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BioDrugs

, Volume 28, Issue 4, pp 383–391 | Cite as

Practical Considerations for the Pharmacokinetic and Immunogenic Assessment of Antibody–Drug Conjugates

  • Melody Sauerborn
  • William van Dongen
Review Article

Abstract

Currently, the most bioanalytically challenging drugs are antibody–drug conjugates (ADCs), constructs comprising a monoclonal antibody and a cytotoxic drug connected by a linker. The bioanalytical challenges arise from the heterogeneous nature of ADCs and their complex in vivo behavior, resulting in a high number of analytes to be measured. Measuring the concentration of biologics in blood/plasma/serum is a necessity to properly assess their pharmacokinetic (PK)/pharmacodynamic behaviors in vivo. An additional bioanalytical challenge is to monitor the stability of the ADCs, as cytotoxic drugs released from the ADC in blood circulation may pose a potential safety risk because of their high cytotoxic potency. The nature of ADCs does not only complicate bioanalysis, but also immunogenicity assessment. Questions, such as ‘Which part of the ADCs is the anti-drug antibodies directed against?’ may arise, and their answer normally includes several immunogenicity risk assessment strategies. This review will focus on the bioanalytical challenges of ADCs, current approaches involving ligand-binding assays (LBAs), liquid chromatography and mass spectrometry platforms, and recommendations on which approach to use for which stage of drug development, and will close with immunogenicity assessment. In order to appropriately tackle the bioanalytical and immunogenic challenges of ADCs and consider every angle, the authors of this review have expertise in ligand binding and liquid chromatography–mass spectrometry.

Keywords

Cetuximab Cytotoxic Drug Therapeutic Antibody Complementarity Determine Region Brentuximab Vedotin 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgments and Disclosures

The authors declare no conflicts of interest in this work and that everything was written by the stated authors.

