Skip to main content

Advertisement

SpringerLink
Log in

Current Considerations for Immunoglobulin Isotype Characterization of Antibody Response against Biotherapeutics

  • Review Article
  • Published:
The AAPS Journal Aims and scope Submit manuscript

Abstract

The ability of biotherapeutics to induce immune response in patients has been broadly accepted. Humoral immune response to biotherapeutics is expected to be polyclonal in nature with a high degree of diversity, including treatment-induced anti-drug antibodies (ADA) immunoglobulin isotype composition. Therapeutics with strong potential to induce immunity may produce a T cell–dependent response resulting in a gradual transition from initial IgM based to mature, IgG-based ADAs. Immunoglobulin class switch and transition to high affinity IgG1 and IgG4 antibodies were linked to a reduced drug efficacy, accelerated clearance, development of drug neutralizing antibodies, and modulation of hypersensitivity reaction rates. Examples presented herein demonstrate that understanding of isotype composition of ADA response can be highly important to predict future of disease progression. Isotype characterization of ADA response can be viewed highly useful, particularly for high immunogenicity risk biotherapeutics although may be less relevant or used as a research tool only for medium and low immunogenicity risk level therapeutics. Isotype-specific characteristics, methods of detection, and several case studies are presented herein.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Schouwenburg PA, Rispens T, Wolbink GJ. Immunogenicity of anti-TNF biologic therapies for rheumatoid arthritis. Nat Rev Rheumatol. 2013;9(3):164–72.

    Article  Google Scholar 

  2. FDA. Immunogenicity testing of therapeutic protein products —developing and validating assays for anti-drug antibody detection. Guidance for Industry. 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). 2019 [cited 2019 July]; Available from: https://www.fda.gov/media/119788/download. Accessed 5 Nov 2020.

  3. EMA. Guideline on immunogenicity assessment of therapeutic proteins European Medicines Agency, EMA; 2017 [cited 2019]; [Available from: https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-immunogenicity-assessment-therapeutic-proteins-revision-1_en.pdf. Accessed 5 Nov 2020.

  4. Koren E, Smith HW, Shores E, Shankar G, Finco-Kent D, Rup B, et al. Recommendations on risk-based strategies for detection and characterization of antibodies against biotechnology products. J Immunol Methods. 2008;333(1–2):1–9. https://doi.org/10.1016/j.jim.2008.01.001.

    Article  CAS  PubMed  Google Scholar 

  5. Shankar G, Pendley C, Stein K. A risk-based bioanalytical strategy for the assessment of antibody immune responses against biological drugs. Nat Biotechnol. 2007;25(5):555–61. https://doi.org/10.1038/nbt1303.

    Article  CAS  PubMed  Google Scholar 

  6. Mohamed M, Abu Lila AS, Shimizu T, Alaaeldin E, Hussein A, Sarhan HA, et al. PEGylated liposomes: immunological responses. Sci Technol Adv Mater. 2019;20(1):710–24. https://doi.org/10.1080/14686996.2019.1627174.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. MacLennan IC, Toellner KM, Cunningham AF, Serre K, Sze DM, Zúñiga E, et al. Extrafollicular antibody responses. Immunol Rev. 2003;194:8–18. https://doi.org/10.1034/j.1600-065x.2003.00058.x.

    Article  CAS  PubMed  Google Scholar 

  8. Rosenberg AS. Immunogenicity of biological therapeutics: a hierarchy of concerns. Dev Biol. 2003;112:15–21.

    CAS  Google Scholar 

  9. Rosenberg AS, Worobec A. A risk-based approach to immunogenicity concerns of therapeutic protein products—part 1—considering consequences of the immune response to a protein. Biopharm Int. 2004;17:22–6.

