We use cookies to improve your experience. By continuing to browse this site, you accept our cookie policy.×
Research Article

Use of generic LC–MS/MS assays to characterize atypical PK profile of a biotherapeutic monoclonal antibody

    Wai Siang Law

    Department of Drug Metabolism & Pharmacokinetics Biologics, Novartis Institute for Biomedical Research, Novartis, Basel, Switzerland

    ClinTec International AG, Baarerstrasse, Zug, Switzerland

    ,
    Jean-Christophe Genin

    Department of Drug Metabolism & Pharmacokinetics Biologics, Novartis Institute for Biomedical Research, Novartis, Basel, Switzerland

    ,
    Christian Miess

    Department of Drug Metabolism & Pharmacokinetics Biologics, Novartis Institute for Biomedical Research, Novartis, Basel, Switzerland

    ,
    Gwenola Treton

    Department of Drug Metabolism & Pharmacokinetics Biologics, Novartis Institute for Biomedical Research, Novartis, Basel, Switzerland

    ,
    Andrew Paul Warren

    Department of Drug Metabolism & Pharmacokinetics Biologics, Novartis Institute for Biomedical Research, Novartis, Basel, Switzerland

    ,
    Peter Lloyd

    Department of Drug Metabolism & Pharmacokinetics Biologics, Novartis Institute for Biomedical Research, Novartis, Basel, Switzerland

    KinDyn Consulting LDT, UK

    ,
    Sherri Dudal

    Department of Drug Metabolism & Pharmacokinetics Biologics, Novartis Institute for Biomedical Research, Novartis, Basel, Switzerland

    KinDyn Consulting LDT, UK

    &
    Carsten Krantz

    *Author for correspondence:

    E-mail Address: carsten.krantz@novartis.com

    Department of Drug Metabolism & Pharmacokinetics Biologics, Novartis Institute for Biomedical Research, Novartis, Basel, Switzerland

    Published Online:https://doi.org/10.4155/bio.14.167

    Background: The fully human monoclonal antibody mAb123, which binds to and neutralizes chemokine motif ligand-21 (CCL21) displays a faster clearance in cynomolgus monkey compared with typical IgG kinetics. A direct and an immunoaffinity LC–MS/MS assays were developed to compare with the previously established ligand-binding assays (LBAs). Results: A strong correlation of LC–MS/MS pharmacokinetic data with LBA data confirmed the rapid drug disposition of mAb123 is an intrinsic property of the molecule, rather than interference of anti-mAb123 antibodies in the LBA. Conclusion: The data illustrate that in cases of unexpected results from LBA, application of orthogonal bioanalytical techniques such as LC–MS/MS can help in in interpretation of pharmacokinetic as determined by LBAs.

    Papers of special note have been highlighted as: • of interest; •• of considerable interest

