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Reporting, Visualization, and Modeling of Immunogenicity Data to Assess Its Impact on Pharmacokinetics, Efficacy, and Safety of Monoclonal Antibodies

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Abstract

The rapidly increasing number of therapeutic biologics in development has led to a growing recognition of the need for improvements in immunogenicity assessment. Published data are often inadequate to assess the impact of an antidrug antibody (ADA) on pharmacokinetics, safety, and efficacy, and enable a fully informed decision about patient management in the event of ADA development. The recent introduction of detailed regulatory guidance for industry should help address many past inadequacies in immunogenicity assessment. Nonetheless, careful analysis of gathered data and clear reporting of results are critical to a full understanding of the clinical relevance of ADAs, but have not been widely considered in published literature to date. Here, we review visualization and modeling of immunogenicity data. We present several relatively simple visualization techniques that can provide preliminary information about the kinetics and magnitude of ADA responses, and their impact on pharmacokinetics and clinical endpoints for a given therapeutic protein. We focus on individual sample- and patient-level data, which can be used to build a picture of any trends, thereby guiding analysis of the overall study population. We also discuss methods for modeling ADA data to investigate the impact of immunogenicity on pharmacokinetics, efficacy, and safety.

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References

  1. European Medicines Agency. Guideline on Immunogenicity Assessment of Biotechnology-Derived Therapeutic Proteins (draft). London: European Medicines Agency; 2015.

    Google Scholar 

  2. Singh SK. Impact of product-related factors on immunogenicity of biotherapeutics. J Pharm Sci. 2011;100:354–87.

    Article  CAS  PubMed  Google Scholar 

  3. Tovey MG, Legrand J, Lallemand C. Overcoming immunogenicity associated with the use of biopharmaceuticals. Expert Rev Clin Pharmacol. 2011;4(5):623–31.

    Article  CAS  PubMed  Google Scholar 

  4. Chirmule N, Jawa V, Meibohm B. Immunogenicity to therapeutic proteins: impact on PK/PD and efficacy. AAPS J. 2012;14(2):296–302.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Ratanji KD, Derrick JP, Dearman RJ, Kimber I. Immunogenicity of therapeutic proteins: influence of aggregation. J Immunotoxicol. 2014;11(2):99–109.

    Article  CAS  PubMed  Google Scholar 

  6. Kuriakose A, Chirmule N, Nair P. Immunogenicity of biotherapeutics: causes and association with posttranslational modifications. J Immunol Res. 2016;2016:1298473.

    Article  PubMed  PubMed Central  Google Scholar 

  7. 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;14(346):469–75.

    Article  Google Scholar 

  8. Schmidt E, Hennig K, Mengede C, Zillikens D, Kromminga A. Immunogenicity of rituximab in patients with severe pemphigus. Clin Immunol. 2009;132(3):334–41.

    Article  CAS  PubMed  Google Scholar 

  9. Banugaria SG, Prater SN, Ng YK, Kobori JA, Finkel RS, Ladda RL, et al. The impact of antibodies on clinical outcomes in diseases treated with therapeutic protein: lessons learned from infantile Pompe disease. Genet Med. 2011;13(8):729–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Sailstad JM, Amaravadi L, Clements-Egan A, Gorovits B, Myler HA, Pillutla RC, et al. A white paper—consensus and recommendations of a global harmonization team on assessing the impact of immunogenicity on pharmacokinetic measurements. AAPS J. 2014;16(3):488–98.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Smith A, Manoli H, Jaw S, Frutoz K, Epstein AL, Khawli LA, et al. Unraveling the effect of immunogenicity on the PK/PD, efficacy, and safety of therapeutic proteins. J Immunol Res. 2016;2016:2342187.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Food and Drug Administration. Guidance for Industry (Draft): Immunogenicity Assessment for Therapeutic Protein Products. Rockville: US Department of Health and Human Services, FDA, Center for Drug Evaluation and Research; 2014.

    Google Scholar 

  13. Food and Drug Administration. Draft Guidance for Industry: Assay Development and Validation for Immunogenicity Testing of Therapeutic Protein Products. Rockville: US Department of Health and Human Services, FDA, Center for Drug Evaluation and Research; 2016.