    Google Scholar 

  10. Tatarewicz SM, Wei X, Gupta S, Masterman D, Swanson SJ, Moxness MS. Development of a maturing T-cell-mediated immune response in patients with idiopathic Parkinson's disease receiving r-metHuGDNF via continuous intraputaminal infusion. J Clin Immunol. 2007;27(6):620–7. https://doi.org/10.1007/s10875-007-9117-8.

    Article  PubMed  Google Scholar 

  11. Siegrist C-A. Vaccine Immunology. In: Plotkin S, Orenstein W, Offit P, Edwards KM (Eds), In Plotkin’s Vaccines. 7th Edition. Elsevier; 2017. p. 1720

  12. Schroeder HW Jr, Cavacini L. Structure and function of immunoglobulins. J Allergy Clin Immunol. 2010;125(2 Suppl 2):S41–52. https://doi.org/10.1016/j.jaci.2009.09.046.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Jönsson F, de Chaisemartin L, Granger V, Gouel-Chéron A, Gillis CM, Zhu Q, et al. An IgG-induced neutrophil activation pathway contributes to human drug-induced anaphylaxis. Sci Transl Med. 2019;11(500):eaat1479. https://doi.org/10.1126/scitranslmed.aat1479.

    Article  CAS  PubMed  Google Scholar 

  14. Jiao D, Liu Y, Lu X, Liu B, Pan Q, Liu Y, et al. Macrophages are the dominant effector cells responsible for IgG-mediated passive systemic anaphylaxis challenged by natural protein antigen in BALB/c and C57BL/6 mice. Cell Immunol. 2014;289(1–2):97–105. https://doi.org/10.1016/j.cellimm.2014.03.018.

    Article  CAS  PubMed  Google Scholar 

  15. Chorny A, Puga I, Cerutti A. Chapter 2 - Innate signaling networks in mucosal IgA class switching. In: Fagarasan S, Cerutti A, editors. Advances in Immunology: Academic Press; 2010. p. 31–69.

  16. Khan F, Chang C. Chapter 11 - human autoantibodies in Urticaria, angioedema, and other atopic diseases. In: Shoenfeld Y, Meroni PL, Gershwin ME, editors. Autoantibodies. Third ed. San Diego: Elsevier; 2014. p. 93–101.

    Chapter  Google Scholar 

  17. Wills-Karp M. Complement activation pathways: a bridge between innate and adaptive immune responses in asthma. Proc Am Thorac Soc. 2007;4(3):247–51. https://doi.org/10.1513/pats.200704-046AW.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Vidarsson G, Dekkers G, Rispens T. IgG subclasses and allotypes: from structure to effector functions. Front Immunol. 2014;5:520. https://doi.org/10.3389/fimmu.2014.00520.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Michaelsen TE, Garred P, Aase A. Human IgG subclass pattern of inducing complement-mediated cytolysis depends on antigen concentration and to a lesser extent on epitope patchiness, antibody affinity and complement concentration. Eur J Immunol. 1991;21(1):11–6. https://doi.org/10.1002/eji.1830210103.

    Article  CAS  PubMed  Google Scholar 

  20. Burton DR, Gregory L, Jefferis R. Aspects of the molecular structure of IgG subclasses. Monogr Allergy. 1986;19:7–35.

    CAS  PubMed  Google Scholar 

  21. Nezlin R. CHAPTER 1 - general characteristics of immunoglobulin molecules. In: Nezlin R, editor. The Immunoglobulins. New York: Academic Press; 1998. p. 3–73.

    Chapter  Google Scholar 

  22. Bindon CI, Hale G, Brüggemann M, Waldmann H. Human monoclonal IgG isotypes differ in complement activating function at the level of C4 as well as C1q. J Exp Med. 1988;168(1):127–42. https://doi.org/10.1084/jem.168.1.127.

    Article  CAS  PubMed  Google Scholar 

  23. Sarma JV, Ward PA. The complement system. Cell Tissue Res. 2011;343(1):227–35. https://doi.org/10.1007/s00441-010-1034-0.

