Quantitation and modeling of post-translational modifications in a therapeutic monoclonal antibody from single- and multiple-dose monkey pharmacokinetic studies using mass spectrometry
Autoři:
Xiaobin Xu aff001; Yu Huang aff001; Hao Pan aff001; Rosalynn Molden aff001; Haibo Qiu aff001; Thomas J. Daly aff001; Ning Li aff001
Působiště autorů:
Regeneron Pharmaceuticals Inc., Tarrytown, New York, United States of America
aff001
Vyšlo v časopise:
PLoS ONE 14(10)
Kategorie:
Research Article
prolekare.web.journal.doi_sk:
https://doi.org/10.1371/journal.pone.0223899
Souhrn
Post-translational modifications (PTMs) of therapeutic monoclonal antibodies (mAbs) are important product quality attributes (PQAs) that can potentially impact drug stability, safety, and efficacy. The PTMs of a mAb may change remarkably in the bloodstream after drug administration compared to in vitro conditions. Thus, monitoring in vivo PTM changes of mAbs helps evaluate the criticality of PQAs during the product risk assessment. In addition, quantitation of the subject exposures to PTM variants helps assess the impact of PTMs on the safety and efficacy of therapeutic mAbs. Here, we developed an immunocapture-liquid chromatography/mass spectrometry (LC/MS) method to quantify in vivo PTM changes a therapeutic mAb overtime in single- and multiple-dose monkey pharmacokinetic (PK) studies. We also built mathematical models to predict the in vivo serum concentrations of PQAs, the subject exposures to PQAs, and the relative abundance of PQAs in single- and multiple-dose regimens. The model predictions are in good agreement with the experimental results. The immunocapture-LC/MS method and mathematical models enable bioanalytical chemists to quantitatively assess the criticality of PQAs during drug development.
Klíčová slova:
Lysine – Liquid chromatography-mass spectrometry – Dose prediction methods – Oxidation – Mannose – Deamidation – Adjustment of dosage at steady state – Affinity purification
Zdroje
1. Kozlowski S, Swann P. Current and future issues in the manufacturing and development of monoclonal antibodies. Advanced drug delivery reviews. 2006;58(5–6):707–22. doi: 10.1016/j.addr.2006.05.002 16828921
2. Liu H, Gaza-Bulseco G, Faldu D, Chumsae C, Sun J. Heterogeneity of monoclonal antibodies. Journal of pharmaceutical sciences. 2008;97(7):2426–47. doi: 10.1002/jps.21180 17828757
3. Goetze AM, Schenauer MR, Flynn GC. Assessing monoclonal antibody product quality attribute criticality through clinical studies. mAbs. 2010;2(5):500–7. doi: 10.4161/mabs.2.5.12897 20671426
4. Wang W, Singh S, Zeng DL, King K, Nema S. Antibody structure, instability, and formulation. Journal of pharmaceutical sciences. 2007;96(1):1–26. doi: 10.1002/jps.20727 16998873
5. Xu X, Qiu H, Li N. LC-MS multi-attribute method for characterization of biologics. Journal of Applied Bioanalysis. 2017;3(2):21–5. doi: 10.17145/jab.17.003
6. Xu X. In vivo characterization of therapeutic monoclonal antibodies. Journal of Applied Bioanalysis. 2016;2(1):6.
7. Guidance for Industry, Immunogenicity Assessment for Therapeutic Protein Products. 2014.
8. Huang L, Lu J, Wroblewski VJ, Beals JM, Riggin RM. In vivo deamidation characterization of monoclonal antibody by LC/MS/MS. Analytical chemistry. 2005;77(5):1432–9. doi: 10.1021/ac0494174 15732928
9. Ouellette D, Chumsae C, Clabbers A, Radziejewski C, Correia I. Comparison of the in vitro and in vivo stability of a succinimide intermediate observed on a therapeutic IgG1 molecule. mAbs. 2013;5(3):432–44. doi: 10.4161/mabs.24458 23608772
10. Yin S, Pastuskovas CV, Khawli LA, Stults JT. Characterization of therapeutic monoclonal antibodies reveals differences between in vitro and in vivo time-course studies. Pharmaceutical research. 2013;30(1):167–78. doi: 10.1007/s11095-012-0860-z 22956170
11. Li Y, Huang Y, Ferrant J, Lyubarskaya Y, Zhang E, Li P et al. Assessing in vivo dynamics of multiple quality attributes from a therapeutic IgG4 monoclonal antibody circulating in cynomolgus monkey. mAbs. 2016:0. doi: 10.1080/19420862.2016.1167298 27030286
12. Li Y, Monine M, Huang Y, Swann P, Nestorov I, Lyubarskaya Y. Quantitation and pharmacokinetic modeling of therapeutic antibody quality attributes in human studies. mAbs. 2016:0. doi: 10.1080/19420862.2016.1186322 27216574
13. Goetze AM, Liu YD, Arroll T, Chu L, Flynn GC. Rates and impact of human antibody glycation in vivo. Glycobiology. 2012;22(2):221–34. doi: 10.1093/glycob/cwr141 21930650
14. Goetze AM, Liu YD, Zhang Z, Shah B, Lee E, Bondarenko PV et al. High-mannose glycans on the Fc region of therapeutic IgG antibodies increase serum clearance in humans. Glycobiology. 2011;21(7):949–59. doi: 10.1093/glycob/cwr027 21421994
15. Alessandri L, Ouellette D, Acquah A, Rieser M, Leblond D, Saltarelli M et al. Increased serum clearance of oligomannose species present on a human IgG1 molecule. mAbs. 2012;4(4):509–20. doi: 10.4161/mabs.20450 22669558
16. Liu YD, Chen X, Enk JZ, Plant M, Dillon TM, Flynn GC. Human IgG2 antibody disulfide rearrangement in vivo. The Journal of biological chemistry. 2008;283(43):29266–72. doi: 10.1074/jbc.M804787200 18713741
17. Gu S, Wen D, Weinreb PH, Sun Y, Zhang L, Foley SF et al. Characterization of trisulfide modification in antibodies. Analytical biochemistry. 2010;400(1):89–98. doi: 10.1016/j.ab.2010.01.019 20085742
18. Liu YD, Goetze AM, Bass RB, Flynn GC. N-terminal glutamate to pyroglutamate conversion in vivo for human IgG2 antibodies. The Journal of biological chemistry. 2011;286(13):11211–7. doi: 10.1074/jbc.M110.185041 21282104
19. Cai B, Pan H, Flynn GC. C-terminal lysine processing of human immunoglobulin G2 heavy chain in vivo. Biotechnology and bioengineering. 2011;108(2):404–12. doi: 10.1002/bit.22933 20830675
20. Rowland M, Tozer TN. Clinical Pharmacokinetics and Pharmacodynamics: Concepts and Applications. Wolters Kluwer Health/Lippincott William & Wilkins; 2011.
