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Scroll through to learn and engage in the fascinating narrative of immunogenicity and its importance in the context of biologic medicines

What is immunogenicity in the context of biologic medicines?

Immunogenicity refers to the potential of any treatment or medication that affects the immune system, such as reference or biosimilar biologics, to trigger an immune response.1–3

This asset is intended for healthcare professionals only.
MLR ID: 415310. Date of preparation: April 2024.

Immunogenicity is an unwanted immune response that, if present in sufficient volume, may stop the treatment from working as effectively and may cause hypersensitivity reactions.1–3

Biologic medicines are a diverse group of biologically-derived therapies, including:4

Biologic medicines are a diverse group of biologically-derived therapies, including4:

These medicines are often comparatively large, recombinant proteins or antibodies and, as a result, may be recognized as foreign bodies by the immune system, leading to the development of an immune response and production of ‘anti-drug’ antibodies (ADAs).5

ADAs that bind to the biologic medicine’s active site and neutralize its action are known as neutralizing antibodies (NAbs).2

Learn how immunogenic potential is matched between a reference biologic medicine and its biosimilar(s)

Understand the possible clinical consequences of an immune reaction to a biologic medicine

Be familiar with differences in the sensitivity, use and interpretation of different types of immunogenicity assays used in clinical practice, or in biologic and biosimilar development programs

It is important for clinicians to be aware of the concept of immunogenicity, both in general and within the context of treatment with biologic medicines, and to1:

Learn how immunogenic potential is matched between a reference biologic medicine and its biosimilar(s)

Understand the possible clinical consequences of an immune reaction to a biologic medicine

Be familiar with differences in the sensitivity, use and interpretation of different types of immunogenicity assays used in clinical practice, or in biologic and biosimilar development programs

It is important for clinicians to be aware of the concept of immunogenicity, both in general and within the context of treatment with biologic medicines, and to1:

How is immunogenicity assessed as part of a biosimilar development program?

A biosimilar is a successor to a biologic medicine (known as the 'reference medicine') for which the patent has expired and exclusivity has been lost. Biosimilars have been shown to have equivalent efficacy, and comparable safety and immunogenicity compared to their reference medicine.2,6–10

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As per US FDA and EMA requirements, testing of immunogenicity should be part of the development program to demonstrate biosimilarity between a proposed biosimilar and the reference biologic, contributing to the systematic totality of evidence that plays a pivotal role in the approval process of a biosimilar.11–14

The comparison of immunogenicity between a reference biologic and a proposed biosimilar will evaluate13:

Incidence of immune responses

Nature and severity of the immune response (e.g. anaphylaxis, NAbs)

Clinical relevance of the immune response (e.g. loss of efficacy and increased safety risks)

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Immunogenicity is evaluated within a biosimilar development program using ‘assays’. These assays are specialized and more sensitive than the assays used in clinical trials, to detect potential differences that could translate to an impact on efficacy and safety in patients.3,13,15

An immunogenicity assessment is a stepwise approach to determine if the proposed biosimilar matches its reference medicine in its potential to trigger the development of ADAs and NAbs, and in the impact of any immunogenic potential on humoral response, hypersensitivity reactions, and clinical outcomes.2,3,13,15

All assays are optimized to have adequate sensitivity (to identify true positives), specificity (to identify true negatives), selectivity (to identify ADAs specific to the therapeutic protein medicine), drug tolerance (which is a concentration limit that blocks ADA detection), precision (to produce consistent results), reproducibility, and robustness, and follow validation standards as per regulatory guidelines.11

Immunogenicity caused by the development of ADAs and NAbs may have no impact on the clinical efficacy of a medicine and no apparent clinical manifestations. However, in cases where many ADAs develop, this may influence the behavior of the medicine, contributing to a loss of efficacy and/or the development of – sometimes serious and life-threatening – side effects.16

Clinical relevance of immunogenicity

An immunogenic response to a biologic medicine can impact…12,16

Therefore, it is vital for clinicians to understand any correlation between the development of ADAs and clinical effects of a given medicine.