    Article  CAS  PubMed  Google Scholar 

  24. Tao MH, Smith RI, Morrison SL. Structural features of human immunoglobulin G that determine isotype-specific differences in complement activation. J Exp Med. 1993;178(2):661–7. https://doi.org/10.1084/jem.178.2.661.

    Article  CAS  PubMed  Google Scholar 

  25. Aalberse RC, Stapel SO, Schuurman J, Rispens T. Immunoglobulin G4: an odd antibody. Clin Exp Allergy. 2009;39(4):469–77. https://doi.org/10.1111/j.1365-2222.2009.03207.x.

    Article  CAS  PubMed  Google Scholar 

  26. van der Neut KM, Schuurman J, Losen M, Bleeker WK, Martinez-Martinez P, Vermeulen E, et al. Anti-inflammatory activity of human IgG4 antibodies by dynamic fab arm exchange. Science. 2007;317(5844):1554–7.

    Article  Google Scholar 

  27. Labrijn AF, Rispens T, Meesters J, Rose RJ, den Bleker TH, Loverix S, et al. Species-specific determinants in the IgG CH3 domain enable fab-arm exchange by affecting the noncovalent CH3-CH3 interaction strength. J Immunol. 2011;187(6):3238–46. https://doi.org/10.4049/jimmunol.1003336.

    Article  CAS  PubMed  Google Scholar 

  28. Rispens T, Davies AM, Ooijevaar-de Heer P, Absalah S, Bende O, Sutton BJ, et al. Dynamics of inter-heavy chain interactions in human immunoglobulin G (IgG) subclasses studied by kinetic Fab arm exchange. J Biol Chem. 2014;289(9):6098–109. https://doi.org/10.1074/jbc.M113.541813.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Zola H, Garland LG, Cox HC, Adcock JJ. Separation of IgE from IgG subclasses using staphylococcal protein a. Int Arch Allergy Appl Immunol. 1978;56(2):123–7. https://doi.org/10.1159/000232014.

    Article  CAS  PubMed  Google Scholar 

  30. van der Zee JS, van Swieten P, Aalberse RC. Inhibition of complement activation by IgG4 antibodies. Clin Exp Immunol. 1986;64(2):415–22.

    PubMed  PubMed Central  Google Scholar 

  31. 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(14):1460–8. https://doi.org/10.1001/jama.2011.406.

    Article  CAS  PubMed  Google Scholar 

  32. Hofbauer CJ, Whelan SF, Hirschler M, Allacher P, Horling FM, Lawo JP, et al. Affinity of FVIII-specific antibodies reveals major differences between neutralizing and nonneutralizing antibodies in humans. Blood. 2015;125(7):1180–8. https://doi.org/10.1182/blood-2014-09-598268.

    Article  CAS  PubMed  Google Scholar 

  33. van Schouwenburg PA, Krieckaert CL, Nurmohamed M, Hart M, Rispens T, Aarden L, et al. IgG4 production against adalimumab during long term treatment of RA patients. J Clin Immunol. 2012;32(5):1000–6. https://doi.org/10.1007/s10875-012-9705-0.

    Article  CAS  PubMed  Google Scholar 

  34. Baker MP, Reynolds HM, Lumicisi B, Bryson CJ. Immunogenicity of protein therapeutics: the key causes, consequences and challenges. Self/nonself. 2010;1(4):314–22. https://doi.org/10.4161/self.1.4.13904.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Jefferis R, Jefferis R. Antibody therapeutics: isotype and glycoform selection. Expert Opin Biol Ther. 2007;7(9):1401–13.

    Article  CAS  Google Scholar 

  36. Sethu S, Govindappa K, Quinn P, Wadhwa M, Stebbings R, Boggild M, et al. Immunoglobulin G1 and immunoglobulin G4 antibodies in multiple sclerosis patients treated with IFNβ interact with the endogenous cytokine and activate complement. Clin Immunol. 2013;148(2):177–85. https://doi.org/10.1016/j.clim.2013.05.008.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. von Wussow P, Jakschies D, Freund M, Deicher H. Humoral response to recombinant interferon-alpha 2b in patients receiving recombinant interferon-alpha 2b therapy. J Interf Res. 1989;9(Suppl 1):S25–31.

