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.

  • Perspective
  • Published:

A risk-based bioanalytical strategy for the assessment of antibody immune responses against biological drugs

Abstract

Bioanalytical assessments of anti-drug antibodies (ADAs) provide an understanding of the immunogenicity of biological drug molecules. The potential to induce ADAs after treatment with biologics is a safety issue that has become an important consideration in the development of biologics and a critical aspect of regulatory filings. US and European regulatory agencies are recommending that sponsors study immunogenicity using a risk-based approach, encouraging sponsors to formulate and implement their own risk management plans and to conduct discussions with the agencies when necessary. It follows from this that the greater the safety risks of ADAs, the more diligently one should clarify the immunogenicity of the product. Here we propose a general strategy to broadly assign immunogenicity risk levels to biological drug products, and present risk level–based 'fit-for-purpose' bioanalytical schemes for the investigations of treatment-related ADAs in clinical and nonclinical studies.

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

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

Similar content being viewed by others

References

  1. Berson, S.A. et al. Insulin-I-131 metabolism in human subjects: demonstration of insulin binding globulin in the circulation of insulin treated subjects. J. Clin. Invest. 35, 170–190 (1956).

    Article  CAS  Google Scholar 

  2. Klee, G.G. Human anti-mouse antibodies. Arch. Pathol. Lab. Med. 124, 921–923 (2000).

    CAS  PubMed  Google Scholar 

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

    Article  CAS  Google Scholar 

  4. Steis, R.G. et al. Loss of interferon antibodies during prolonged continuous interferon-α2a therapy in hairy cell leukemia. Blood 77, 792–798 (1991).

    CAS  PubMed  Google Scholar 

  5. Schellekens, H. & Casadevall, N. Immunogenicity of recombinant human proteins. J. Neurol. 251 (Suppl. 2), II/4–II/9 (2004).

    CAS  Google Scholar 

  6. Green, D. Spontaneous inhibitors to coagulation factors. Clin. Lab. Haematol. 22 (Suppl. 1), 21–25 (2000).

    Article  Google Scholar 

  7. Chiefetz, A. & Mayer, L. Monoclonal antibodies, immunogenicity, and associated infusion reactions. Mt. Sinai J. Med. 72, 250–256 (2005).

    Google Scholar 

  8. Shankar, G., Shores, E., Wagner, C. & Mire-Sluis, A.R. Scientific and regulatory considerations on the immunogenicity of biologics. Trends Biotechnol. 24, 274–280 (2006).

    Article  CAS  Google Scholar 

  9. Proceedings of the International Conference on Harmonization (ICH) of Technical Requirements for Registration of Pharmaceuticals for Human Use: Tripartite guideline, S6: Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals, July 1997.

  10. U.S. Department of Health and Human Services/Food and Drug Administration. Guidance for industry: premarketing risk assessment, March 2005.

  11. The European Agency for the Evaluation of Medicinal Products (EMEA), Committee for Medicinal Products for Human Use (CHMP). Guideline on immunogenicity assessment of biotechnology-derived therapeutic proteins. EMEA/CHMP/BMWP/14327/2006 <http://www.emea.europa.eu/pdfs/human/biosimilar/1432706en.pdf> (24 January 2007).

  12. Rosenberg, A.S. & 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. 17, 22–26 (2004).

    Google Scholar 

  13. Rosenberg, A.S. & Worobec, A. A risk-based approach to immunogenicity concerns of therapeutic protein products—Part 2—considering host-specific and product-specific factors impacting immunogenicity. Biopharm. Int. 17, 34–42 (2004).

    Google Scholar 

  14. Rosenberg, A.S. & Worobec, A. A risk-based approach to immunogenicity concerns of therapeutic protein products—Part 3—effects of manufacturing changes in immunogenicity and the utility of animal immunogenicity studies. Biopharm. Int. 18, 32–36 (2005).

    Google Scholar 

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

    Article  CAS  Google Scholar 

  16. Schnabel, C.A., Fineberg, S.E. & Kim, D.D. Immunogenicity of xenopeptide hormone therapies. Peptides 27, 1902–1910 (2006).

    Article  CAS  Google Scholar 

  17. Li, J. et al. Thrombocytopenia caused by the development of antibodies to thrombopoietin. Blood 98, 3241–8 (2001).

    Article  CAS  Google Scholar 

  18. Mire-Sluis, A.R. et al. Recommendations for the design and optimization of immunoassays used in the detection of host antibodies against biotechnology products. J. Immunol. Methods 289, 1–16 (2004).

