Advertisement

Analytical and Bioanalytical Chemistry

, Volume 410, Issue 11, pp 2829–2836 | Cite as

Development of an analytical method to assess the occupational health risk of therapeutic monoclonal antibodies using LC-HRMS

  • Lars M. H. Reinders
  • Martin D. Klassen
  • Martin Jaeger
  • Thorsten Teutenberg
  • Jochen Tuerk
Research Paper

Abstract

Monoclonal antibodies are a group of commonly used therapeutics, whose occupational health risk is still discussed controversially. The long-term low-dose exposure side effects are insufficiently evaluated; hence, discussions are often based on a theoretical level or extrapolating side effects from therapeutic dosages. While some research groups recommend applying the precautionary principle for monoclonal antibodies, others consider the exposure risk too low for measures taken towards occupational health and safety. However, both groups agree that airborne monoclonal antibodies have the biggest risk potential. Therefore, we developed a peptide-based analytical method for occupational exposure monitoring of airborne monoclonal antibodies. The method will allow collecting data about the occupational exposure to monoclonal antibodies. Thus, the mean daily intake for personnel in pharmacies and the pharmaceutical industry can be determined for the first time and will help to substantiate the risk assessment by relevant data. The introduced monitoring method includes air sampling, sample preparation and detection by liquid chromatography coupled with high-resolution mass spectrometry of individual monoclonal antibodies as well as sum parameter. For method development and validation, a chimeric (rituximab), humanised (trastuzumab) and a fully humanised (daratumumab) monoclonal antibody are used. A limit of detection between 1 μg per sample for daratumumab and 25 μg per sample for the collective peptide is achieved.

Graphical abstract

Demonstration of the analytical workflow, from the release of monoclonal antibodies to the detection as single substances as well as sum parameter.

Keywords

Monoclonal antibody Occupational exposure Sensitising High-resolution mass spectrometry Airborne Sum parameter 

Notes

Acknowledgements

We thank Agilent Technologies and especially Dr. Bita Kolahgar for providing the HPLC-QTOF system and the technical support.

Compliance with ethical standards

Conflict of interest

The authors declare they have no conflict of interest.

Supplementary material

216_2018_966_MOESM1_ESM.docx (68 kb)
ESM 1 (DOCX 67 kb)