An immunogenic response to a biologic medicine can impact…12,16

Therefore, it is vital for clinicians to understand any correlation between the development of ADAs and clinical effects of a given medicine.

Choosing the most suitable assay for ADA screening is a crucial factor in the development of biologics and biosimilars.17

Screening assays should be validated before use, to ensure they have adequate sensitivity and specificity and are able to identify all antibodies that may be produced in response to a given medicine.12

Commonly used ADA screening assays and their key elements12,17,18

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Why do immunogenicity values reported for a biosimilar development program sometimes differ from those of reference biologic programs?

The demonstration of matching minimal potential differences in immunogenicity using state-of-the-art, high-sensitivity assays is a critical requirement for establishing biosimilarity between a biosimilar and the respective reference medicine, and is subject to specific guidance from the FDA and EMA.19,20

The demonstration of matching minimal potential differences in immunogenicity using state-of-the-art, high-sensitivity assays is a critical requirement for establishing biosimilarity between a biosimilar and the respective reference medicine, and is subject to specific guidance from the FDA and EMA.19,20

Why do immunogenicity values reported for a biosimilar development program sometimes differ from those of reference biologic programs?

With advancements in technology, new assays developed for use in biosimilar development programs have greatly enhanced sensitivity and drug tolerance, thus improving the detection of ADAs.19,20

Consequently, there may be a marked difference – even increase – in the values retrieved in biosimilar programs from different or older assays used in real-world clinical practice or when the reference medicine was developed.19,20

With advancements in technology, new assays developed for use in biosimilar development programs have greatly enhanced sensitivity and drug tolerance, thus improving the detection of ADAs.19,20

Consequently, there may be a marked difference – even increase – in the values retrieved in biosimilar programs from different or older assays used in real-world clinical practice or when the reference medicine was developed.19,20

Thus, different assays should not directly be compared with each other unless the assay cut points, relative sensitivity, drug tolerance, and precision are evaluated to be equivalent.19,20

Example: An ADA incidence of 10–51% was reported for reference infliximab during its development program.21 An ADA incidence of 34% has been reported in real-world clinical practice.22 However, when biosimilar infliximab SB2 was compared with reference infliximab in a Phase III study of patients with rheumatoid arthritis, ADA-positivity was 62.4% and 57.5% for SB2 and reference infliximab, respectively.23

The increase in the magnitude of biosimilar ADA values compared to previous reports was attributed to the increased sensitivity of the immunogenicity assay used in the biosimilar development program. Importantly, the values for the biosimilar and reference were comparable to each other.23

Example: An ADA incidence of 10–51% was reported for reference infliximab during its development program.21 An ADA incidence of 34% has been reported in real-world clinical practice.22 However, when biosimilar infliximab SB2 was compared with reference infliximab in a Phase III study of patients with rheumatoid arthritis, ADA-positivity was 62.4% and 57.5% for SB2 and reference infliximab, respectively.23

The increase in the magnitude of biosimilar ADA values compared to previous reports was attributed to the increased sensitivity of the immunogenicity assay used in the biosimilar development program. Importantly, the values for the biosimilar and reference were comparable to each other.23

The key point to remember is that if the number of positive ADA responses between a biosimilar and reference medicine is ‘highly similar’ or presents what is described as ‘no clinically meaningful differences’ to each other within the same assay format, then this demonstrates that the two medicines match in terms of immunogenic potential and can be used with equal confidence.8,13–15

Immunogenicity in the context
of biologic medicines:

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  1. Shakhnovich V, Meibohm B, Rosenberg R, et al. Immunogenicity in clinical practice and drug development: When is it significant? Clin Transl Sci 2020;13(2):219–223.
  2. Padda IS, Bhatt R, Rehman O, et al. Biosimilars use in medicine for inflammatory diseases. 2023. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan. Available from: https://www.ncbi.nlm.nih.gov/books/NBK574572/. Accessed October 17, 2023.
  3. Liu PM, Zou L, Sadhu, C, et al. Comparative immunogenicity assessment: a critical consideration for biosimilar development. Bioanalysis 2015;7(3):373–381.
  4. World Health Organization. Health topics: Biologicals. 2023. Available at: https://www.who.int/health-topics/biologicals. Accessed October 17, 2023.
  5. Krishna M, Nadler SG. Immunogenicity to biotherapeutics – the role of anti-drug immune complexes. Front Immunol 2016;7:21.
  6. Weise M, Bielsky MC, De Smet K, et al. Biosimilars: what clinicians should know. Blood 2012;120:5111–5117.
  7. Kay J. A ‘wind of change’ to biosimilars: the NOR-SWITCH trial and its extension. J Intern Med 2019;285:693–695.
  8. Kaida-Yip F, Deshpande K, Saran T, et al. Biosimilars: Review of current applications, obstacles, and their future in medicine. World J Clin Cases 2018;6(8):161–166.
  9. US FDA. Biosimilars: Are they the same quality? 2023. Available at: https://www.fda.gov/media/161628/download. Accessed October 17, 2023.
  10. US FDA. Biological product definitions. 2023. Available at: https://www.fda.gov/files/drugs/published/Biological-Product-Definitions.pdf. Accessed October 17, 2023.
  11. US FDA. Immunogenicity testing of therapeutic protein products — Developing and validating assays for anti-drug antibody detection. 2019. Available at: https://www.fda.gov/media/119788/download. Accessed October 17, 2023.
  12. EMA.Guideline on immunogenicity assessment of therapeutic proteins. 2017. Available at: https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-immunogenicity-assessment-therapeutic-proteins-revision-1_en.pdf. Accessed October 17, 2023.
  13. US FDA. 2015. Scientific considerations in demonstrating biosimilarity to a reference product. Available at: https://www.fda.gov/media/82647/download. Accessed October 17, 2023.
  14. Schreitmüller T, Barton B, Zharkov A, et al. Comparative immunogenicity assessment of biosimilars. Future Oncol 2019;15(3):319–329.
  15. EMA. Biosimilars in the EU. 2019. Available at: https://www.ema.europa.eu/en/documents/leaflet/biosimilars-eu-information-guide-healthcare-professionals_en.pdf. Accessed October 17, 2023.
  16. US FDA. Guidance for Industry. Immunogenicity assessment for therapeutic protein products. 2014. Available at: https://www.fda.gov/media/85017/download. Accessed October 17, 2023.
  17. Pineda C, Castañeda Hernández G, Jacobs IA, et al. Assessing the immunogenicity of biopharmaceuticals. BioDrugs 2016;30(3):195–206.
  18. Wadhwa M, Knezevic I, Kang HN, et al. Immunogenicity assessment of biotherapeutic products: An overview of assays and their utility. Biologicals 2015;43(5):298–306.
  19. Song S, Yang L, Trepicchio WL, et al. Understanding the supersensitive anti-drug antibody assay: Unexpected high anti-drug antibody incidence and its clinical relevance. J Immunol Res 2016;2016:3072586.
  20. Civoli F, Kasinath A, Cai XY, et al. Recommendations for the development and validation of immunogenicity assays in support of biosimilar programs. AAPS J 2019;22(1):7.
  21. Remicade® (infliximab). Prescribing information. 2021. Available at: https://www.janssenlabels.com/package-insert/product-monograph/prescribing-information/REMICADE-pi.pdf. Accessed October 17, 2023.
  22. Kharlamova N, Hermanrud C, Dunn N, et al. Drug tolerant anti-drug antibody assay for infliximab treatment in clinical practice identifies positive cases earlier. Front Immunol 2020;11:1365.
  23. Smolen JS, Choe JY, Prodanovic N, et al. Comparing biosimilar SB2 with reference infliximab after 54 weeks of a double-blind trial: clinical, structural and safety results. Rheumatology (Oxford) 2017;56(10):1771–1779.
  1. akhnovich V, Meibohm B, Rosenberg R, et al. Immunogenicity in clinical practice and drug development: When is it significant?
    Clin Transl Sci 2020;13(2):219–223.
  2. Padda IS, Bhatt R, Rehman O, et al. Biosimilars use in medicine for inflammatory diseases. 2023. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan. Available from: https://www.ncbi.nlm.nih.gov/books/NBK574572/. Accessed October 17, 2023.
  3. Liu PM, Zou L, Sadhu, C, et al. Comparative immunogenicity assessment: a critical consideration for biosimilar development. Bioanalysis 2015;7(3):373–381.
  4. World Health Organization. Health topics: Biologicals. 2023. Available at: https://www.who.int/health-topics/biologicals. Accessed October 17, 2023.
  5. Krishna M, Nadler SG. Immunogenicity to biotherapeutics – the role of anti-drug immune complexes. Front Immunol 2016;7:21.
  6. Weise M, Bielsky MC, De Smet K, et al. Biosimilars: what clinicians should know.
    Blood 2012;120:5111–5117.
  7. Kay J. A ‘wind of change’ to biosimilars: the NOR-SWITCH trial and its extension. J Intern Med 2019;285(6):693–695.
  8. Kaida-Yip F, Deshpande K, Saran T, et al. Biosimilars: Review of current applications, obstacles, and their future in medicine. World J Clin Cases 2018;6(8):161–166.
  9. US FDA. Biosimilars: Are they the same quality? 2023. Available at: https://www.fda.gov/media/161628/download. Accessed October 17, 2023.
  10. US FDA. Biological product definitions. 2023. Available at: https://www.fda.gov/files/drugs/published/Biological-Product-Definitions.pdf. Accessed October 17, 2023.
  11. US FDA. Immunogenicity testing of therapeutic protein products — Developing and validating assays for anti-drug antibody detection. 2019. Available at: https://www.fda.gov/media/119788/download. Accessed October 17, 2023.
  12. EMA.Guideline on immunogenicity assessment of therapeutic proteins. 2017. Available at: https://www.ema.europa.eu/en/documents/scientific -guideline/guideline-immunogenicity-assessment-therapeutic-proteins-revision-1_en.pdf. Accessed October 17, 2023.
  13. US FDA. 2015. Scientific considerations in demonstrating biosimilarity to a reference product. Available at: https://www.fda.gov/media/82647/download. Accessed October 17, 2023.
  14. Schreitmüller T, Barton B, Zharkov A, et al. Comparative immunogenicity assessment of biosimilars. Future Oncol 2019;15(3):319–329.
  15. EMA. Biosimilars in the EU. 2019. Available at: https://www.ema.europa.eu/en/documents/leaflet/biosimilars-eu-information-guide-healthcare-professionals_en.pdf. Accessed October 17, 2023.
  16. US FDA. Guidance for Industry. Immunogenicity assessment for therapeutic protein products. 2014. Available at: https://www.fda.gov/media/85017/download. Accessed October 17, 2023.
  17. Pineda C, Castañeda Hernández G, Jacobs IA, et al. Assessing the immunogenicity of biopharmaceuticals. BioDrugs 2016;30(3):195–206.
  18. Wadhwa M, Knezevic I, Kang HN, et al. Immunogenicity assessment of biotherapeutic products: An overview of assays and their utility. Biologicals 2015;43(5):298–306.
  19. Song S, Yang L, Trepicchio WL, et al. Understanding the supersensitive anti-drug antibody assay: Unexpected high anti-drug antibody incidence and its clinical relevance. J Immunol Res 2016;2016:3072586.
  20. Civoli F, Kasinath A, Cai XY, et al. Recommendations for the development and validation of immunogenicity assays in support of biosimilar programs. AAPS J 2019;22(1):7.
  21. Remicade® (infliximab). Prescribing information. 2021. Available at: https://www.janssenlabels.com/package-insert/product-monograph/prescribing-information/REMICADE-pi.pdf. Accessed October 17, 2023.
  22. Kharlamova N, Hermanrud C, Dunn N, et al. Drug tolerant anti-drug antibody assay for infliximab treatment in clinical practice identifies positive cases earlier. Front Immunol 2020;11:1365.
  23. Smolen JS, Choe JY, Prodanovic N, et al. Comparing biosimilar SB2 with reference infliximab after 54 weeks of a double-blind trial: clinical, structural and safety results. Rheumatology (Oxford) 2017;56(10):1771–1779
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This asset is intended for healthcare professionals only.