References

  1. 1.
    Flygare JA, Pillow TH, Aristoff P. Antibody–drug conjugates for the treatment of cancer. Chem Biol Drug Des. 2013;81(1):113–21.PubMedCrossRefGoogle Scholar
  2. 2.
    Iyer U, Kadambi VJ. Antibody drug conjugates—Trojan horses in the war on cancer. J Pharmacol Toxicol Methods. 2011;64(3):207–12.PubMedCrossRefGoogle Scholar
  3. 3.
    Lambert JM. Drug-conjugated antibodies for the treatment of cancer. Br J Clin Pharmacol. 2013;76(2):248–62.PubMedCrossRefGoogle Scholar
  4. 4.
    Senter PD, Sievers EL. The discovery and development of brentuximab vedotin for use in relapsed Hodgkin lymphoma and systemic anaplastic large cell lymphoma. Nat Biotechnol. 2012;30(7):631–7.PubMedCrossRefGoogle Scholar
  5. 5.
    Lewis Phillips GD, et al. Targeting HER2-positive breast cancer with trastuzumab-DM1, an antibody-cytotoxic drug conjugate. Cancer Res. 2008;68(22):9280–90.Google Scholar
  6. 6.
    Hamblett KJ, et al. Effects of drug loading on the antitumor activity of a monoclonal antibody drug conjugate. Clin Cancer Res. 2004;10(20):7063–70.PubMedCrossRefGoogle Scholar
  7. 7.
    Xu K, et al. Characterization of intact antibody–drug conjugates from plasma/serum in vivo by affinity capture capillary liquid chromatography-mass spectrometry. Anal Biochem. 2011;412(1):56–66.PubMedCrossRefGoogle Scholar
  8. 8.
    Sun X, et al. Design of antibody-maytansinoid conjugates allows for efficient detoxification via liver metabolism. Bioconjug Chem. 2011;22(4):728–35.PubMedCrossRefGoogle Scholar
  9. 9.
    Gorovits B, et al. Bioanalysis of antibody–drug conjugates: American Association of Pharmaceutical Scientists Antibody–Drug Conjugate Working Group position paper. Bioanalysis. 2013;5(9):997–1006.PubMedCrossRefGoogle Scholar
  10. 10.
    Hopfgartner G, Bourgogne E. Quantitative high-throughput analysis of drugs in biological matrices by mass spectrometry. Mass Spectrom Rev. 2003;22(3):195–214.PubMedCrossRefGoogle Scholar
  11. 11.
    Xu RN, et al. Recent advances in high-throughput quantitative bioanalysis by LC–MS/MS. J Pharm Biomed Anal. 2007;44(2):342–55.PubMedCrossRefGoogle Scholar
  12. 12.
    Stephan JP, Kozak KR, Wong WL. Challenges in developing bioanalytical assays for characterization of antibody–drug conjugates. Bioanalysis. 2011;3(6):677–700.PubMedCrossRefGoogle Scholar
  13. 13.
    Sanderson RJ, et al. In vivo drug-linker stability of an anti-CD30 dipeptide-linked auristatin immunoconjugate. Clin Cancer Res. 2005;11(2 Pt 1):843–52.PubMedGoogle Scholar
  14. 14.
    Stephan JP, et al. Anti-CD22-MCC-DM1 and MC-MMAF conjugates: impact of assay format on pharmacokinetic parameters determination. Bioconjug Chem. 2008;19(8):1673–83.PubMedCrossRefGoogle Scholar
  15. 15.
    Wakankar A, et al. Analytical methods for physicochemical characterization of antibody drug conjugates. MAbs. 2011;3(2):161–72.PubMedCentralPubMedCrossRefGoogle Scholar
  16. 16.
    Kozak KR, et al. Total antibody quantification for MMAE-conjugated antibody–drug conjugates: impact of assay format and reagents. Bioconjug Chem. 2013;24(5):772–9.PubMedCrossRefGoogle Scholar
  17. 17.
    Li H, et al. General LC–MS/MS method approach to quantify therapeutic monoclonal antibodies using a common whole antibody internal standard with application to preclinical studies. Anal Chem. 2012;84(3):1267–73.PubMedCrossRefGoogle Scholar
  18. 18.
    van den Broek I, Niessen WM, van Dongen WD. Bioanalytical LC–MS/MS of protein-based biopharmaceuticals. J Chromatogr B Analyt Technol Biomed Life Sci. 2013;929:161–79.PubMedCrossRefGoogle Scholar
  19. 19.
    Fernandez Ocana M, et al. Clinical pharmacokinetic assessment of an anti-MAdCAM monoclonal antibody therapeutic by LC–MS/MS. Anal Chem. 2012;84(14):5959–67.Google Scholar
  20. 20.
    Kaur S, et al. Bioanalytical assay strategies for the development of antibody–drug conjugate biotherapeutics. Bioanalysis. 2013;5(2):201–26.PubMedCrossRefGoogle Scholar
  21. 21.
    Lin K, Tibbitts J. Pharmacokinetic considerations for antibody drug conjugates. Pharm Res. 2012;29(9):2354–66.PubMedCrossRefGoogle Scholar
  22. 22.
    Rispens T, et al. Mechanism of immunoglobulin G4 Fab-arm exchange. J Am Chem Soc. 2011;133(26):10302–11.PubMedCrossRefGoogle Scholar
  23. 23.
    Labrijn AF, et al. Therapeutic IgG4 antibodies engage in Fab-arm exchange with endogenous human IgG4 in vivo. Nat Biotechnol. 2009;27(8):767–71.PubMedCrossRefGoogle Scholar
  24. 24.
    Stubenrauch K, et al. Impact of molecular processing in the hinge region of therapeutic IgG4 antibodies on disposition profiles in cynomolgus monkeys. Drug Metab Dispos. 2010;38(1):84–91.PubMedCrossRefGoogle Scholar