    Google Scholar 

  38. Reding MT, Lei S, Lei H, Green D, Gill J, Conti-Fine BM. Distribution of Th1- and Th2-induced anti-factor VIII IgG subclasses in congenital and acquired hemophilia patients. Thromb Haemost. 2002;88(4):568–75.

    CAS  PubMed  Google Scholar 

  39. 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(5):657–61. https://doi.org/10.1111/j.1398-9995.2009.02280.x.

    Article  CAS  PubMed  Google Scholar 

  40. Leach MW, Rottman JB, Hock MB, Finco D, Rojko JL, Beyer JC. Immunogenicity/hypersensitivity of biologics. Toxicol Pathol. 2014;42(1):293–300. https://doi.org/10.1177/0192623313510987.

    Article  CAS  PubMed  Google Scholar 

  41. Vultaggio A, Nencini F, Pratesi S, Petroni G, Maggi E, Matucci A. Manifestations of antidrug antibodies response: hypersensitivity and infusion reactions. J Interf Cytokine Res. 2014;34(12):946–52. https://doi.org/10.1089/jir.2012.0139.

    Article  CAS  Google Scholar 

  42. Kantor AB, Herzenberg LA. Origin of murine B cell lineages. Annu Rev Immunol. 1993;11:501–38. https://doi.org/10.1146/annurev.iy.11.040193.002441.

    Article  CAS  PubMed  Google Scholar 

  43. Isabwe GAC, Garcia Neuer M, de Las Vecillas Sanchez L, Lynch DM, Marquis K, Castells M. Hypersensitivity reactions to therapeutic monoclonal antibodies: phenotypes and endotypes. J Allergy Clin Immunol. 2018;142(1):159–70.e2. https://doi.org/10.1016/j.jaci.2018.02.018.

    Article  CAS  PubMed  Google Scholar 

  44. Chung CH, Mirakhur B, Chan E, Le Q-T, Berlin J, Morse M, et al. Cetuximab-induced anaphylaxis and IgE specific for galactose-alpha-1,3-galactose. N Engl J Med. 2008;358(11):1109–17. https://doi.org/10.1056/NEJMoa074943.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Vultaggio A, Matucci A, Nencini F, Pratesi S, Maggi E. Skin testing and infliximab-specific antibodies detection as a combined strategy for preventing infusion reaction. Intern Emerg Med. 2012;7(Suppl 2):S77–9. https://doi.org/10.1007/s11739-011-0611-x.

    Article  PubMed  Google Scholar 

  46. Galli SJ, Tsai M. IgE and mast cells in allergic disease. Nat Med. 2012;18(5):693–704. https://doi.org/10.1038/nm.2755.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Weeraratne DK, Kuck AJ, Chirmule N, Mytych DT. Measurement of anti-erythropoiesis-stimulating agent IgG4 antibody as an indicator of antibody-mediated pure red cell aplasia. Clin Vaccine Immunol. 2013;20(1):46–51. https://doi.org/10.1128/CVI.00435-12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Whelan SF, Hofbauer CJ, Horling FM, Allacher P, Wolfsegger MJ, Oldenburg J, et al. Distinct characteristics of antibody responses against factor VIII in healthy individuals and in different cohorts of hemophilia A patients. Blood. 2013;121(6):1039–48. https://doi.org/10.1182/blood-2012-07-444877.

    Article  CAS  PubMed  Google Scholar 

  49. Jutel M, Akdis CA. Immunological mechanisms of allergen-specific immunotherapy. Allergy. 2011;66(6):725–32. https://doi.org/10.1111/j.1398-9995.2011.02589.x.

