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Clinical Immunogenicity Risk Assessment for a Fusion Protein

  • Review Article
  • Theme: Compendium of Immunogenicity Risk Assessments: an Industry Guidance Built on Experience and Published Work
  • Published:
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Abstract

This document highlights some relevant factors in the assessment of immunogenicity risk of fusion protein therapeutics. Our aim is to highlight specific risks associated with this type of molecule, while also aligning with general risk assessment factors, through a hypothetical case study, where the therapeutic molecule of interest is a Receptor-Fc Fusion protein (RFF) expressed within a typical manufacturing process in Chinese Hamster Ovary Cells (CHO). Given that the components are comprised of endogenous sequences, the risk of developing an ADA response to this molecule is generally considered to be low. However, the consequences of such an immune response may be more severe, specifically, if there is cross reactivity with the endogenous receptor, inducing cell lysis, or if any ADA act as an agonist to trigger receptor signaling. The risk factors described below are not meant to provide a comprehensive list, but rather a framework for factors that should be considered. Immunogenicity risk is difficult to quantify and relies on a comprehensive analysis of both product and patient-related factors. The goal is not necessarily to quantify risk, but rather to demonstrate an understanding of factors that may pose a risk, implement a strategy to minimize risk factors and then align overall risk with a bioanalytical immunogenicity monitoring strategy. The consequences resulting from unexpected outcome will likely depend on severity and impact on patient safety. An immunogenicity risk assessment is an ongoing and continuous process throughout clinical development with the goal of maximizing the safety of patients.

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References

  1. Chamberlain P. Effective presentation of immunogenicity risk assessments and related data in regulatory dossiers. Bioanalysis. 2019.

  2. FDA. Guidance for Industry, Immunogenicity Assessment for Therapeutic Protein Products. 2014.

  3. Enbrel® (etanercept) Solution for Subcutaneous Use [Internet]. 2012. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/103795s5503lbl.pdf.

  4. Roopenian DC, Akilesh S. FcRn: the neonatal fc receptor comes of age. Nat Rev Immunol. 2007;7(9):715–25.

    Article  CAS  Google Scholar 

  5. ORENCIA (abatacept) for injection, for intravenous use for subcutaneous use [Internet]. 2017. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/125118s209lbl.pdf.

  6. NULOJIX (belatacept) for injection, for intravenous use [Internet]. 2017. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/125288s070lbl.pdf.

  7. Nplate™ (romiplostim) for subcutaneous injection [Internet]. 2008. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/125268s0026lbl.pdf.

  8. ARCALYSTTM (rilonacept) Injection for Subcutaneous Use [Internet]. 2008. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2008/125249lbl.pdf.

  9. Brezski RJ, Kinder M, Grugan KD, Soring KL, Carton J, Greenplate AR, et al. A monoclonal antibody against hinge-cleaved IgG restores effector function to proteolytically-inactivated IgGs in vitro and in vivo. MAbs. 2014;6(5):1265–73.

    Article  Google Scholar 

  10. Scapin G, Yang X, Prosise WW, McCoy M, Reichert P, Johnston JM, et al. Structure of full-length human anti-PD1 therapeutic IgG4 antibody pembrolizumab. Nat Struct Mol Biol. 2015;22(12):953–8.

    Article  CAS  Google Scholar 

  11. Wang X, Mathieu M, Brezski RJ. IgG fc engineering to modulate antibody effector functions. Protein Cell. 2018;9(1):63–73.

    Article  Google Scholar 

  12. Jacobsen FW, Stevenson R, Li C, Salimi-Moosavi H, Liu L, Wen J, et al. Engineering an IgG scaffold lacking effector function with optimized Developability. J Biol Chem. 2017;292(5):1865–75.

    Article  CAS  Google Scholar 

  13. Silva JP, Vetterlein O, Jose J, Peters S, Kirby H. The S228P mutation prevents in vivo and in vitro IgG4 fab-arm exchange as demonstrated using a combination of novel quantitative immunoassays and physiological matrix preparation. J Biol Chem. 2015;290(9):5462–9.

    Article  CAS  Google Scholar 

  14. Harmonisation ICo. ICH quality implementation working group, points to consider (R2); ICH-endorsed guide for Q8/Q9/Q10 implementation. 2011.

  15. Alt N, Zhang TY, Motchnik P, Taticek R, Quarmby V, Schlothauer T, et al. Determination of critical quality attributes for monoclonal antibodies using quality by design principles. Biologicals. 2016;44(5):291–305.

    Article  CAS  Google Scholar 

  16. Immunogenicity Testing of Therapeutic Protein Products — Developing and Validating Assays for Anti-Drug Antibody Detection, Guidance for Industry [Internet]. 2019. Available from: https://www.fda.gov/media/119788/download.

  17. Starcevic Manning M, Kroenke MA, Lee SA, Harrison SE, Hoofring SA, Mytych DT, et al. Assay signal as an alternative to titer for assessment of magnitude of an antidrug antibody response. Bioanalysis. 2017;9(23):1849–58.

    Article  CAS  Google Scholar 

  18. Lagasse HAD, Hengel H, Golding B, Sauna ZE. Fc-fusion drugs have FcgammaR/C1q binding and signaling properties that may affect their immunogenicity. AAPS J. 2019;21(4):62.

    Article  Google Scholar 

  19. Sazonovs A, Kennedy NA, Moutsianas L, Heap GA, Rice DL, Reppell M, et al. HLA-DQA1*05 carriage associated with development of anti-drug antibodies to infliximab and Adalimumab in patients with Crohn's disease. Gastroenterology. 2019.

  20. Voskuil MD, Bangma A, Weersma RK, Festen EAM. Predicting (side) effects for patients with inflammatory bowel disease: the promise of pharmacogenetics. World J Gastroenterol. 2019;25(21):2539–48.

    Article  CAS  Google Scholar 

  21. Rath T, Baker K, Dumont JA, Peters RT, Jiang H, Qiao SW, et al. Fc-fusion proteins and FcRn: structural insights for longer-lasting and more effective therapeutics. Crit Rev Biotechnol. 2015;35(2):235–54.

    Article  CAS  Google Scholar 

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Acknowledgments

We thank Valerie Quarmby (Genentech, Inc.) and Sally Fischer (Genentech, Inc.) for their careful review of this manuscript.

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Author notes

  1. Gizette Sperinde and Diana Montgomery contributed equally to this work.

Authors and Affiliations

  1. BioAnalytical Sciences, Genentech, Inc., 1 DNA Way, South San Francisco, CA, USA

    Gizette Sperinde

  2. Predictive and Clinical Immunogenicity, Merck & Co., Inc., West Point, PA, USA

    Diana Montgomery

  3. Clinical Immunology-Translational Medicine, Amgen Inc., Thousand Oaks, CA, USA

    Daniel T. Mytych

Authors
  1. Gizette Sperinde
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  2. Diana Montgomery
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  3. Daniel T. Mytych
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Correspondence to Gizette Sperinde.

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Guest Editor: Johanna Mora

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Sperinde, G., Montgomery, D. & Mytych, D.T. Clinical Immunogenicity Risk Assessment for a Fusion Protein. AAPS J 22, 64 (2020). https://doi.org/10.1208/s12248-020-00447-y

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  • DOI: https://doi.org/10.1208/s12248-020-00447-y

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