21. Chelius D, Rehder DS, Bondarenko PV. Identification and characterization of deamidation sites in the conserved regions of human immunoglobulin gamma antibodies. Analytical chemistry. 2005;77(18):6004–11. doi: 10.1021/ac050672d 16159134
22. Robinson NE, Robinson AB. Prediction of primary structure deamidation rates of asparaginyl and glutaminyl peptides through steric and catalytic effects. The journal of peptide research: official journal of the American Peptide Society. 2004;63(5):437–48. doi: 10.1111/j.1399-3011.2004.00148.x 15140161
23. Pace AL, Wong RL, Zhang YT, Kao YH, Wang YJ. Asparagine deamidation dependence on buffer type, pH, and temperature. Journal of pharmaceutical sciences. 2013;102(6):1712–23. doi: 10.1002/jps.23529 23568760
24. DeLano WL, Ultsch MH, de Vos AM, Wells JA. Convergent solutions to binding at a protein-protein interface. Science. 2000;287(5456):1279–83. doi: 10.1126/science.287.5456.1279 10678837
25. Geiger T, Clarke S. Deamidation, isomerization, and racemization at asparaginyl and aspartyl residues in peptides. Succinimide-linked reactions that contribute to protein degradation. The Journal of biological chemistry. 1987;262(2):785–94. 3805008
26. Pan H, Chen K, Chu L, Kinderman F, Apostol I, Huang G. Methionine oxidation in human IgG2 Fc decreases binding affinities to protein A and FcRn. Protein science: a publication of the Protein Society. 2009;18(2):424–33. doi: 10.1002/pro.45 19165723
27. Schilling S, Wasternack C, Demuth HU. Glutaminyl cyclases from animals and plants: a case of functionally convergent protein evolution. Biological chemistry. 2008;389(8):983–91. doi: 10.1515/BC.2008.111 18979624
28. Dick LW Jr., Qiu D, Mahon D, Adamo M, Cheng KC. C-terminal lysine variants in fully human monoclonal antibodies: investigation of test methods and possible causes. Biotechnology and bioengineering. 2008;100(6):1132–43. doi: 10.1002/bit.21855 18553400
29. Mould DR, Sweeney KR. The pharmacokinetics and pharmacodynamics of monoclonal antibodies—mechanistic modeling applied to drug development. Current opinion in drug discovery & development. 2007;10(1):84–96.
30. Yan B, Steen S, Hambly D, Valliere-Douglass J, Vanden Bos T, Smallwood S et al. Succinimide formation at Asn 55 in the complementarity determining region of a recombinant monoclonal antibody IgG1 heavy chain. Journal of pharmaceutical sciences. 2009;98(10):3509–21. doi: 10.1002/jps.21655 19475547
31. Haberger M, Bomans K, Diepold K, Hook M, Gassner J, Schlothauer T et al. Assessment of chemical modifications of sites in the CDRs of recombinant antibodies: Susceptibility vs. functionality of critical quality attributes. mAbs. 2014;6(2):327–39. doi: 10.4161/mabs.27876 24441081
Článok vyšiel v časopise
PLOS One
2019 Číslo 10
- Metamizol jako analgetikum první volby: kdy, pro koho, jak a proč?
- Nejasný stín na plicích – kazuistika
- Masturbační chování žen v ČR − dotazníková studie
- Je Fuchsova endotelová dystrofie rohovky neurodegenerativní onemocnění?
- Fixní kombinace paracetamol/kodein nabízí synergické analgetické účinky
Najčítanejšie v tomto čísle
- Correction: Low dose naltrexone: Effects on medication in rheumatoid and seropositive arthritis. A nationwide register-based controlled quasi-experimental before-after study
- Combining CDK4/6 inhibitors ribociclib and palbociclib with cytotoxic agents does not enhance cytotoxicity
- Prevalence of pectus excavatum (PE), pectus carinatum (PC), tracheal hypoplasia, thoracic spine deformities and lateral heart displacement in thoracic radiographs of screw-tailed brachycephalic dogs
- Risk factors associated with IgA vasculitis with nephritis (Henoch–Schönlein purpura nephritis) progressing to unfavorable outcomes: A meta-analysis