    Article  CAS  PubMed  Google Scholar 

  50. Nouri-Aria KT, Wachholz PA, Francis JN, Jacobson MR, Walker SM, Wilcock LK, et al. Grass pollen immunotherapy induces mucosal and peripheral IL-10 responses and blocking IgG activity. J Immunol. 2004;172(5):3252–9. https://doi.org/10.4049/jimmunol.172.5.3252.

    Article  CAS  PubMed  Google Scholar 

  51. Ottesen EA, Skvaril F, Tripathy SP, Poindexter RW, Hussain R. Prominence of IgG4 in the IgG antibody response to human filariasis. J Immunol. 1985;134(4):2707–12.

    CAS  PubMed  Google Scholar 

  52. Adjobimey T, Hoerauf A. Induction of immunoglobulin G4 in human filariasis: an indicator of immunoregulation. Ann Trop Med Parasitol. 2010;104(6):455–64. https://doi.org/10.1179/136485910x12786389891407.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. 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 https://doi.org/10.1093/ndt/gfs392.

    Article  CAS  Google Scholar 

  54. Boylan B, Rice AS, Dunn AL, Tarantino MD, Brettler DB, Barrett JC, et al. Characterization of the anti-factor VIII immunoglobulin profile in patients with hemophilia A by use of a fluorescence-based immunoassay. J Thromb Haemost. 2015;13(1):47–53. https://doi.org/10.1111/jth.12768.

    Article  CAS  PubMed  Google Scholar 

  55. Svenson M, Geborek P, Saxne T, Bendtzen K. Monitoring patients treated with anti-TNF-alpha biopharmaceuticals: assessing serum infliximab and anti-infliximab antibodies. Rheumatology (Oxford). 2007;46(12):1828–34. https://doi.org/10.1093/rheumatology/kem261.

    Article  CAS  Google Scholar 

  56. Van Stappen T, Vande Casteele N, Van Assche G, Ferrante M, Vermeire S, Gils A. Clinical relevance of detecting anti-infliximab antibodies with a drug-tolerant assay: post hoc analysis of the TAXIT trial. Gut. 2018;67(5):818–26. https://doi.org/10.1136/gutjnl-2016-313071.

    Article  CAS  PubMed  Google Scholar 

  57. Gottlieb AB, Evans R, Li S, Dooley LT, Guzzo CA, Baker D, et al. Infliximab induction therapy for patients with severe plaque-type psoriasis: a randomized, double-blind, placebo-controlled trial. J Am Acad Dermatol. 2004;51(4):534–42. https://doi.org/10.1016/j.jaad.2004.02.021.

    Article  PubMed  Google Scholar 

  58. Rispens T, Ooijevaar-de Heer P, Bende O, Aalberse RC. Mechanism of immunoglobulin G4 fab-arm exchange. J Am Chem Soc. 2011;133(26):10302–11. https://doi.org/10.1021/ja203638y.

    Article  CAS  PubMed  Google Scholar 

  59. Labrijn AF, Buijsse AO, van den Bremer ET, Verwilligen AY, Bleeker WK, Thorpe SJ, et al. Therapeutic IgG4 antibodies engage in fab-arm exchange with endogenous human IgG4 in vivo. Nat Biotechnol. 2009;27(8):767–71. https://doi.org/10.1038/nbt.1553.

    Article  CAS  PubMed  Google Scholar 

  60. Dafa'alla TH, Ghalib HW, Abdelmageed A, Williams JF. The profile of IgG and IgG subclasses of onchocerciasis patients. Clin Exp Immunol. 1992;88(2):258–63. https://doi.org/10.1111/j.1365-2249.1992.tb03070.x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Lighaam LC, Rispens T. The immunobiology of immunoglobulin G4. Semin Liver Dis. 2016;36(3):200–15. https://doi.org/10.1055/s-0036-1584322.