    Google Scholar 

  14. Shankar G, Arkin S, Cocea L, Devanarayan V, Kirshner S, Kromminga A, et al. Assessment and reporting of the clinical immunogenicity of therapeutic proteins and peptides-harmonized terminology and tactical recommendations. AAPS J. 2014;16(4):658–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Wang YM, Wang J, Hon YY, Zhou L, Fang L, Ahn HY. Evaluating and reporting the immunogenicity impacts for biological products—a clinical pharmacology perspective. AAPS J. 2016;18(2):395–403.

    Article  CAS  PubMed  Google Scholar 

  16. Wang YM, Fang L, Zhou L, Wang J, Ahn HY. A survey of applications of biological products for drug interference of immunogenicity assays. Pharm Res. 2012;29(12):3384–92.

    Article  CAS  PubMed  Google Scholar 

  17. Gunn GR 3rd, Sealey DC, Jamali F, Meibohm B, Ghosh S, Shankar G. From the bench to clinical practice: understanding the challenges and uncertainties in immunogenicity testing for biopharmaceuticals. Clin Exp Immunol. 2016;184(2):137–46.

    Article  PubMed  PubMed Central  Google Scholar 

  18. YERVOY. (ipilimumab) [package insert]. Bristol-Myers Squibb Company: Princeton; 2017.

    Google Scholar 

  19. KEYTRUDA. (pembrolizumab) [package insert]. Whitehouse Station (NJ): Merck & Co. Inc.; 2016.

    Google Scholar 

  20. DARZALEX. (daratumumab) [prescribing information]. Horsham (PA): Janssen Biotech, Inc.; 2016.

    Google Scholar 

  21. ERBITUX. (cetuximab) [prescribing information]. ImClone LLC, a wholly-owned subsidiary of Eli Lilly: Indianapolis (IN); 2016.

    Google Scholar 

  22. TECENTRIQ. (atezolizumab) [prescribing information]. South San Francisco: Genentech, Inc.; 2016.

    Google Scholar 

  23. CIMZIA. (certolizumab pegol) [prescribing information]. Smyrna: UCB, Inc.; 2016.

    Google Scholar 

  24. Tatarewicz SM, Mytych DT, Manning MS, Swanson SJ, Moxness MS, Chirmule N. Strategic characterization of anti-drug antibody responses for the assessment of clinical relevance and impact. Bioanalysis. 2014;6(11):1509–23.

    Article  CAS  PubMed  Google Scholar 

  25. Gunsior, M. Implications of Immunogenicity in Drug Development. Global bioanalytical services: white paper [Internet]. 2017 May 15 [cited 2017 Sep 28]. Available from: http://www.covance.com/content/dam/covance/assetLibrary/whitepapers/adawhitepaperpdf.pdf.

  26. Gorovits B, Clements-Egan A, Birchler M, Liang M, Myler H, Peng K, et al. Pre-existing antibody: biotherapeutic modality-based review. AAPS J. 2016;18(2):311–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Agrawal S, Statkevich P, Bajaj G, Feng Y, Saeger S, Desai DD, et al. Evaluation of immunogenicity of nivolumab monotherapy and its clinical relevance in patients with metastatic solid tumors. J Clin Pharmacol. 2017;57(3):394–400.

    Article  CAS  PubMed  Google Scholar 

  28. Mytych DT, Hock MB, Kroenke M, Jawa V, Kaliyaperumal A, Zhou Y. A proposal to redefine clinical immunogenicity assessment. AAPS J. 2017;19(3):599–602.

    Article  CAS  PubMed  Google Scholar 

  29. Passey C, Mora J, Dodge R, Gibiansky L, Sheng J, Roy A, et al. An integrated assessment of the effects of immunogenicity on the pharmacokinetics, safety, and efficacy of elotuzumab. AAPS J. 2017;19(2):557–67.

    Article  CAS  PubMed  Google Scholar 

  30. Lecluse LL, Driessen RJ, Spuls PI, de Jong EM, Stapel SO, van Doorn MB, et al. Extent and clinical consequences of antibody formation against adalimumab in patients with plaque psoriasis. Arch Dermatol. 2010;146(2):127–32.

    Article  CAS  PubMed  Google Scholar 

  31. Zhou L, Hoofring SA, Wu Y, Vu T, Ma P, Swanson SJ, et al. Stratification of antibody-positive subjects by antibody level reveals an impact of immunogenicity on pharmacokinetics. AAPS J. 2013;15(1):30–40.

    Article  CAS  PubMed  Google Scholar 

  32. Menting SP, van Lümig PP, de Vries AC, van den Reek JM, de Jong EM, Spuls PI, et al. Extent and consequences of antibody formation against adalimumab in patients with psoriasis: one-year follow-up. JAMA Dermatol. 2014;150(2):130–6.