    Article  CAS  Google Scholar 

  19. Pendley, C., Schantz, A. & Wagner, C. Immunogenicity of therapeutic monoclonal antibodies. Curr. Opin. Mol. Ther. 5, 172–179 (2003).

    CAS  PubMed  Google Scholar 

  20. Schellekens, H. Bioequivalence and the immunogenicity of biopharmaceuticals. Nat. Rev. Drug Discov. 1, 457–462 (2002).

    Article  CAS  Google Scholar 

  21. Suh, B.K., Jorgensen, E.V. & Root, A.W. Facilitation of the growth-promoting effect of growth hormone (GH) by an antibody to methionyl-GH. J. Pediatr. Endocrinol. Metab. 8, 97–102 (1995).

    Article  CAS  Google Scholar 

  22. 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  Google Scholar 

  23. Goldstein, G. et al. OKT3 monoclonal antibody plasma levels during therapy and the subsequent development of host antibodies to OKT3. Transplantation 42, 507–511 (1986).

    Article  CAS  Google Scholar 

  24. Schroeder, T.J. et al. Immunologic monitoring with Orthoclone OKT3 therapy. J. Heart Transplant. 8, 371–380 (1989).

    CAS  PubMed  Google Scholar 

  25. Casadevall, N. et al. Pure red-cell aplasia and antierythropoietin antibodies in patients treated with recombinant erythropoietin. N. Engl. J. Med. 346, 469–475 (2002).

    Article  CAS  Google Scholar 

  26. 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  Google Scholar 

  27. D'Arcy, C.A. & Mannik, M. Serum sickness secondary to treatment with the murine-human chimeric antibody IDEC-C2B8 (rituximab). Arthritis Rheum. 44, 1717–1718 (2001).

    Article  CAS  Google Scholar 

  28. Dharnidharka, V.R. et al. Membranous glomerulonephritis and nephrosis post factor IX infusions in hemophilia B. Pediatr. Nephrol. 12, 654–657 (1998).

    Article  CAS  Google Scholar 

  29. Hunley, T.E. et al. Nephrotic syndrome complicating α-glucosidase replacement therapy for Pompe disease. Pediatrics 114, e532–e535 (2004)

    Article  Google Scholar 

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

    Article  CAS  Google Scholar 

  31. DeShazo, R.D. & Kemp, S.F. Allergic reactions to drugs and biologic agents. JAMA 278, 1895–1906.

  32. Wollina, U. & Conrad, H. Managing adverse events associated with botulinum toxin type A: a focus on cosmetic procedures. Am. J. Clin. Dermatol. 6, 141–150 (2005).

    Article  Google Scholar 

  33. Hermann, J. et al. Clinical impact of antibody formation to botulinum toxin A in children. Ann. Neurol. 55, 732–735 (2004).

    Article  Google Scholar 

  34. Bugelski, P.J. & Treacy, G. Predictive power of preclinical studies in animals for the immunogenicity of recombinant therapeutic proteins in humans. Curr. Opin. Mol. Ther. 6, 10–16 (2004).

    CAS  PubMed  Google Scholar 

  35. Dale, D. et al. Chronic thrombocytopenia is induced in dogs by development of cross-reacting antibodies to the MpL ligand. Blood 90, 3456–3461 (1997).

    Article  CAS  Google Scholar 

  36. Abina, M-A. et al. Thrombopoietin (TPO) knockout phenotype induced by cross-reactive antibodies against TPO following injection of mice with recombinant adenovirus encoding human TPO. J. Immunol. 160, 4481–4489 (1998).

    CAS  PubMed  Google Scholar 

  37. Koren, E. From characterization of antibodies to prediction of immunogenicity. Dev. Biol. 109, 87–95 (2002).

    CAS  Google Scholar 

Download references

Acknowledgements

The authors express their gratitude to the following individuals for their review and feedback on this manuscript: Kristan Phillips and Syd Johnson (MacroGenics, Inc.); Eugen Koren (Scios, Inc.); Hugh Davis, George Treacy, Robert Jordan and Joseph Marini (Centocor Research & Development, Inc.); Vishwanath Devanarayan (Merck, Inc.) and John Ghrayeb.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Gopi Shankar.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Shankar, G., Pendley, C. & Stein, K. A risk-based bioanalytical strategy for the assessment of antibody immune responses against biological drugs. Nat Biotechnol 25, 555–561 (2007). https://doi.org/10.1038/nbt1303

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nbt1303

This article is cited by

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