    Article  CAS  PubMed  Google Scholar 

  62. Kurniawan A, Yazdanbakhsh M, van Ree R, Aalberse R, Selkirk ME, Partono F, et al. Differential expression of IgE and IgG4 specific antibody responses in asymptomatic and chronic human filariasis. J Immunol. 1993;150(9):3941–50.

    CAS  PubMed  Google Scholar 

  63. Losen M, Stassen MH, Martínez-Martínez P, Machiels BM, Duimel H, Frederik P, et al. Increased expression of rapsyn in muscles prevents acetylcholine receptor loss in experimental autoimmune myasthenia gravis. Brain. 2005;128(Pt 10):2327–37. https://doi.org/10.1093/brain/awh612.

    Article  PubMed  Google Scholar 

  64. Hussain R, Ottesen EA. IgE responses in human filariasis. IV. Parallel antigen recognition by IgE and IgG4 subclass antibodies. J Immunol. 1986;136(5):1859–63.

    CAS  PubMed  Google Scholar 

  65. FDA. Food Allergen Labeling Exemption Petitions and Notifications: Guidance for Industry 2015; Available from: https://www.fda.gov/media/88332/download. Accessed 5 Nov 2020

  66. CLSI. Design and Validation of Immunoassays for Assessment of Human Allergenicity of New Biotherapeutic Drugs; Approved Guideline. In: Institute CaLS, editor. CLSI document I/LA34-A. Wayne, PA, USA (2010). Clinical and Laboratory Standards Institute. 2010.

  67. Partridge MA, Purushothama S, Elango C, Lu Y. Emerging technologies and generic assays for the detection of anti-drug antibodies. J Immunol Res. 2016;2016:6262383–6. https://doi.org/10.1155/2016/6262383.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Johnson M, Wagstaffe HR, Gilmour KC, Mai AL, Lewis J, Hunt A, et al. Evaluation of a novel multiplexed assay for determining IgG levels and functional activity to SARS-CoV-2. J Clin Virol. 2020;130:104572. https://doi.org/10.1016/j.jcv.2020.104572.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Jenkins R, Duggan JX, Aubry A-F, Zeng J, Lee JW, Cojocaru L, et al. Recommendations for validation of LC-MS/MS bioanalytical methods for protein biotherapeutics. AAPS J. 2015;17(1):1–16. https://doi.org/10.1208/s12248-014-9685-5.

    Article  CAS  PubMed  Google Scholar 

  70. Chen L-Z, Roos D, Philip E. Development of immunocapture-LC/MS assay for simultaneous ADA isotyping and semiquantitation. J Immunol Res. 2016;2016:7682472. https://doi.org/10.1155/2016/7682472.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Lefranc MP, Lefranc G. Human Gm, Km, and Am allotypes and their molecular characterization: a remarkable demonstration of polymorphism. Methods Mol Biol. 2012;882:635–80. https://doi.org/10.1007/978-1-61779-842-9_34.

    Article  CAS  PubMed  Google Scholar 

  72. Shankar G, Devanarayan V, Amaravadi L, Barrett YC, Bowsher R, Finco-Kent D, et al. Recommendations for the validation of immunoassays used for detection of host antibodies against biotechnology products. J Pharm Biomed Anal. 2008;48(5):1267–81. https://doi.org/10.1016/j.jpba.2008.09.020.

    Article  CAS  PubMed  Google Scholar 

  73. Jiang H, Myler H, Zeng J, Mora J, Kolaitis G, Pillutla R. Perspectives on exploring hybrid LBA/LC-MS approach for clinical immunogenicity testing. Bioanalysis. 2019;11(17):1605–17. https://doi.org/10.4155/bio-2018-0107.

