. J. Pharm. Sci. 95, 1084–1096 (2006).

    Article  CAS  PubMed  Google Scholar 

  72. Somerfield, J. et al. A novel strategy to reduce the immunogenicity of biological therapies. J. Immunol. 185, 763–768 (2010).

    Article  CAS  PubMed  Google Scholar 

  73. Kohno, T., Tam, L. T., Stevens, S. R. & Louie, J. S. Binding characteristics of tumor necrosis factor receptor–Fc fusion proteins vs anti-tumor necrosis factor mAbs. J. Investig. Dermatol. Symp. Proc. 12, 5–8 (2007).

    Article  CAS  PubMed  Google Scholar 

  74. Kim, M. S. et al. Comparative analyses of complex formation and binding sites between human tumor necrosis factor-α and its three antagonists elucidate their different neutralizing mechanisms. J. Mol. Biol. 374, 1374–1388 (2007).

    Article  CAS  PubMed  Google Scholar 

  75. High, K., Meng, Y., Washabaugh, M. W. & Zhao, Q. Determination of picomolar equilibrium dissociation constants in solution by enzyme-linked immunosorbent assay with fluorescence detection. Anal. Biochem. 347, 159–161 (2005).

    Article  CAS  PubMed  Google Scholar 

  76. Richards, J. et al. Phase I evaluation of humanized OKT3: toxicity and immunomodulatory effects of hOKT3γ4. Cancer Res. 59, 2096–2101 (1999).

    CAS  PubMed  Google Scholar 

  77. Silva, H. M. et al. Novel humanized anti-CD3 antibodies induce a predominantly immunoregulatory profile in human peripheral blood mononuclear cells. Immunol. Lett. 125, 129–136 (2009).

    Article  CAS  PubMed  Google Scholar 

  78. Jamnitski, A. et al. Patients non-responding to etanercept obtain lower etanercept concentrations compared with responding patients. Ann. Rheum. Dis. 71, 88–91 (2012).

    Article  CAS  PubMed  Google Scholar 

  79. Brusic, V., Bajic, V. B. & Petrovsky, N. Computational methods for prediction of T-cell epitopes—a framework for modelling, testing, and applications. Methods 34, 436–443 (2004).

    Article  CAS  PubMed  Google Scholar 

  80. Jones, T. D. et al. Identification and removal of a promiscuous CD4+ T cell epitope from the C1 domain of factor VIII. J. Thromb. Haemost. 3, 991–1000 (2005).

    Article  CAS  PubMed  Google Scholar 

  81. Yeung, V. P. et al. Elimination of an immunodominant CD4+ T cell epitope in human IFN-β does not result in an in vivo response directed at the subdominant epitope. J. Immunol. 172, 6658–6665 (2004).

    Article  CAS  PubMed  Google Scholar 

  82. Moise, L. et al. Effect of HLA DR epitope de-immunization of factor VIII in vitro and in vivo. Clin. Immunol. 142, 320–331 (2012).

    Article  CAS  PubMed  Google Scholar 

  83. van Haren, S. D. et al. Requirements for immune recognition and processing of factor VIII by antigen-presenting cells. Blood Rev. 26, 43–49 (2012).

    Article  CAS  PubMed  Google Scholar 

  84. Stickler, M. M. et al. The human G1m1 allotype associates with CD4+ T-cell responsiveness to a highly conserved IgG1 constant region peptide and confers an asparaginyl endopeptidase cleavage site. Genes Immun. 12, 213–221 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Schellekens, H. Immunogenicity of therapeutic proteins. Nephrol. Dial. Transplant. 18, 1257–1259 (2003).

    Article  CAS  PubMed  Google Scholar 

  86. Jaffers, G. J. et al. Monoclonal antibody therapy. Anti-idiotypic and non-anti-idiotypic antibodies to OKT3 arising despite intense immunosuppression. Transplantation 41, 572–578 (1986).

    Article  CAS  PubMed  Google Scholar 

  87. Chatenoud, L. et al. The human immune response to the OKT3 monoclonal antibody is oligoclonal. Science 232, 1406–1408 (1986).

    Article  CAS  PubMed  Google Scholar 

  88. Chatenoud, L. et al. Restriction of the human in vivo immune response against the mouse monoclonal antibody OKT3. J. Immunol. 137, 830–838 (1986).

    CAS  PubMed  Google Scholar 

  89. Magdelaine-Beuzelin, C. et al. IgG1 heavy chain-coding gene polymorphism (G1m allotypes) and development of antibodies-to-infliximab. Pharmacogenet. Genomics 19, 383–387 (2009).

    Article  CAS  PubMed  Google Scholar 

  90. Christen, U., Thuerkauf, R., Stevens, R. & Lesslauer, W. Immune response to a recombinant human TNFR55–IgG1 fusion protein: auto-antibodies in rheumatoid arthritis (RA) and multiple sclerosis (MS) patients have neither neutralizing nor agonist activities. Hum. Immunol. 60, 774–790 (1999).