References

  1. 1.
    Beck A, Sanglier-Cianferani S, Van Dorsselaer A. Biosimilar, biobetter, and next generation antibody characterization by mass spectrometry. Anal Chem. 2012;84(11):4637–46.  https://doi.org/10.1021/ac3002885.CrossRefGoogle Scholar
  2. 2.
    Rodgers KR, Chou RC. Therapeutic monoclonal antibodies and derivatives: historical perspectives and future directions. Biotechnol Adv. 2016;34(6):1149–58.  https://doi.org/10.1016/j.biotechadv.2016.07.004.CrossRefGoogle Scholar
  3. 3.
    Brian A. Baldo, (2017) Safety of biologics therapy: monoclonal antibodies, cytokines, fusion proteins, hormones, enzymes, coagulation proteins, vaccines, botulinum toxins, 1st Edition, Springer, 2016, Print Book ISBN: 978-3-319-30470-0, e-Book ISBN 978-3-319-30472-4. Drug Saf 40 (10):933–934.Google Scholar
  4. 4.
    Weiner GJ. Building better monoclonal antibody-based therapeutics. Nat Rev Cancer. 2015;15(6):361–70.  https://doi.org/10.1038/nrc3930.CrossRefGoogle Scholar
  5. 5.
    Lindsley CW. New 2016 data and statistics for global pharmaceutical products and projections through 2017. ACS Chem Neurosci. 2017;8(8):1635–6.  https://doi.org/10.1021/acschemneuro.7b00253.CrossRefGoogle Scholar
  6. 6.
    Beck A, Goetsch L, Dumontet C, Corvaia N. Strategies and challenges for the next generation of antibody drug conjugates. Nat Rev Drug Discov. 2017;16(5):315–37.  https://doi.org/10.1038/nrd.2016.268.CrossRefGoogle Scholar
  7. 7.
    Carter PJ, Lazar GA. Next generation antibody drugs: pursuit of the high-hanging fruit. Nat Rev Drug Discov. 2017;  https://doi.org/10.1038/nrd.2017.227.
  8. 8.
    Halsen G, Krämer I. Assessing the risk to health care staff from long-term exposure to anticancer drugs—the case of monoclonal antibodies. J Oncol Pharm Pract. 2011;17(1):68–80.  https://doi.org/10.1177/1078155210376847.CrossRefGoogle Scholar
  9. 9.
    King J, Alexander M, Byrne J, MacMillan K, Mollo A, Kirsa S, et al. A review of the evidence for occupational exposure risks to novel anticancer agents—a focus on monoclonal antibodies. J Oncol Pharm Pract. 2016;22(1):121–34.  https://doi.org/10.1177/1078155214550729.CrossRefGoogle Scholar
  10. 10.
    Langford S, Fradgley S, Evans M, Blanks C. Assessing the risk of handling monoclonal antibodies. Hosp Pharm. 2008;15:60–4.Google Scholar
  11. 11.
    Alexander M, King J, Bajel A, Doecke C, Fox P, Lingaratnam S, et al. Australian consensus guidelines for the safe handling of monoclonal antibodies for cancer treatment by healthcare personnel. Intern Med J. 2014;44(10):1018–26.  https://doi.org/10.1111/imj.12564.CrossRefGoogle Scholar
  12. 12.
    Bos JD, Meinardi M. The 500 Dalton rule for the skin penetration of chemical compounds and drugs. Exp Dermatol. 2000;9(3):165–9.  https://doi.org/10.1034/j.1600-0625.2000.009003165.x.CrossRefGoogle Scholar
  13. 13.
    Ferri N, Bellosta S, Baldessin L, Boccia D, Racagni G, Corsini A. Pharmacokinetics interactions of monoclonal antibodies. Pharmacol Res. 2016;111:592–9.  https://doi.org/10.1016/j.phrs.2016.07.015.CrossRefGoogle Scholar
  14. 14.
    Fellner RC, Terryah ST, Tarran R. Inhaled protein/peptide-based therapies for respiratory disease. Mol Cell Pediatr. 2016;3(1):16.  https://doi.org/10.1186/s40348-016-0044-8.CrossRefGoogle Scholar
  15. 15.
    Maillet A, Congy-Jolivet N, Le Guellec S, Vecellio L, Hamard S, Courty Y, et al. Aerodynamical, immunological and pharmacological properties of the anticancer antibody cetuximab. Pharm Res. 2008;25(6):1318–26.  https://doi.org/10.1007/s11095-007-9481-3.CrossRefGoogle Scholar
  16. 16.
    Kaestli LZ, Fonzo-Christe C, Bonfillon C, Desmeules J, Bonnabry P. Development of a standardised method to recommend protective measures to handle hazardous drugs in hospitals. Eur J Hosp Pharm-Sci Pract. 2013;20(2):100–5.  https://doi.org/10.1136/ejhpharm-2012-000222.CrossRefGoogle Scholar
  17. 17.
    Halsen G, Krämer I. Bewertung monoklonaler Antikörper zum Schutz Beschäftigter. Berufsgenossenschaft für Gesundheitsdienst und Wohlfahrtspflege. Germany: Hamburg; 2008.Google Scholar
  18. 18.
  19. 19.
    Mandel J. The statistical analysis of experimental data. Washington: Wiley; 1964.Google Scholar
  20. 20.
    Sandra K, Vandenheede I, Sandra P. Modern chromatographic and mass spectrometric techniques for protein biopharmaceutical characterization. J Chromatogr A. 2014;1335:81–103.  https://doi.org/10.1016/j.chroma.2013.11.057.CrossRefGoogle Scholar
  21. 21.
    van den Broek I, Niessen WMA, van Dongen WD. Bioanalytical LC-MS/MS of protein-based biopharmaceuticals. J Chromatogr B. 2013;929:161–79.  https://doi.org/10.1016/j.jchromb.2013.04.030.CrossRefGoogle Scholar
  22. 22.
    Beck A, Wagner-Rousset E, Ayoub D, Van Dorsselaer A, Sanglier-Cianferani S. Characterization of therapeutic antibodies and related products. Anal Chem. 2013;85(2):715–36.  https://doi.org/10.1021/ac3032355.CrossRefGoogle Scholar
  23. 23.
    Leurs U, Mistarz UH, Rand KD. Getting to the core of protein pharmaceuticals—comprehensive structure analysis by mass spectrometry. Eur J Pharm Biopharm. 2015;93:95–109.  https://doi.org/10.1016/j.ejpb.2015.03.012.CrossRefGoogle Scholar
  24. 24.
    Nowak C, Cheung J, Dellatore S, Katiyar A, Bhat R, Sun J, Ponniah G, Neill A, Mason B, Beck A, Liu H. Forced degradation of recombinant monoclonal antibodies: a practical guide. mAbs. 2017; 1–14.  https://doi.org/10.1080/19420862.2017.1368602.
  25. 25.
    Schey KL, Finley EL. Identification of peptide oxidation by tandem mass spectrometry. Accounts Chem Res. 2000;33(5):299–306.  https://doi.org/10.1021/ar9800744.CrossRefGoogle Scholar
  26. 26.
    Joubert MK, Luo QZ, Nashed-Samuel Y, Wypych J, Narhi LO. Classification and characterization of therapeutic antibody aggregates. J Biol Chem. 2011;286(28):25118–33.  https://doi.org/10.1074/jbc.M110.160457.CrossRefGoogle Scholar
  27. 27.
    Wu HX, Kroe-Barrett R, Singh S, Robinson AS, Roberts CJ. Competing aggregation pathways for monoclonal antibodies. FEBS Lett. 2014;588(6):936–41.  https://doi.org/10.1016/j.febslet.2014.01.051.CrossRefGoogle Scholar
  28. 28.
  29. 29.
    Wei T, Kaewtathip S, Shing K. Buffer effect on protein adsorption at liquid/solid interface. J Phys Chem C. 2009;113(6):2053–62.  https://doi.org/10.1021/jp806586n.CrossRefGoogle Scholar
  30. 30.
    ISPE. Good practice guide: assessing the particulate containment performance of pharmaceutical equipment. 2nd ed. Bethesda: International Society for Pharmaceutical Engineering; 2012.Google Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Lars M. H. Reinders
    • 1
    • 2
  • Martin D. Klassen
    • 1
  • Martin Jaeger
    • 2
  • Thorsten Teutenberg
    • 1
  • Jochen Tuerk
    • 1
  1. 1.Institut für Energie und Umwelttechnik e. V. (IUTA, Institute of Energy and Environmental Technology)DuisburgGermany
  2. 2.Hochschule Niederrhein (University of Applied Science Niederrhein)KrefeldGermany

Personalised recommendations