    Article  CAS  PubMed  Google Scholar 

  74. Song S, Yang L, Trepicchio WL, Wyant T. Understanding the supersensitive anti-drug antibody assay: unexpected high anti-drug antibody incidence and its clinical relevance. J Immunol Res. 2016;2016:3072586. https://doi.org/10.1155/2016/3072586.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Gorovits B, Wang Y, Zhu L, Araya M, Kamerud J, Lepsy C. Anti-drug antibody assay conditions significantly impact assay screen and confirmatory cut-points. AAPS J. 2019;21(4):71. https://doi.org/10.1208/s12248-019-0342-x.

    Article  PubMed  Google Scholar 

  76. Liang M, Klakamp SL, Funelas C, Lu H, Lam B, Herl C, et al. Detection of high- and low-affinity antibodies against a human monoclonal antibody using various technology platforms. Assay Drug Dev Technol. 2007;5(5):655–62. https://doi.org/10.1089/adt.2007.089.

    Article  CAS  PubMed  Google Scholar 

  77. Yang J, Qiu Y, Pan L. Generation of assay positive controls for detection of isotype anti-drug antibodies for immunogenicity monitoring. Bioanalysis. 2017;9(20):1603–15. https://doi.org/10.4155/bio-2017-0136.

    Article  CAS  PubMed  Google Scholar 

  78. 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.

    Article  CAS  Google Scholar 

  79. Hovland DN Jr, Boyd RB, Butt MT, Engelhardt JA, Moxness MS, Ma MH, et al. Six-month continuous intraputamenal infusion toxicity study of recombinant methionyl human glial cell line-derived neurotrophic factor (r-metHuGDNF in rhesus monkeys). Toxicol Pathol. 2007;35(7):1013–29. https://doi.org/10.1177/01926230701481899.

    Article  CAS  PubMed  Google Scholar 

  80. Bennett CL, Luminari S, Nissenson AR, Tallman MS, Klinge SA, McWilliams N, et al. Pure red-cell aplasia and epoetin therapy. N Engl J Med. 2004;351(14):1403–8. https://doi.org/10.1056/NEJMoa040528.

    Article  CAS  PubMed  Google Scholar 

  81. Pollock C, Johnson DW, Horl WH, Rossert J, Casadevall N, Schellekens H, et al. Pure red cell aplasia induced by erythropoiesis-stimulating agents. Clin J Am Soc Nephrol. 2008;3(1):193–9. https://doi.org/10.2215/cjn.02440607.

    Article  CAS  PubMed  Google Scholar 

  82. Casadevall N, Nataf J, Viron B, Kolta A, Kiladjian JJ, Martin-Dupont P, et al. Pure red-cell aplasia and antierythropoietin antibodies in patients treated with recombinant erythropoietin. N Engl J Med. 2002;346(7):469–75. https://doi.org/10.1056/NEJMoa011931.

    Article  CAS  PubMed  Google Scholar 

  83. Gorovits B, Baltrukonis DJ, Bhattacharya I, Birchler MA, Finco D, Sikkema D, et al. Immunoassay methods used in clinical studies for the detection of anti-drug antibodies to adalimumab and infliximab. Clin Exp Immunol. 2018;192(3):348–65. https://doi.org/10.1111/cei.13112.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Kosmač M, Avčin T, Toplak N, Simonini G, Cimaz R, Curin ŠV. Exploring the binding sites of anti-infliximab antibodies in pediatric patients with rheumatic diseases treated with infliximab. Pediatr Res. 2011;69(3):243–8. https://doi.org/10.1203/PDR.0b013e318208451d.

    Article  CAS  PubMed  Google Scholar 

  85. Candon S, Mosca A, Ruemmele F, Goulet O, Chatenoud L, Cézard JP. Clinical and biological consequences of immunization to infliximab in pediatric Crohn's disease. Clin Immunol. 2006;118(1):11–9. https://doi.org/10.1016/j.clim.2005.07.010.

    Article  CAS  PubMed  Google Scholar 

  86. Tiede A, Hofbauer CJ, Werwitzke S, Knöbl P, Gottstein S, Scharf RE, et al. Anti-factor VIII IgA as a potential marker of poor prognosis in acquired hemophilia A: results from the GTH-AH 01/2010 study. Blood. 2016;127(19):2289–97. https://doi.org/10.1182/blood-2015-09-672774.

    Article  CAS  PubMed  Google Scholar 

  87. Nagao Y, Yamanaka H, Harada H. A patient with hypereosinophilic syndrome that manifested with acquired hemophilia and elevated IgG4: a case report. J Med Case Rep. 2012;6:63. https://doi.org/10.1186/1752-1947-6-63.

    Article  PubMed  PubMed Central  Google Scholar 

  88. Li X, Duan W, Zhu X, Xu J. Immunoglobulin G4-related acquired hemophilia: a case report. Exp Ther Med. 2016;12(6):3988–92. https://doi.org/10.3892/etm.2016.3898.

    Article  PubMed  PubMed Central  Google Scholar 

  89. Narazaki T, Haji S, Nakashima Y, Tsukamoto Y, Tsuda M, Takamatsu A, et al. Acquired hemophilia a associated with autoimmune pancreatitis with serum IgG4 elevation. Int J Hematol. 2018;108(3):335–8. https://doi.org/10.1007/s12185-018-2441-3.

    Article  PubMed  Google Scholar 

  90. Lenders M, Brand E. Effects of enzyme replacement therapy and antidrug antibodies in patients with Fabry disease. J Am Soc Nephrol. 2018;29(9):2265–78. https://doi.org/10.1681/ASN.2018030329.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Bénichou B, Goyal S, Sung C, Norfleet AM, O’Brien F. A retrospective analysis of the potential impact of IgG antibodies to agalsidase β on efficacy during enzyme replacement therapy for Fabry disease. Mol Genet Metab. 2009;96(1):4–12. https://doi.org/10.1016/j.ymgme.2008.10.004.

    Article  CAS  PubMed  Google Scholar 

  92. Lenders M, Schmitz B, Brand S-M, Foell D, Brand E. Characterization of drug-neutralizing antibodies in patients with Fabry disease during infusion. J Allergy Clin Immunol. 2018;141(6):2289–92.e7. https://doi.org/10.1016/j.jaci.2017.12.1001.

    Article  PubMed  Google Scholar 

  93. Gupta S, Lau K, Harding CO, Shepherd G, Boyer R, Atkinson JP, et al. Association of immune response with efficacy and safety outcomes in adults with phenylketonuria administered pegvaliase in phase 3 clinical trials. EBioMedicine. 2018;37:366–73. https://doi.org/10.1016/j.ebiom.2018.10.038.

    Article  PubMed  PubMed Central  Google Scholar 

  94. Olas K, Butterweck H, Teschner W, Schwarz HP, Reipert B. Immunomodulatory properties of human serum immunoglobulin A: anti-inflammatory and pro-inflammatory activities in human monocytes and peripheral blood mononuclear cells. Clin Exp Immunol. 2005;140(3):478–90. https://doi.org/10.1111/j.1365-2249.2005.02779.x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Pasquier B, Launay P, Kanamaru Y, Moura IC, Pfirsch S, Ruffié C, et al. Identification of FcalphaRI as an inhibitory receptor that controls inflammation: dual role of FcRgamma ITAM. Immunity. 2005;22(1):31–42. https://doi.org/10.1016/j.immuni.2004.11.017.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Pfizer, 1 Burtt Rd, Andover, Massachusetts, 01810, USA

    Boris Gorovits

Authors
  1. Boris Gorovits
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Boris Gorovits.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Gorovits, B. Current Considerations for Immunoglobulin Isotype Characterization of Antibody Response against Biotherapeutics. AAPS J 22, 144 (2020). https://doi.org/10.1208/s12248-020-00530-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1208/s12248-020-00530-4

Key words

Search

Navigation