  25. 25.
    Casadevall A, Scharff MD. Serum therapy revisited: animal models of infection and development of passive antibody therapy. Antimicrob Agents Chemother. 1994;38(8):1695–702.PubMedCentralPubMedCrossRefGoogle Scholar
  26. 26.
    Baker MP, et al. Immunogenicity of protein therapeutics: the key causes, consequences and challenges. Self Nonself. 2010;1(4):314–22.PubMedCentralPubMedCrossRefGoogle Scholar
  27. 27.
    Schellekens H. Factors influencing the immunogenicity of therapeutic proteins. Nephrol Dial Transplant. 2005;20(Suppl 6):vi3–9.Google Scholar
  28. 28.
    Reichert JM. Antibodies to watch in 2014. MAbs 2013;6(1):5–14.Google Scholar
  29. 29.
    Hansel TT, et al. The safety and side effects of monoclonal antibodies. Nat Rev Drug Discov. 2010;9(4):325–38.PubMedCrossRefGoogle Scholar
  30. 30.
    Chung CH, et al. Cetuximab-induced anaphylaxis and IgE specific for galactose-alpha-1,3-galactose. N Engl J Med. 2008;358(11):1109–17.PubMedCentralPubMedCrossRefGoogle Scholar
  31. 31.
    Ghaderi D, et al. Production platforms for biotherapeutic glycoproteins. Occurrence, impact, and challenges of non-human sialylation. Biotechnol Genet Eng Rev. 2012;28:147–75.PubMedCrossRefGoogle Scholar
  32. 32.
    Yin BJ, et al. Generation of glyco-engineered BY2 cell lines with decreased expression of plant-specific glycoepitopes. Protein Cell. 2011;2(1):41–7.PubMedCrossRefGoogle Scholar
  33. 33.
    Moore WV, Leppert P. Role of aggregated human growth hormone (hGH) in development of antibodies to hGH. J Clin Endocrinol Metab. 1980;51(4):691–7.PubMedCrossRefGoogle Scholar
  34. 34.
    Sauerborn M, et al. Immunological mechanism underlying the immune response to recombinant human protein therapeutics. Trends Pharmacol Sci. 2010;31(2):53–9.PubMedCrossRefGoogle Scholar
  35. 35.
    Ratanji KD, et al. Immunogenicity of therapeutic proteins: influence of aggregation. J Immunotoxicol. 2014;11(2):99–109.Google Scholar
  36. 36.
    Vugmeyster Y, et al. Pharmacokinetics and toxicology of therapeutic proteins: Advances and challenges. World J Biol Chem. 2012;3(4):73–92.PubMedCentralPubMedCrossRefGoogle Scholar
  37. 37.
    Krieckaert C, Rispens T, Wolbink G. Immunogenicity of biological therapeutics: from assay to patient. Curr Opin Rheumatol. 2012;24(3):306–11.PubMedCrossRefGoogle Scholar
  38. 38.
    Shin SK, et al. Anti-erythropoietin and anti-thrombopoietin antibodies induced after administration of recombinant human erythropoietin. Int Immunopharmacol. 2011;11(12):2237–41.PubMedCrossRefGoogle Scholar
  39. 39.
    Peyvandi F, Garagiola I, Seregni S. Future of coagulation factor replacement therapy. J Thromb Haemost. 2013;11(Suppl 1):84–98.PubMedCrossRefGoogle Scholar
  40. 40.
    Finco D, et al. Comparison of competitive ligand-binding assay and bioassay formats for the measurement of neutralizing antibodies to protein therapeutics. J Pharm Biomed Anal. 2011;54(2):351–8.PubMedCrossRefGoogle Scholar
  41. 41.
    Buttel IC, et al. Taking immunogenicity assessment of therapeutic proteins to the next level. Biologicals. 2011;39(2):100–9.PubMedCrossRefGoogle Scholar
  42. 42.
    Jawa V, et al. T-cell dependent immunogenicity of protein therapeutics: Preclinical assessment and mitigation. Clin Immunol. 2013;149(3):534–55.PubMedCrossRefGoogle Scholar
  43. 43.
    Hollander I, Kunz A, Hamann PR. Selection of reaction additives used in the preparation of monomeric antibody-calicheamicin conjugates. Bioconjug Chem. 2008;19(1):358–61.PubMedCrossRefGoogle Scholar
  44. 44.
    Gorovits B, Krinos-Fiorotti C. Proposed mechanism of off-target toxicity for antibody–drug conjugates driven by mannose receptor uptake. Cancer Immunol Immunother. 2013;62(2):217–23.PubMedCrossRefGoogle Scholar
  45. 45.
    Hoofring SA, et al. Immunogenicity testing strategy and bioanalytical assays for antibody–drug conjugates. Bioanalysis. 2013;5(9):1041–55.PubMedCrossRefGoogle Scholar
  46. 46.
    Koren E, et al. Recommendations on risk-based strategies for detection and characterization of antibodies against biotechnology products. J Immunol Methods. 2008;333(1–2):1–9.PubMedCrossRefGoogle Scholar
  47. 47.
    Barbosa MD, et al. Addressing drug effects on cut point determination for an anti-drug antibody assay. J Immunol Methods. 2012;384(1–2):152–6.PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2014

Authors and Affiliations

  1. 1.Department of BioanalysisTNO TriskelionZeistThe Netherlands

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