    References

    • 1 Adams GP, Weiner LM. Monoclonal antibody therapy of cancer. Nat. Biotech. 23(9), 1147–1157 (2005).
    • 2 Schrama D, Reisfeld RA, Becker JC. Antibody targeted drugs as cancer therapeutics. Nat. Rev Drug Discov. 5(2), 147–159 (2006).
    • 3 Weiner LM. Fully human therapeutic monoclonal antibodies. J. Immunother 29(1), 1–9 (2006).
    • 4 Zioncheck TF, Chen SA, Richardson L et al. Pharmacokinetics and tissue distribution of recombinant human transforming growth-factor beta(1) after topical and intravenous administration in male-rats. Pharm. Res 11(2), 213–220 (1994).
    • 5 Desilva B, Smith W, Weiner R et al. Recommendations for the bioanalytical method validation of ligand-binding assays to support pharmacokinetic assessments of macromolecules. Pharm. Res. 20(11), 1885–1900 (2003).
    • 6 Lee JW, Kelley M, King LE et al. Bioanalytical approaches to quantify “total” and “free” therapeutic antibodies and their targets: technical challenges and PK/PD applications over the course of drug development. AAPS J. 13(1), 99–110 (2011).•• Describes the impact of quantifying total and free drug on PK and pharmacodynamik data intepretation.
    • 7 Li Hy, Ortiz R, Tran L 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. 84(3), 1267–1273 (2012).
    • 8 Domon B, Aebersold R. Review – mass spectrometry and protein analysis. Science 312(5771), 212–217 (2006).• Eight interesting reviews on the protein analysis by mass spectrometry.
    • 9 Furlong MT, Ouyang Z, Wu S et al. A universal surrogate peptide to enable LC–MS/MS bioanalysis of a diversity of human monoclonal antibody and human Fc-fusion protein drug candidates in pre-clinical animal studies. Biomed. Chromatogr. 26(8), 1024–1032.
    • 10 Heudi O, Barteau S, Zimmer D et al. Towards absolute quantification of therapeutic monoclonal antibody in serum by LC–MS/MS using isotope-labeled antibody standard and protein cleavage isotope dilution mass spectrometry. Anal. Chem. 80(11), 4200–4207 (2008).
    • 11 Hagman C, Ricke D, Ewert S et al. Absolute quantification of monoclonal antibodies in biofluids by liquid chromatography-tandem mass spectrometry. Anal. Chem. 80(4), 1290–1296 (2008).• Describes absolute quantification of therapeutic antibody using LC–MS.
    • 12 Ji CJ, Sadagopan N, Zhang YZ, Lepsy C. A universal strategy for development of a method for absolute quantification of therapeutic monoclonal antibodies in biological matrices using differential dimethyl labeling coupled with ultra-performance liquid chromatography-tandem mass spectrometry. Anal. Chem. 81(22), 9321–9328 (2009).
    • 13 Yang ZP, Hayes M, Fang XP et al. LC–MS/MS approach therapeutic proteins for quantification of in plasma using a protein internal standard and 2D-solid-phase extraction cleanup. Anal. Chem. 79(24), 9294–9301 (2007).
    • 14 Mire-Sluis AR, Barrett YC, Devanarayan V et al. Recommendations for the design and optimization of immunoassays used in the detection of host antibodies against biotechnology products. J. Immunol. Methods 289(1–2), 1–16 (2004).
    • 15 Koren E, Smith HW, Shores E et al. Recommendations on risk-based strategies for detection and characterization of antibodies against biotechnology products. J. Immunol. Methods 333(1–2), 1–9 (2008).
    • 16 Shankar G, Devanarayan V, Amaravadi L et al. Recommendations for the validation of immunoassays used for detection of host antibodies against biotechnology products. J. Pharm. Biomed. Anal. 48(5), 1267–1281 (2008).
    • 17 Wang SJ, Wu ST, Gokemeijer J et al. Attribution of the discrepancy between ELISA and LC–MS/MS assay results of a PEGylated scaffold protein in post-dose monkey plasma samples due to the presence of anti-drug antibodies. Anal. Biol. Chem. 402(3), 1229–1239 (2012).• Compares the PK data from ligand-binding assays and LC–MS.
    • 18 Sailstad JM, Amaravadi L, Clements-Egan A et al. A white paper-consensus and recommendations of a global harmonization team on assessing the impact of immunogenicity on pharmacokinetic measurements. AAPS J. 1–11 (2014).
    • 19 Ji QC, Rodila R, Morgan SJ et al. Investigation of the immunogenicity of a protein drug using equilibrium dialysis and liquid chromatography tandem mass spectrometry detection. Anal. Chem. 77(17), 5529–5533 (2005).
    • 20 Kelley M, Ahene AB, Gorovits B et al. Theoretical considerations and practical approaches to address the effect of anti-drug antibody (ADA) on quantification of biotherapeutics in circulation. AAPS J. 15(3), 646–658 (2013).
    • 21 Darwish IA, Al-Obaid ARM, Al-Malaq HAM. Preparation of a highly specific polyclonal antibody against fluvastatin and its use in development of ELISA for determination of fluvastatin in plasma. Anal. Met. 1(3), 220–224 (2009).
    • 22 Stubenrauch K, Wessels U, Essig U et al. Evaluation of a generic immunoassay with drug tolerance to detect immune complexes in serum samples from cynomolgus monkeys after administration of human antibodies. J. Pharm. Biomed. Anal. 52(2), 249–254 (2010).
    • 23 De Dios K, Manibusan A, Marsden R et al. Comparison of bioanalytical methods for the quantitation of PEGylated human insulin. J. Immunol. Methods 396(1–2), 1–7 (2013).• Comares the PK data from ligand-binding assays and LC–MS
    • 24 Huang LH, Li JR, Wroblewski VJ et al. In vivo deamidation characterization of monoclonal antibody by LC/MS/MS. Anal. Chem. 77(5), 1432–1439 (2005).
    • 25 Tous GI, Wei ZP, Feng JH et al. Characterization of a novel modification to monoclonal antibodies: thioether cross-link of heavy and light chains. Anal. Chem. 77(9), 2675–2682 (2005).
    • 26 Yates JR. Mass spectrometry – from genomics to proteomics. Trends Genet. 16(1), 5–8 (2000).
    • 27 Lange V, Picotti P, Domon B, Aebersold R. Selected reaction monitoring for quantitative proteomics: a tutorial. Mol. Syst. Biol. 4, 222 (2008).•• Provides overview of selected reaction monitoring.
    • 28 Mallick P, Kuster B. Proteomics: a pragmatic perspective. Nat. Biotech. 28(7), 695–709 (2010).
    • 29 Domon B, Aebersold R. Options and considerations when selecting a quantitative proteomics strategy. Nat. Biotech. 28(7), 710–721 (2010).
    • 30 Kiyonami R, Schoen A, Prakash A et al. Increased selectivity, analytical precision, and throughput in targeted proteomics. Mol. Cell. Proteomics 10(2), M110.002931 (2011).
    • 31 Wu SL, Amato H, Biringer R et al. Targeted proteomics of low-level proteins in human plasma by LC/MSn: Using human growth hormone as a model system. J. Proteome Res. 1(5), 459–465 (2002).
    • 32 Nagele E, Vollmer M, Horth P et al. 2D-LC/MS techniques for the identification of proteins in highly complex mixtures. Expert Rev. Proteomics 1(1), 37–46 (2004).
    • 33 Delahunty C, Yates JR. Protein identification using 2D-LC–MS/MS. Methods 35(3), 248–255 (2005).
    • 34 Taylor PJ. Matrix effects: The Achilles heel of quantitative high-performance liquid chromatography-electrospray-tandem mass spectrometry. Clin. Biochem. 38(4), 328–334 (2005).
    • 35 Anderson L, Hunter CL. Quantitative mass spectrometric multiple reaction monitoring assays for major plasma proteins. Mol. Cell. Proteomics 5(4), 573–588 (2006).
    • 36 Xu Y, Mehl JT, Bakhtiar R et al. Immunoaffinity purification using anti-PEG antibody followed by two-dimensional liquid chromatography/tandem mass spectrometry for the quantification of a PEGylated therapeutic peptide in human plasma. Anal. Chem. 82(16), 6877–6886 (2010).
    • 37 Ackermann BL, Berna MJ. Coupling immunoaffinity techniques with MS for quantitative analysis of low-abundance protein biomarkers. Expert Rev. Proteomics 4(2), 175–186 (2007).
    • 38 Knutsson M, Schmidt R, Timmerman P. LC–MS/MS of large molecules in a regulated bioanalytical environment – which acceptance criteria to apply? Bioanalysis 5(18), 2211–2214 (2013).• Describes the acceptance criteria for LC–MS/MS of large molecule in regulated environment.
    • 39 Hotzel I, Theil FP, Bernstein LJ et al. A strategy for risk mitigation of antibodies with fast clearance. MAbs 4(6), 753–760 (2012).
    • 40 Deng R, Iyer S, Theil FP et al. Projecting human pharmacokinetics of therapeutic antibodies from nonclinical data. What have we learned? MAbs 3(1), 61–66 (2011).