    Article  CAS  PubMed  Google Scholar 

  33. Creeke PI, Farrell RA. Clinical testing for neutralizing antibodies to interferon-β in multiple sclerosis. Ther Adv Neurol Disord. 2013;6(1):3–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Calabresi PA, Giovannoni G, Confavreux C, Galetta SL, Havrdova E, Hutchinson M, et al. AFFIRM and SENTINEL Investigators. The incidence and significance of anti-natalizumab antibodies: results from AFFIRM and SENTINEL. Neurology. 2007;69(14):1391–403.

    Article  CAS  PubMed  Google Scholar 

  35. Aubin F, Carbonnel F, Wendling D. The complexity of adverse side-effects to biological agents. J Crohns Colitis. 2013;7(4):257–62.

    Article  PubMed  Google Scholar 

  36. Pichler WJ. Adverse side-effects to biological agents. Allergy. 2006;61(8):912–20.

    Article  CAS  PubMed  Google Scholar 

  37. Gibiansky L, Gibiansky E. Immunogenicity in PK of monoclonal antibodies: detection and unbiased estimation of model parameters. Proceedings of the Population Approach Group 2013 Annual meeting; 2013 Jun 11–14; Glasgow, Scotland. Available at: http://www.quantpharm.com/pdf_files/PAGE_2013_Immunogenicity_Poster.pdf.

  38. Perez Ruixo JJ, Ma P, Chow AT. The utility of modeling and simulation approaches to evaluate immunogenicity effect on the therapeutic protein pharmacokinetics. AAPS J. 2013;15(1):172–82.

    Article  PubMed  Google Scholar 

  39. Bajaj G, Wang X, Agrawal S, Gupta M, Roy A, Feng Y. Model-based population pharmacokinetic analysis of nivolumab in patients with solid tumors. CPT Pharmacometrics Syst Pharmacol. 2017;6(1):58–66.

    Article  CAS  PubMed  Google Scholar 

  40. Diao L, Hang Y, Othman AA, Nestorov I, Tran JQ. Population pharmacokinetics of daclizumab high-yield process in healthy volunteers and subjects with multiple sclerosis: analysis of phase I-III clinical trials. Clin Pharmacokinet. 2016;55(8):943–55.

    Article  CAS  PubMed  Google Scholar 

  41. Nader A, Beck D, Noertersheuser P, Williams D, Mostafa N. Population pharmacokinetics and immunogenicity of adalimumab in adult patients with moderate-to-severe hidradenitis suppurativa. Clin Pharmacokinet. 2017;56(9):1091–1102.

  42. Gibiansky L, Passey C, Roy A, Bello A, Gupta M. Model-based pharmacokinetic analysis of elotuzumab in patients with relapsed/refractory multiple myeloma. J Pharmacokinet Pharmacodyn. 2016;43(3):243–57.

    Article  CAS  PubMed  Google Scholar 

  43. Yang H, Zhang J, Yu B, Zhao W. Statistical methods for immunogenicity. Boca Raton: Chapman and Hall/CRC Press; 2015.

    Google Scholar 

  44. Rup B, Pallardy M, Sikkema D, Albert T, Allez M, Broet P, et al. Standardizing terms, definitions and concepts for describing and interpreting unwanted immunogenicity of biopharmaceuticals: recommendations of the Innovative Medicines Initiative ABIRISK consortium. Clin Exp Immunol. 2015;181(3):385–400.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Anti-Biopharmaceutical Immunization: prediction and analysis of clinical relevance to minimize the RISK (ABIRISK) project [Internet]; 2017 [cited 2017 Sep 28]. Available from: http://www.abirisk.eu.

  46. Bachelet D, Hässler S, Mbogning C, Link J, Ryner M, Ramanujam R, et al. ABIRISK consortium. Occurrence of anti-drug antibodies against interferon-beta and natalizumab in multiple sclerosis: a collaborative cohort analysis. PLoS One. 2016;11(11):e0162752.

    Article  PubMed  PubMed Central  Google Scholar 

  47. Link J, Ramanujam R, Auer M, Ryner M, Hässler S, Bachelet D, et al. Clinical practice of analysis of anti-drug antibodies against interferon beta and natalizumab in multiple sclerosis patients in Europe: a descriptive study of test results. PLoS One. 2017;12(2):e0170395.