    Article  CAS  PubMed  Google Scholar 

  91. Fulcher, C. A. et al. Localization of human factor FVIII inhibitor epitopes to two polypeptide fragments. Proc. Natl Acad. Sci. USA 82, 7728–7732 (1985).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Gilles, J. G. & Saint-Remy, J. M. Healthy subjects produce both anti-factor VIII and specific anti-idiotypic antibodies. J. Clin. Invest. 94, 1496–1505 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Lollar, P. et al. Inhibition of human factor VIIIa by anti-A2 subunit antibodies. J. Clin. Invest. 93, 2497–2504 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Prescott, R. et al. The inhibitor antibody response is more complex in hemophilia A patients than in most nonhemophiliacs with factor VIII autoantibodies. Recombinate and Kogenate Study Groups. Blood 89, 3663–3671 (1997).

    CAS  PubMed  Google Scholar 

  95. Scandella, D. et al. Epitope specificity and functional characterization of factor VIII inhibitors. Adv. Exp. Med. Biol. 386, 47–63 (1995).

    Article  CAS  PubMed  Google Scholar 

  96. Mitoma, H. et al. Infliximab induces potent anti-inflammatory responses by outside-to-inside signals through transmembrane TNF-α. Gastroenterology 128, 376–392 (2005).

    Article  CAS  PubMed  Google Scholar 

  97. Scandella, D. et al. Epitope mapping of human factor VIII inhibitor antibodies by deletion analysis of factor VIII fragments expressed in Escherichia coli. Proc. Natl Acad. Sci. USA 85, 6152–6156 (1988).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Shima, M. et al. Factor VIII polypeptide specificity of monoclonal anti-factor VIII antibodies. Br. J. Haematol. 70, 63–69 (1988).

    Article  CAS  PubMed  Google Scholar 

  99. Parker, E. T. et al. Reduction of the inhibitory antibody response to human factor VIII in hemophilia A mice by mutagenesis of the A2 domain B-cell epitope. Blood 104, 704–710 (2004).

    Article  CAS  PubMed  Google Scholar 

  100. Mayer, A. et al. Modifying an immunogenic epitope on a therapeutic protein: a step towards an improved system for antibody-directed enzyme prodrug therapy (ADEPT). Br. J. Cancer 90, 2402–2410 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Tsutsumi, Y. et al. Site-specific chemical modification with polyethylene glycol of recombinant immunotoxin anti-Tac(Fv)–PE38 (LMB-2) improves antitumor activity and reduces animal toxicity and immunogenicity. Proc. Natl Acad. Sci. USA 97, 8548–8553 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Rosenberg, A. S. Effects of protein aggregates: an immunologic perspective. AAPS J. 8, E501–E507 (2006).

    Article  PubMed  PubMed Central  Google Scholar 

  103. Lavigne-Lissalde, G., Schved, J. F., Granier, C. & Villard, S. Anti-factor VIII antibodies: a 2005 update. Thromb. Haemost. 94, 760–769 (2005).

    PubMed  Google Scholar 

  104. Rosendaal, F. R. et al. A sudden increase in factor VIII inhibitor development in multitransfused hemophilia A patients in The Netherlands. Dutch Hemophilia Study Group. Blood 81, 2180–2186 (1993).

    CAS  PubMed  Google Scholar 

  105. Locatelli, F., Del, V. L. & Pozzoni, P. Pure red-cell aplasia “epidemic”—mystery completely revealed? Perit. Dial. Int. 27 (Suppl. 2), S303–S307 (2007).

    PubMed  Google Scholar 

  106. Jefferis, R. Glycosylation of recombinant antibody therapeutics. Biotechnol. Prog. 21, 11–16 (2005).

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Immunopathology, Sanquin Research and Landsteiner Laboratory Academic Medical Centre, Plesmanlaan 125, Amsterdam, 1066 CX, The Netherlands

    Pauline A. van Schouwenburg & Theo Rispens

  2. Department of Rheumatology, Jan van Breemen Research Institute, Reade, Dr Jan van Breemenstraat 2, Amsterdam, 1056 AB, The Netherlands

    Gerrit Jan Wolbink

Authors
  1. Pauline A. van Schouwenburg
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Theo Rispens
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Gerrit Jan Wolbink
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors provided substantial contributions to discussions of content, and to reviewing and editing the manuscript before submission. P A van Schouwenburg researched the data and wrote the article.

Corresponding author

Correspondence to Gerrit Jan Wolbink.

Ethics declarations

Competing interests

G. J. Wolbink declares that he is a member of the speakers' bureau or has received honoraria from Abbott, Amgen, BMS, Pfizer and UCB, and that he has received grant or research support from Wyeth Pharmaceuticals. T. Rispens declares that he is a member of the speakers' bureau or has received honoraria from Abbott and Pfizer. P. A. van Schouwenburg declares no competing interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

van Schouwenburg, P., Rispens, T. & Wolbink, G. Immunogenicity of anti-TNF biologic therapies for rheumatoid arthritis. Nat Rev Rheumatol 9, 164–172 (2013). https://doi.org/10.1038/nrrheum.2013.4

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrrheum.2013.4

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing