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Drugs

, Volume 77, Issue 4, pp 363–377 | Cite as

Incidence, Prevention and Management of Anti-Drug Antibodies Against Therapeutic Antibodies in Inflammatory Bowel Disease: A Practical Overview

  • Pieter Hindryckx
  • Gregor Novak
  • Niels Vande Casteele
  • Reena Khanna
  • Debby Laukens
  • Jairath Vipul
  • Brian G. FeaganEmail author
Review Article

Abstract

The introduction of biologic therapy has revolutionized the treatment of inflammatory bowel disease (IBD). However, like all therapeutic proteins, monoclonal antibodies have immunogenic potential which is influenced by multiple drug- and patient-related factors. The reported incidence of anti-drug antibodies (ADAs) towards biologic drugs in IBD varies greatly in the literature and depends not only on differences in sensitization but also on the assay methodology and the timepoint of measurement. Sensitization with formation of ADAs is associated with an increased risk of infusion reactions, accelerated drug clearance, and a loss of response (LOR) to drug. Recently, a greater understanding of the pharmacokinetics of therapeutic antibodies has led to the development of new strategies to reduce immunogenicity and more efficient use of these drugs. These preventive strategies include regular scheduled dosing with maintenance of stable therapeutic trough drug concentrations, and co-administration of an immunosuppressive. Sub-therapeutic drug concentrations with low levels of ADAs can generally be overcome with dose escalation, whereas the presence of high concentrations of ADAs requires a switch to another therapeutic agent.

Keywords

Inflammatory Bowel Disease Infliximab Adalimumab Inflammatory Bowel Disease Patient Ustekinumab 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Compliance with Ethical Standards

Conflict of interest

PH has received consulting fees from Abbvie and Takeda, and speaker’s fees from Ferring, Falk Pharma, Vifor Pharma, Tillotts Pharma, Chiesi, Takeda, and Abbvie. GN has received speaker’s fees from Abbvie and Merck. NVC is a Postdoctoral Fellow of the Research Foundation-Flanders (FWO). RK has received consulting fees from AbbVie, Janssen, and Takeda Pharma. DL has no relevant disclosures. VJ has received consulting fees from AbbVie and Sandoz, and speaker’s fees from Takeda and Janssen. BGF has received grant/research support from Millennium Pharmaceuticals, Merck, Tillotts Pharma AG, AbbVie, Novartis Pharmaceuticals, Centocor Inc., Elan/Biogen, UCB Pharma, Bristol-Myers Squibb, Genentech, ActoGenix, and Wyeth Pharmaceuticals Inc.; consulting fees from Millennium Pharmaceuticals, Merck, Centocor Inc., Elan/Biogen, Janssen-Ortho, Teva Pharmaceuticals, Bristol-Myers Squibb, Celgene, UCB Pharma, AbbVie, Astra Zeneca, Serono, Genentech, Tillotts Pharma AG, Unity Pharmaceuticals, Albireo Pharma, Given Imaging Inc., Salix Pharmaceuticals, Novonordisk, GSK, Actogenix, Prometheus Therapeutics and Diagnostics, Athersys, Axcan, Gilead, Pfizer, Shire, and Wyeth. VJ has received consulting fees from AbbVie and Sandoz, and speaker’s fees from Takeda and Janssen.

References

  1. 1.
    Pouillon L, Bossuyt P, Peyrin-Biroulet L. Considerations, challenges and future of anti-TNF therapy in treating inflammatory bowel disease. Expert Opin Biol Ther. 2016;16:1277–90. doi: 10.1080/14712598.2016.1203897.CrossRefPubMedGoogle Scholar
  2. 2.
    Danese S, Fiorino G, Reinisch W. Review article: causative factors and the clinical management of patients with Crohn’s disease who lose response to anti-TNF-alpha therapy. Aliment Pharmacol Ther. 2011;34:1–10. doi: 10.1111/j.1365-2036.2011.04679.x.CrossRefPubMedGoogle Scholar
  3. 3.
    Steenholdt C, Brynskov J, Bendtzen K. Letter: persistence of anti-infliximab antibodies after discontinuation of infliximab in patients with IBD. Aliment Pharmacol Ther. 2012;36:499–500. doi: 10.1111/j.1365-2036.2012.05204.x (author reply 1).
  4. 4.
    Krintel SB, Grunert VP, Hetland ML, Johansen JS, Rothfuss M, Palermo G, et al. The frequency of anti-infliximab antibodies in patients with rheumatoid arthritis treated in routine care and the associations with adverse drug reactions and treatment failure. Rheumatology (Oxford, England). 2013;52:1245–53. doi: 10.1093/rheumatology/ket017.
  5. 5.
    Ungar B, Chowers Y, Yavzori M, Picard O, Fudim E, Har-Noy O, et al. The temporal evolution of antidrug antibodies in patients with inflammatory bowel disease treated with infliximab. Gut. 2014;63:1258–64. doi: 10.1136/gutjnl-2013-305259.CrossRefPubMedGoogle Scholar
  6. 6.
    Lichtenstein GR. Comprehensive review: antitumor necrosis factor agents in inflammatory bowel disease and factors implicated in treatment response. Ther Adv Gastroenterol. 2013;6:269–93. doi: 10.1177/1756283x13479826.CrossRefGoogle Scholar
  7. 7.
    Cassinotti A, Travis S. Incidence and clinical significance of immunogenicity to infliximab in Crohn’s disease: a critical systematic review. Inflamm Bowel Dis. 2009;15:1264–75. doi: 10.1002/ibd.20899.CrossRefPubMedGoogle Scholar
  8. 8.
    Wang W, Wang EQ, Balthasar JP. Monoclonal antibody pharmacokinetics and pharmacodynamics. Clin Pharmacol Ther. 2008;84:548–58. doi: 10.1038/clpt.2008.170.CrossRefPubMedGoogle Scholar
  9. 9.
    Van Stappen T, Billiet T, Vande Casteele N, Compernolle G, Brouwers E, Vermeire S, et al. An optimized anti-infliximab bridging enzyme-linked immunosorbent assay for harmonization of anti-infliximab antibody titers in patients with inflammatory bowel diseases. Inflamm Bowel Dis. 2015;21:2172–7. doi: 10.1097/mib.0000000000000434.CrossRefPubMedGoogle Scholar
  10. 10.
    Vande Casteele N, Gils A. Pharmacokinetics of anti-TNF monoclonal antibodies in inflammatory bowel disease: adding value to current practice. J Clin Pharmacol. 2015;55:S39–50. doi: 10.1002/jcph.374.CrossRefPubMedGoogle Scholar
  11. 11.
    Nencini F, Pratesi S, Petroni G, Matucci A, Maggi E, Vultaggio A. Assays and strategies for immunogenicity assessment of biological agents. Drug Dev Res. 2014;75:S4–6. doi: 10.1002/ddr.21184.CrossRefPubMedGoogle Scholar
  12. 12.
    Van Stappen T, Brouwers E, Vermeire S, Gils A. Validation of a sample pretreatment protocol to convert a drug-sensitive into a drug-tolerant anti-infliximab antibody immunoassay. Drug test Anal. 2016. doi: 10.1002/dta.1968 (Epub ahead of print).
  13. 13.
    Ben-Horin S, Yavzori M, Katz L, Kopylov U, Picard O, Fudim E, 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. 2011;60:41–8. doi: 10.1136/gut.2009.201533.CrossRefPubMedGoogle Scholar
  14. 14.
    Afonso J, Lopes S, Goncalves R, Caldeira P, Lago P, Tavares de Sousa H, et al. Detection of anti-infliximab antibodies is impacted by antibody titer, infliximab level and IgG4 antibodies: a systematic comparison of three different assays. Ther Adv Gastroenterol. 2016;9:781–94. doi: 10.1177/1756283x16658223.CrossRefGoogle Scholar
  15. 15.
    Gils A, Vande Casteele N, Poppe R, Van de Wouwer M, Compernolle G, Peeters M, et al. Development of a universal anti-adalimumab antibody standard for interlaboratory harmonization. Ther Drug Monit. 2014;36:669–73. doi: 10.1097/ftd.0000000000000074.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Vande Casteele N, Khanna R, Levesque BG, Stitt L, Zou GY, Singh S, et al. The relationship between infliximab concentrations, antibodies to infliximab and disease activity in Crohn’s disease. Gut. 2015;64:1539–45. doi: 10.1136/gutjnl-2014-307883.CrossRefPubMedGoogle Scholar
  17. 17.
    Vande Casteele N, Buurman DJ, Sturkenboom MG, Kleibeuker JH, Vermeire S, Rispens T, et al. Detection of infliximab levels and anti-infliximab antibodies: a comparison of three different assays. Aliment Pharmacol Ther. 2012;36:765–71. doi: 10.1111/apt.12030.CrossRefPubMedGoogle Scholar
  18. 18.
    Afif W, Loftus EV Jr, Faubion WA, Kane SV, Bruining DH, Hanson KA, et al. Clinical utility of measuring infliximab and human anti-chimeric antibody concentrations in patients with inflammatory bowel disease. Am J Gastroenterol. 2010;105:1133–9. doi: 10.1038/ajg.2010.9.CrossRefPubMedGoogle Scholar
  19. 19.
    Baert F, Noman M, Vermeire S, Van Assche G, D’haens G, Carbonez A, et al. Influence of immunogenicity on the long-term efficacy of infliximab in Crohn’s disease. N Engl J Med. 2003;348:601–8. doi: 10.1056/NEJMoa020888.CrossRefPubMedGoogle Scholar
  20. 20.
    Hanauer SB, Feagan BG, Lichtenstein GR, Mayer LF, Schreiber S, Colombel JF, et al. Maintenance infliximab for Crohn’s disease: the ACCENT I randomised trial. Lancet. 2002;359:1541–9. doi: 10.1016/S0140-6736(02)08512-4.CrossRefPubMedGoogle Scholar
  21. 21.
    Rutgeerts P, Sandborn WJ, Feagan BG, Reinisch W, Olson A, Johanns J, et al. Infliximab for induction and maintenance therapy for ulcerative colitis. N Engl J Med. 2005;353:2462–76. doi: 10.1056/NEJMoa050516.CrossRefPubMedGoogle Scholar
  22. 22.
    Colombel JF, Sandborn WJ, Reinisch W, Mantzaris GJ, Kornbluth A, Rachmilewitz D, et al. Infliximab, azathioprine, or combination therapy for Crohn’s disease. N Engl J Med. 2010;362:1383–95. doi: 10.1056/NEJMoa0904492.CrossRefPubMedGoogle Scholar
  23. 23.
    Paul S, Moreau AC, Del Tedesco E, Rinaudo M, Phelip JM, Genin C, et al. Pharmacokinetics of adalimumab in inflammatory bowel diseases: a systematic review and meta-analysis. Inflamm Bowel Dis. 2014;20:1288–95. doi: 10.1097/MIB.0000000000000037.CrossRefPubMedGoogle Scholar
  24. 24.
    Matsumoto T, Motoya S, Watanabe K, Hisamatsu T, Nakase H, Yoshimura N, et al. Adalimumab monotherapy and a combination with azathioprine for Crohn’s disease: a prospective, randomized trial. J Crohns Colitis. 2016;10:1259–66. doi: 10.1093/ecco-jcc/jjw152.CrossRefPubMedGoogle Scholar
  25. 25.
    Bartelds GM, Wijbrandts CA, Nurmohamed MT, Stapel S, Lems WF, Aarden L, et al. Clinical response to adalimumab: relationship to anti-adalimumab antibodies and serum adalimumab concentrations in rheumatoid arthritis. Ann Rheum Dis. 2007;66:921–6. doi: 10.1136/ard.2006.065615.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Bartelds GM, Krieckaert CL, Nurmohamed MT, van Schouwenburg PA, Lems WF, Twisk JW, et al. Development of antidrug antibodies against adalimumab and association with disease activity and treatment failure during long-term follow-up. JAMA. 2011;305:1460–8. doi: 10.1001/jama.2011.406.CrossRefPubMedGoogle Scholar
  27. 27.
    van Schouwenburg PA, Bartelds GM, Hart MH, Aarden L, Wolbink GJ, Wouters D. 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. 2010;362:82–8. doi: 10.1016/j.jim.2010.09.005.CrossRefPubMedGoogle Scholar
  28. 28.
    Barnes T, Moots R. Targeting nanomedicines in the treatment of rheumatoid arthritis: focus on certolizumab pegol. Int J Nanomed. 2007;2:3–7.CrossRefGoogle Scholar
  29. 29.
    Lichtenstein GR, Thomsen OO, Schreiber S, Lawrance IC, Hanauer SB, Bloomfield R, et al. Continuous therapy with certolizumab pegol maintains remission of patients with Crohn’s disease for up to 18 months. Clin Gastroenterol Hepatol. 2010;8:600–9. doi: 10.1016/j.cgh.2010.01.014.CrossRefPubMedGoogle Scholar
  30. 30.
    Schreiber S, Khaliq-Kareemi M, Lawrance IC, Thomsen OO, Hanauer SB, McColm J, et al. Maintenance therapy with certolizumab pegol for Crohn’s disease. N Engl J Med. 2007;357:239–50. doi: 10.1056/NEJMoa062897.CrossRefPubMedGoogle Scholar
  31. 31.
    Schreiber S, Rutgeerts P, Fedorak RN, Khaliq-Kareemi M, Kamm MA, Boivin M, et al. A randomized, placebo-controlled trial of certolizumab pegol (CDP870) for treatment of Crohn’s disease. Gastroenterology. 2005;129:807–18. doi: 10.1053/j.gastro.2005.06.064.CrossRefPubMedGoogle Scholar
  32. 32.
    Sandborn WJ, Feagan BG, Stoinov S, Honiball PJ, Rutgeerts P, Mason D, et al. Certolizumab pegol for the treatment of Crohn’s disease. N Engl J Med. 2007;357:228–38. doi: 10.1056/NEJMoa067594.CrossRefPubMedGoogle Scholar
  33. 33.
    Sandborn WJ, Feagan BG, Marano C, Zhang H, Strauss R, Johanns J, et al. Subcutaneous golimumab maintains clinical response in patients with moderate-to-severe ulcerative colitis. Gastroenterology. 2014;146(96–109):e1. doi: 10.1053/j.gastro.2013.06.010.Google Scholar
  34. 34.
    Smolen JS, Kay J, Doyle MK, Landewe R, Matteson EL, Wollenhaupt J, et al. Golimumab in patients with active rheumatoid arthritis after treatment with tumour necrosis factor alpha inhibitors (GO-AFTER study): a multicentre, randomised, double-blind, placebo-controlled, phase III trial. Lancet. 2009;374:210–21. doi: 10.1016/s0140-6736(09)60506-7.CrossRefPubMedGoogle Scholar
  35. 35.
    Detrez I, Dreesen E, Van Stappen T, de Vries A, Brouwers E, Van Assche G, et al. Variability in golimumab exposure: a ‘real-life’ observational study in active ulcerative colitis. J Crohns Colitis. 2016;10:575–81. doi: 10.1093/ecco-jcc/jjv241.CrossRefPubMedGoogle Scholar
  36. 36.
    Thomas SS, Borazan N, Barroso N, Duan L, Taroumian S, Kretzmann B, et al. Comparative immunogenicity of TNF inhibitors: impact on clinical efficacy and tolerability in the management of autoimmune diseases. A systematic review and meta-analysis. BioDrugs. 2015;29:241–58. doi: 10.1007/s40259-015-0134-5.CrossRefPubMedGoogle Scholar
  37. 37.
    Baert F, Kondragunta V, Lockton S, Vande Casteele N, Hauenstein S, Singh S, et al. Antibodies to adalimumab are associated with future inflammation in Crohn’s patients receiving maintenance adalimumab therapy: a post hoc analysis of the Karmiris trial. Gut. 2016;65:1126–31. doi: 10.1136/gutjnl-2014-307882.CrossRefPubMedGoogle Scholar
  38. 38.
    Vermeire S, Noman M, Van Assche G, Baert F, D’Haens G, Rutgeerts P. Effectiveness of concomitant immunosuppressive therapy in suppressing the formation of antibodies to infliximab in Crohn’s disease. Gut. 2007;56:1226–31. doi: 10.1136/gut.2006.099978.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Goncalves J, Araujo F, Cutolo M, Fonseca JE. Biosimilar monoclonal antibodies: preclinical and clinical development aspects. Clin Exp Rheumatol. 2016;34:698–705.PubMedGoogle Scholar
  40. 40.
    Park W, Hrycaj P, Jeka S, Kovalenko V, Lysenko G, Miranda P, et al. A randomised, double-blind, multicentre, parallel-group, prospective study comparing the pharmacokinetics, safety, and efficacy of CT-P13 and innovator infliximab in patients with ankylosing spondylitis: the PLANETAS study. Ann Rheum Dis. 2013;72:1605–12. doi: 10.1136/annrheumdis-2012-203091.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Yoo DH, Hrycaj P, Miranda P, Ramiterre E, Piotrowski M, Shevchuk S, et al. A randomised, double-blind, parallel-group study to demonstrate equivalence in efficacy and safety of CT-P13 compared with innovator infliximab when coadministered with methotrexate in patients with active rheumatoid arthritis: the PLANETRA study. Ann Rheum Dis. 2013;72:1613–20. doi: 10.1136/annrheumdis-2012-203090.CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Ben-Horin S, Yavzori M, Benhar I, Fudim E, Picard O, Ungar B, et al. Cross-immunogenicity: antibodies to infliximab in Remicade-treated patients with IBD similarly recognise the biosimilar Remsima. Gut. 2015;65:1132–8. doi: 10.1136/gutjnl-2015-309290.CrossRefPubMedGoogle Scholar
  43. 43.
    Jørgensen KKOI, Goll GL, Lorentzen M, Bolstad N, Haavardsholm EA, Lundin KEA, Mørk C, Jahnsen J, Kvien TK. Biosimilar infliximab (CT-P13) is not inferior to originator infliximab: results from the 52-week randomized NOR-SWITCH trial. United Eur Gastroenterol J. 2016;2:S1.Google Scholar
  44. 44.
    Hyland E, Mant T, Vlachos P, Attkins N, Ullmann M, Roy S, et al. Comparison of the pharmacokinetics, safety, and immunogenicity of MSB11022, a biosimilar of adalimumab, with Humira((R)) in healthy subjects. Br J Clin Pharmacol. 2016;82:983–93. doi: 10.1111/bcp.13039.CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Wynne C, Altendorfer M, Sonderegger I, Gheyle L, Ellis-Pegler R, Buschke S, et al. Bioequivalence, safety and immunogenicity of BI 695501, an adalimumab biosimilar candidate, compared with the reference biologic in a randomized, double-blind, active comparator phase I clinical study (VOLTAIRE(R)-PK) in healthy subjects. Expert Opin Investig Drugs. 2016;25:1361–70. doi: 10.1080/13543784.2016.1255724.CrossRefPubMedGoogle Scholar
  46. 46.
    Kaur P, Chow V, Zhang N, Moxness M, Kaliyaperumal A, Markus R. A randomised, single-blind, single-dose, three-arm, parallel-group study in healthy subjects to demonstrate pharmacokinetic equivalence of ABP 501 and adalimumab. Ann Rheum Dis. 2016. doi: 10.1136/annrheumdis-2015-208914 (Epub ahead of print).
  47. 47.
    Sandborn WJ, Colombel JF, Enns R, Feagan BG, Hanauer SB, Lawrance IC, et al. Natalizumab induction and maintenance therapy for Crohn’s disease. N Engl J Med. 2005;353:1912–25. doi: 10.1056/NEJMoa043335.CrossRefPubMedGoogle Scholar
  48. 48.
    Feagan BG, Rutgeerts P, Sands BE, Hanauer S, Colombel JF, Sandborn WJ, et al. Vedolizumab as induction and maintenance therapy for ulcerative colitis. N Engl J Med. 2013;369:699–710. doi: 10.1056/NEJMoa1215734.CrossRefPubMedGoogle Scholar
  49. 49.
    Sandborn WJ, Feagan BG, Rutgeerts P, Hanauer S, Colombel JF, Sands BE, et al. Vedolizumab as induction and maintenance therapy for Crohn’s disease. N Engl J Med. 2013;369:711–21. doi: 10.1056/NEJMoa1215739.CrossRefPubMedGoogle Scholar
  50. 50.
    Colombel JF, Sands BE, Rutgeerts P, Sandborn W, Danese S, D’Haens G, et al. The safety of vedolizumab for ulcerative colitis and Crohn’s disease. Gut. 2016. doi: 10.1136/gutjnl-2015-311079 (Epub ahead of print).
  51. 51.
    Loftus EV Jr, Colombel JF, Feagan BG, Vermeire S, Sandborn WJ, Sands BE, et al. Long-term efficacy of vedolizumab for ulcerative colitis. J Crohns Colitis. 2016. doi: 10.1093/ecco-jcc/jjw177 (Epub ahead of print).
  52. 52.
    Vermeire S, Loftus EV Jr, Colombel JF, Feagan BG, Sandborn WJ, Sands BE, et al. Long-term efficacy of vedolizumab for Crohn’s disease. J Crohns Colitis. 2016. doi: 10.1093/ecco-jcc/jjw176 (Epub ahead of print).
  53. 53.
    Sandborn WJ, Gasink C, Gao LL, Blank MA, Johanns J, Guzzo C, et al. Ustekinumab induction and maintenance therapy in refractory Crohn’s disease. N Engl J Med. 2012;367:1519–28. doi: 10.1056/NEJMoa1203572.CrossRefPubMedGoogle Scholar
  54. 54.
    Feagan BG, Sandborn WJ, Gasink C, Jacobstein D, Lang Y, Friedman JR, et al. Ustekinumab as induction and maintenance therapy for Crohn’s disease. N Engl J Med. 2016;375:1946–60. doi: 10.1056/NEJMoa1602773.CrossRefPubMedGoogle Scholar
  55. 55.
    Leonardi CL, Kimball AB, Papp KA, Yeilding N, Guzzo C, Wang Y, et al. Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 76-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 1). Lancet. 2008;371:1665–74. doi: 10.1016/s0140-6736(08)60725-4.CrossRefPubMedGoogle Scholar
  56. 56.
    Papp KA, Langley RG, Lebwohl M, Krueger GG, Szapary P, Yeilding N, et al. Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 52-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 2). Lancet. 2008;371:1675–84. doi: 10.1016/s0140-6736(08)60726-6.CrossRefPubMedGoogle Scholar
  57. 57.
    Hsu L, Snodgrass BT, Armstrong AW. Antidrug antibodies in psoriasis: a systematic review. Br J Dermatol. 2014;170:261–73. doi: 10.1111/bjd.12654.CrossRefPubMedGoogle Scholar
  58. 58.
    Farrell RJ, Alsahli M, Jeen YT, Falchuk KR, Peppercorn MA, Michetti P. Intravenous hydrocortisone premedication reduces antibodies to infliximab in Crohn’s disease: a randomized controlled trial. Gastroenterology. 2003;124:917–24. doi: 10.1053/gast.2003.50145.CrossRefPubMedGoogle Scholar
  59. 59.
    Nanda KS, Cheifetz AS, Moss AC. Impact of antibodies to infliximab on clinical outcomes and serum infliximab levels in patients with inflammatory bowel disease (IBD): a meta-analysis. Am J Gastroenterol. 2013;108:40–7. doi: 10.1038/ajg.2012.363 (quiz 8).
  60. 60.
    O’Meara S, Nanda KS, Moss AC. Antibodies to infliximab and risk of infusion reactions in patients with inflammatory bowel disease: a systematic review and meta-analysis. Inflamm Bowel Dis. 2014;20:1–6. doi: 10.1097/01.MIB.0000436951.80898.6d.CrossRefPubMedGoogle Scholar
  61. 61.
    Feuerstein JD, Cullen G, Cheifetz AS. Immune-mediated reactions to anti-tumor necrosis factors in inflammatory bowel disease. Inflamm Bowel Dis. 2015;21:1176–86. doi: 10.1097/mib.0000000000000279.CrossRefPubMedGoogle Scholar
  62. 62.
    Felice C, Marzo M, Pugliese D, Papa A, Rapaccini GL, Guidi L, et al. Therapeutic drug monitoring of anti-TNF-alpha agents in inflammatory bowel diseases. Expert Opin Biol Ther. 2015;15:1107–17. doi: 10.1517/14712598.2015.1044434.CrossRefPubMedGoogle Scholar
  63. 63.
    Vande Casteele N, Gils A, Singh S, Ohrmund L, Hauenstein S, Rutgeerts P, et al. Antibody response to infliximab and its impact on pharmacokinetics can be transient. Am J Gastroenterol. 2013;108:962–71. doi: 10.1038/ajg.2013.12.CrossRefPubMedGoogle Scholar
  64. 64.
    Steenholdt C, Frederiksen MT, Bendtzen K, Ainsworth MA, Thomsen OO, Brynskov J. Time course and clinical implications of development of antibodies against adalimumab in patients with inflammatory bowel disease. J Clin Gastroenterol. 2016;50:483–9. doi: 10.1097/mcg.0000000000000375.CrossRefPubMedGoogle Scholar
  65. 65.
    Paul S, Dronne W, Roblin X. Kinetics of antibodies against adalimumab are not associated with poor outcomes in IBD. Am J Gastroenterol. 2015;110:777–8. doi: 10.1038/ajg.2015.79.CrossRefPubMedGoogle Scholar
  66. 66.
    Bendtzen K. Immunogenicity of anti-TNF-alpha biotherapies: II. Clinical relevance of methods used for anti-drug antibody detection. Front Immunol. 2015;6:109. doi: 10.3389/fimmu.2015.00109.
  67. 67.
    van Schouwenburg PA, van de Stadt LA, de Jong RN, van Buren EE, Kruithof S, de Groot E, et al. Adalimumab elicits a restricted anti-idiotypic antibody response in autoimmune patients resulting in functional neutralisation. Ann Rheum Dis. 2013;72:104–9. doi: 10.1136/annrheumdis-2012-201445.CrossRefPubMedGoogle Scholar
  68. 68.
    Vande Casteele N, Mould D, Kosutic G, Spearman M, Feagan B, Sandborn W. Refinement of population pharmacokinetic model of certolizumab pegol in Crohn’s disease patients to account for time varying nature of covariates. Inflamm Bowel Dis. 2016;22:P103.Google Scholar
  69. 69.
    Vande Casteele N, Stitt L, Spearman M, Kosutic G, Oliver R, Coarse J, et al. Effect of using a composite endpoint on placebo response and certolizumab pegol exposure-efficacy relationship: a post-hoc analysis from the PRECiSE1 and 2 studies. Gastroenterology. 2016;150:S409–10.Google Scholar
  70. 70.
    Vande Casteele N, Stitt L, Spearman M, Kosutic G, Oliver R, Coarse J, et al. Exposure-response relationship for certolizumab pegol during the induction phase in patients with Crohn’s disease. Gastroenterology. 2016;150:S409.Google Scholar
  71. 71.
    Neu KE, Wilson PC. Taking the broad view on B cell affinity maturation. Immunity. 2016;44:518–20. doi: 10.1016/j.immuni.2016.03.001.CrossRefPubMedGoogle Scholar
  72. 72.
    Victora GD, Nussenzweig MC. Germinal centers. Annu Rev Immunol. 2012;30:429–57. doi: 10.1146/annurev-immunol-020711-075032.CrossRefPubMedGoogle Scholar
  73. 73.
    van Schouwenburg PA, Kruithof S, Votsmeier C, van Schie K, Hart MH, de Jong RN, et al. Functional analysis of the anti-adalimumab response using patient-derived monoclonal antibodies. J Biol Chem. 2014;289:34482–8. doi: 10.1074/jbc.M114.615500.CrossRefPubMedPubMedCentralGoogle Scholar
  74. 74.
    Kosmac M, Avcin T, Toplak N, Simonini G, Cimaz R, Curin Serbec V. Exploring the binding sites of anti-infliximab antibodies in pediatric patients with rheumatic diseases treated with infliximab. Pediatr Res. 2011;69:243–8. doi: 10.1203/PDR.0b013e318208451d.CrossRefPubMedGoogle Scholar
  75. 75.
    Vultaggio A, Matucci A, Nencini F, Pratesi S, Parronchi P, Rossi O, et al. Anti-infliximab IgE and non-IgE antibodies and induction of infusion-related severe anaphylactic reactions. Allergy. 2010;65:657–61. doi: 10.1111/j.1398-9995.2009.02280.x.CrossRefPubMedGoogle Scholar
  76. 76.
    Puxeddu I, Caltran E, Rocchi V, Del Corso I, Tavoni A, Migliorini P. Hypersensitivity reactions during treatment with biological agents. Clin Exp Rheumatol. 2016;34:129–32.PubMedGoogle Scholar
  77. 77.
    Krishna M, Nadler SG. Immunogenicity to biotherapeutics—the role of anti-drug immune complexes. Front Immunol. 2016;7:21. doi: 10.3389/fimmu.2016.00021.CrossRefPubMedPubMedCentralGoogle Scholar
  78. 78.
    Burnet and Medawar Share Nobel Award in physiology and medicine. Science (New York, NY). 1960;132:1300–4. doi: 10.1126/science.132.3436.1300.
  79. 79.
    Clark M. Antibody humanization: a case of the ‘Emperor’s new clothes’? Immunol Today. 2000;21:397–402.CrossRefPubMedGoogle Scholar
  80. 80.
    Miller LL, Korn EL, Stevens DS, Janik JE, Gause BL, Kopp WC, et al. Abrogation of the hematological and biological activities of the interleukin-3/granulocyte-macrophage colony-stimulating factor fusion protein PIXY321 by neutralizing anti-PIXY321 antibodies in cancer patients receiving high-dose carboplatin. Blood. 1999;93:3250–8.PubMedGoogle Scholar
  81. 81.
    Ottesen JLNP, Jami J, et al. The potential immunogenicity of human insulin and insulin analogues evaluated in a transgenic mouse model. Diabetologia. 1994;37:1178–85.CrossRefPubMedGoogle Scholar
  82. 82.
    Giovannoni G. Strategies to treat and prevent the development of neutralizing anti-interferon-β antibodies. Neurology. 2003;61:S13–7.CrossRefPubMedGoogle Scholar
  83. 83.
    Billiet T, Vande Casteele N, Van Stappen T, Princen F, Singh S, Gils A, et al. Immunogenicity to infliximab is associated with HLA-DRB1. Gut. 2015;64:1344–5. doi: 10.1136/gutjnl-2015-309698.CrossRefPubMedGoogle Scholar
  84. 84.
    Bartelds GM, de Groot E, Nurmohamed MT, Hart MH, van Eede PH, Wijbrandts CA, et al. Surprising negative association between IgG1 allotype disparity and anti-adalimumab formation: a cohort study. Arthritis Res Ther. 2010;12:R221. doi: 10.1186/ar3208.CrossRefPubMedPubMedCentralGoogle Scholar
  85. 85.
    Ternant D, Arnoult C, Pugniere M, Dhommee C, Drocourt D, Perouzel E, et al. IgG1 allotypes influence the pharmacokinetics of therapeutic monoclonal antibodies through FcRn binding. J Immunol (Baltimore, Md: 1950). 2016;196:607–13. doi: 10.4049/jimmunol.1501780.
  86. 86.
    Ragnhammar P, Friesen HJ, Frodin JE, Lefvert AK, Hassan M, Osterborg A, et al. Induction of anti-recombinant human granulocyte-macrophage colony-stimulating factor (Escherichia coli-derived) antibodies and clinical effects in nonimmunocompromised patients. Blood. 1994;84:4078–87.PubMedGoogle Scholar
  87. 87.
    Ha C, Mathur J, Kornbluth A. Anti-TNF levels and anti-drug antibodies, immunosuppressants and clinical outcomes in inflammatory bowel disease. Expert Rev Gastroenterol Hepatol. 2015;9:497–505. doi: 10.1586/17474124.2015.983079.CrossRefPubMedGoogle Scholar
  88. 88.
    LeMaoult J, Szabo P, Weksler ME. Effect of age on humoral immunity, selection of the B-cell repertoire and B-cell development. Immunol Rev. 1997;160:115–26.CrossRefPubMedGoogle Scholar
  89. 89.
    van der Laken CJ, Voskuyl AE, Roos JC, Stigter van Walsum M, de Groot ER, Wolbink G, 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. 2007;66:253–6. doi: 10.1136/ard.2006.057406.
  90. 90.
    Schellekens H. Factors influencing the immunogenicity of therapeutic proteins. Nephrol Dial Transplant. 2005;20:vi3–9. doi: 10.1093/ndt/gfh1092.
  91. 91.
    U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research (CBER). Guidance for industry: Immunogenicity assessment for therapeutic protein products. http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm338856.pdf.
  92. 92.
    Wei X, Decker JM, Wang S, Hui H, Kappes JC, Wu X, et al. Antibody neutralization and escape by HIV-1. Nature. 2003;422:307–12. doi: 10.1038/nature01470.CrossRefPubMedGoogle Scholar
  93. 93.
    Harris JM, Martin NE, Modi M. Pegylation: a novel process for modifying pharmacokinetics. Clin Pharmacokinet. 2001;40:539–51. doi: 10.2165/00003088-200140070-00005.CrossRefPubMedGoogle Scholar
  94. 94.
    Schellekens H, Hennink WE, Brinks V. The immunogenicity of polyethylene glycol: facts and fiction. Pharm Res. 2013;30:1729–34. doi: 10.1007/s11095-013-1067-7.CrossRefPubMedGoogle Scholar
  95. 95.
    Rutgeerts P, Feagan BG, Lichtenstein GR, Mayer LF, Schreiber S, Colombel JF, et al. Comparison of scheduled and episodic treatment strategies of infliximab in Crohn’s disease. Gastroenterology. 2004;126:402–13.CrossRefPubMedGoogle Scholar
  96. 96.
    Rutgeerts P, Diamond RH, Bala M, Olson A, Lichtenstein GR, Bao W, et al. Scheduled maintenance treatment with infliximab is superior to episodic treatment for the healing of mucosal ulceration associated with Crohn’s disease. Gastrointest endosc. 2006;63:433–42. doi: 10.1016/j.gie.2005.08.011 (quiz 64).
  97. 97.
    Panaccione R, Ghosh S, Middleton S, Marquez JR, Scott BB, Flint L, et al. Combination therapy with infliximab and azathioprine is superior to monotherapy with either agent in ulcerative colitis. Gastroenterology. 2014;146(392–400):e3. doi: 10.1053/j.gastro.2013.10.052.Google Scholar
  98. 98.
    Feagan BG, McDonald JW, Panaccione R, Enns RA, Bernstein CN, Ponich TP, et al. Methotrexate in combination with infliximab is no more effective than infliximab alone in patients with Crohn’s disease. Gastroenterology. 2014;146(681–8):e1. doi: 10.1053/j.gastro.2013.11.024.Google Scholar
  99. 99.
    Farhangian ME, Feldman SR. Immunogenicity of biologic treatments for psoriasis: therapeutic consequences and the potential value of concomitant methotrexate. Am J Clin Dermatol. 2015;16:285–94. doi: 10.1007/s40257-015-0131-y.CrossRefPubMedGoogle Scholar
  100. 100.
    Rosario M, Fox I, Milch C, Parikh A, Feagan B, Sandborn W, et al. Pharmacokinetic/pharmacodynamic relationship and immunogenicity of vedolizumab in adults with inflammatory bowel disease: additional results from GEMINI 1 and 2. Inflamm Bowel Dis. 2013;19:S80.CrossRefGoogle Scholar
  101. 101.
    Kavanaugh A, Puig L, Gottlieb AB, Ritchlin C, You Y, Li S, et al. Efficacy and safety of ustekinumab in psoriatic arthritis patients with peripheral arthritis and physician-reported spondylitis: post-hoc analyses from two phase III, multicentre, double-blind, placebo-controlled studies (PSUMMIT-1/PSUMMIT-2). Ann Rheum Dis. 2016;75:1984–8. doi: 10.1136/annrheumdis-2015-209068.CrossRefPubMedGoogle Scholar
  102. 102.
    Hanauer SB, Wagner CL, Bala M, Mayer L, Travers S, Diamond RH, et al. Incidence and importance of antibody responses to infliximab after maintenance or episodic treatment in Crohn’s disease. Clin Gastroenterol Hepatol. 2004;2:542–53.CrossRefPubMedGoogle Scholar
  103. 103.
    Segal S, Tzehoval E, Feldman M. Immunological tolerance: high-dose antigen-induced suppressor cells from tolerant animals inactivate antigen-presenting macrophages. Proc Natl Acad Sci. 1979;76:2405–9.CrossRefPubMedPubMedCentralGoogle Scholar
  104. 104.
    Vande Casteele N, Ferrante M, Van Assche G, Ballet V, Compernolle G, Van Steen K, et al. Trough concentrations of infliximab guide dosing for patients with inflammatory bowel disease. Gastroenterology. 2015;148:1320–9. doi: 10.1053/j.gastro.2015.02.031.CrossRefPubMedGoogle Scholar
  105. 105.
    Berns M, Hommes DW. Anti-TNF-alpha therapies for the treatment of Crohn’s disease: the past, present and future. Expert Opin Investig Drugs. 2016;25:129–43. doi: 10.1517/13543784.2016.1126247.CrossRefPubMedGoogle Scholar
  106. 106.
    Vandepapeliere P, Rogler G, van der Bijl A, Kruger FC, Kruger D, Grouard-Vogel G, et al. Phase I-II safety, immunogenicity and clinical results of TNFα-kinoid immunotherapeutic immunization in Crohn’s disease patients. J Crohns Colitis. 2011;5:OP009.Google Scholar
  107. 107.
    Harris MS, Hartman D, Lemos BR, Erlich EC, Spence S, Kennedy S, et al. AVX-470, an orally delivered anti-tumour necrosis factor antibody for treatment of active ulcerative colitis: results of a first-in-human trial. J Crohns Colitis. 2016;10:631–40. doi: 10.1093/ecco-jcc/jjw036.CrossRefPubMedGoogle Scholar
  108. 108.
    Velayos FS, Kahn JG, Sandborn WJ, Feagan BG. A test-based strategy is more cost effective than empiric dose escalation for patients with Crohn’s disease who lose responsiveness to infliximab. Clin Gastroenterol Hepatol. 2013;11:654–66. doi: 10.1016/j.cgh.2012.12.035.CrossRefPubMedGoogle Scholar
  109. 109.
    Steenholdt C, Brynskov J, Thomsen OO, Munck LK, Fallingborg J, Christensen LA, et al. Individualised therapy is more cost-effective than dose intensification in patients with Crohn’s disease who lose response to anti-TNF treatment: a randomised, controlled trial. Gut. 2014;63:919–27. doi: 10.1136/gutjnl-2013-305279.CrossRefPubMedGoogle Scholar
  110. 110.
    Roda G, Jharap B, Neeraj N, Colombel JF. Loss of response to anti-TNFs: definition, epidemiology, and management. Clin Transl Gastroenterol. 2016;7:e135. doi: 10.1038/ctg.2015.63.CrossRefPubMedPubMedCentralGoogle Scholar
  111. 111.
    Katz L, Gisbert JP, Manoogian B, Lin K, Steenholdt C, Mantzaris GJ, et al. Doubling the infliximab dose versus halving the infusion intervals in Crohn’s disease patients with loss of response. Inflamm Bowel Dis. 2012;18:2026–33. doi: 10.1002/ibd.22902.CrossRefPubMedGoogle Scholar
  112. 112.
    Ben-Horin S, Waterman M, Kopylov U, Yavzori M, Picard O, Fudim E, et al. Addition of an immunomodulator to infliximab therapy eliminates antidrug antibodies in serum and restores clinical response of patients with inflammatory bowel disease. Clin Gastroenterol Hepatol. 2013;11:444–7. doi: 10.1016/j.cgh.2012.10.020.CrossRefPubMedGoogle Scholar
  113. 113.
    Ong DE, Kamm MA, Hartono JL, Lust M. Addition of thiopurines can recapture response in patients with Crohn’s disease who have lost response to anti-tumor necrosis factor monotherapy. J Gastroenterol Hepatol. 2013;28:1595–9. doi: 10.1111/jgh.12263.PubMedGoogle Scholar
  114. 114.
    Yanai H, Lichtenstein L, Assa A, Mazor Y, Weiss B, Levine A, et al. Levels of drug and antidrug antibodies are associated with outcome of interventions after loss of response to infliximab or adalimumab. Clin Gastroenterol Hepatol. 2015;13(522–30):e2. doi: 10.1016/j.cgh.2014.07.029.Google Scholar
  115. 115.
    Yarur AJ, Jain A, Sussman DA, Barkin JS, Quintero MA, Princen F, et al. The association of tissue anti-TNF drug levels with serological and endoscopic disease activity in inflammatory bowel disease: the ATLAS study. Gut. 2016;65(2):249–55. doi: 10.1136/gutjnl-2014-308099.CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2017

Authors and Affiliations

  • Pieter Hindryckx
    • 1
    • 2
  • Gregor Novak
    • 1
    • 3
  • Niels Vande Casteele
    • 1
    • 4
  • Reena Khanna
    • 1
    • 5
  • Debby Laukens
    • 2
  • Jairath Vipul
    • 1
    • 5
    • 6
  • Brian G. Feagan
    • 1
    • 5
    • 6
    Email author
  1. 1.Robarts Clinical TrialsUniversity of Western OntarioLondonCanada
  2. 2.Department of GastroenterologyUniversity of GhentGhentBelgium
  3. 3.Department of GastroenterologyLjubljana University Medical CentreLjubljanaSlovenia
  4. 4.Department of MedicineUniversity of California San DiegoLa JollaUSA
  5. 5.Department of MedicineUniversity of Western OntarioLondonCanada
  6. 6.Department of Epidemiology and BiostatisticsUniversity of Western OntarioLondonCanada

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