    Article  PubMed  PubMed Central  Google Scholar 

  48. OPDIVO. (nivolumab) [package insert]. Bristol-Myers Squibb Company: Princeton (NJ); 2017.

    Google Scholar 

  49. Morrissey KM, Yuraszeck TM, Li CC, Zhang Y, Kasichayanula S. Immunotherapy and novel combinations in oncology: current landscape, challenges, and opportunities. Clin Transl Sci. 2016;9(2):89–104.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Statkevich P, Passey C, Park J, Saeger S, Bello A, Roy A, et al. Assessment of the immunogenicity of nivolumab (nivo) and ipilimumab (ipi) in combination and potential impact on safety and efficacy in patients with advanced melanoma. Clin Pharmacol Ther 2016;99. https://doi.org/10.1002/cpt.310. Abstract available at: http://onlinelibrary.wiley.com/doi/10.1002/cpt.310/epdf.

  51. Zhu L, Chan P, Vezina H, Wang X, Feng Y, Statkevich P, et al. Model-based assessment of drug-drug interaction and immunogenicity on the pharmacokinetics (PK) of nivolumab and ipilimumab in combination in advanced melanoma patients. Clin Pharmacol Ther 2016;99. https://doi.org/10.1002/cpt1310.

  52. European Medicines Agency. Guideline on Similar Biological Medicinal Products Containing Biotechnology-Derived Proteins as Active Substance: Non-Clinical and Clinical Issues. London: European Medicines Agency; 2014.

    Google Scholar 

  53. Food and Drug Administration. Draft Guidance for Industry: Considerations in Demonstrating Interchangeability With a Reference Product. Rockville: US Department of Health and Human Services, FDA, Center for Drug Evaluation and Research; 2017.

    Google Scholar 

  54. Food and Drug Administration. Guidance for Industry: Scientific Considerations in Demonstrating Biosimilarity to a Reference Product. Rockville: US Department of Health and Human Services, FDA, Center for Drug Evaluation and Research; 2015.

    Google Scholar 

  55. Pineda C, Castañeda Hernández G, Jacobs IA, Alvarez DF, Carini C. Assessing the immunogenicity of biopharmaceuticals. BioDrugs. 2016;30(3):195–206.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Vultaggio A, Petroni G, Pratesi S, Nencini F, Cammelli D, Ferraro A, et al. How the immune system responds to therapeutic biological agents. J Int Med Res. 2016;44(1 suppl):38–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Vultaggio A, Petroni G, Pratesi S, Nencini F, Cammelli D, Milla M, et al. Circulating T cells to infliximab are detectable mainly in treated patients developing anti-drug antibodies and hypersensitivity reactions. Clin Exp Immunol. 2016;186(3):364–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Pandey GS, Sauna ZE. Pharmacogenetics and the immunogenicity of protein therapeutics. J Interf Cytokine Res. 2014;34(12):931–7.

    Article  CAS  Google Scholar 

  59. Schuck RN, Grillo JA. Pharmacogenomic biomarkers: an FDA perspective on utilization in biological product labeling. AAPS J. 2016;18(3):573–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

Professional medical writing and editorial assistance were provided by Stephan Lindsey, PhD, Melissa Kirk, PhD, and Cara Hunsberger at StemScientific, an Ashfield Company, funded by Bristol-Myers Squibb.

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This study was supported by Bristol-Myers Squibb.

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Authors and Affiliations

  1. Clinical Pharmacology & Pharmacometrics, Bristol-Myers Squibb, Princeton, New Jersey, USA

    Chaitali Passey, Satyendra Suryawanshi, Kinjal Sanghavi & Manish Gupta

Authors
  1. Chaitali Passey
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  2. Satyendra Suryawanshi
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  3. Kinjal Sanghavi
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  4. Manish Gupta
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Correspondence to Manish Gupta.

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C. Passey, S. Suryawanshi, K. Sanghavi, and M. Gupta are all employed by Bristol-Myers Squibb.

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The submitted manuscript is an original work and has not been submitted for publication elsewhere.

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Passey, C., Suryawanshi, S., Sanghavi, K. et al. Reporting, Visualization, and Modeling of Immunogenicity Data to Assess Its Impact on Pharmacokinetics, Efficacy, and Safety of Monoclonal Antibodies. AAPS J 20, 35 (2018). https://doi.org/10.1208/s12248-018-0194-9

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