Investigation of monoclonal antibody dimers in a final formulated drug by separation techniques coupled to native mass spectrometry

References

• Yver A, Homery MC, Fuseau E, E G, Dhainaut F, Quagliaroli D, Beliard R, Prost JF. Pharmacokinetics and safety of roledumab, a novel human recombinant monoclonal anti-RhD antibody with an optimized Fc for improved engagement of FCγRIII, in healthy volunteers. Vox Sanguinis. 2012;103:213–11. doi:https://doi.org/10.1111/j.1423-0410.2012.01603.x.
   PubMed Web of Science ®Google Scholar
• Hmiel LK, Brorson KA, Boyne IIMT. Post-translational structural modifications of immunoglobulin G and their effect on biological activity. Anal Bioanal Chem. 2015;407:79–94. doi:https://doi.org/10.1007/s00216-014-8108-x.
   PubMed Web of Science ®Google Scholar
• Chumsae CM. Discovery of unknown modifications recombinant monoclonal antibodies. Chemistry Dissertations. 2015:Paper;99.
   Google Scholar
• Manning MC, Chou DK, Murphy BM, Payne RW, Katayama DS. Stability of protein pharmaceuticals: an update. Pharm Res. 2010;27:544–75. doi:https://doi.org/10.1007/s11095-009-0045-6.
   PubMed Web of Science ®Google Scholar
• Fischer S, Hoernschemeyer J, Mahler HC..Glycation during storage and administration of monoclonal antibody formulations. Eur J Pharm Biopharm. 2008;70:42–50. doi:https://doi.org/10.1016/j.ejpb.2008.04.021.
   PubMed Web of Science ®Google Scholar
• LW D Jr, Kim C, Qiu D, Cheng KC. Determination of the origin of the N-terminal pyro-glutamate variation in monoclonal antibodies using model peptides. Biotechnol Bioeng. 2007;97:544–53. doi:https://doi.org/10.1002/bit.21260.
   PubMed Web of Science ®Google Scholar
• Vlasak J, Ionescu R. Fragmentation of monoclonal antibodies. MAbs. 2011;3:253–63. doi:https://doi.org/10.4161/mabs.3.3.15608.
   PubMed Web of Science ®Google Scholar
• Liu H, Gaza-Bulseco G, Faldu D, Chumsae C, Sun J. Heterogeneity of monoclonal antibodies. J Pharm. Sci. 2008;97:2426–47. doi:https://doi.org/10.1002/jps.21180.
   PubMed Web of Science ®Google Scholar
• Liu H, May K. Disulfide bond structures of IgG molecules: structural variations, chemical modifications and possible impacts to stability and biological function. MAbs. 2012;4:17–23. doi:https://doi.org/10.4161/mabs.4.1.18347.
   PubMed Web of Science ®Google Scholar
• Arosio P, Barolo G, Müller-Späth T, Wu H, Morbidelli M. Aggregation stability of a monoclonal antibody during downstream processing. Pharm Res. 2011;28:1884–94. doi:https://doi.org/10.1007/s11095-011-0416-7.
   PubMed Web of Science ®Google Scholar
• Cromwell MEM, Hilario E, Jacobson F. Protein aggregation and bioprocessing. AAPS J. 2006;8:572–79. doi:https://doi.org/10.1208/aapsj080366.
   PubMed Web of Science ®Google Scholar
• Vermeer AWP, Norde W. The thermal stability of immunoglobulin: unfolding and aggregation of a multi-domain protein. Biophys J. 2000;78:394–404. doi:https://doi.org/10.1016/S0006-3495(00)76602-1.
   PubMed Web of Science ®Google Scholar
• Vázquez-Rey M, Lang DA. Aggregates in monoclonal antibody manufacturing processes. Biotechnol Bioeng. 2011;108:1494–508. doi:https://doi.org/10.1002/bit.23155.
   PubMed Web of Science ®Google Scholar
• Brader ML, Estey T, Bai S, Alston RW, Lucas KK, Lantz S, Landsman P, Maloney KM. Examination of thermal unfolding and aggregation profiles of a series of developable therapeutic monoclonal antibodies. Mol Pharmaceutics. 2015;12:1005–17. doi:https://doi.org/10.1021/mp400666b.
   PubMed Web of Science ®Google Scholar
• Wang W. Protein aggregation and its inhibition in biopharmaceutics. Int J Pharm. 2005;289:1–30. doi:https://doi.org/10.1021/mp400666b.
   PubMed Web of Science ®Google Scholar
• Mahler HC, Friess W, Grauschopf U, Kiese S. Protein aggregation: pathways, induction Factors and analysis. J of Pharm Sc. 2009;59:407–17. doi:https://doi.org/10.1002/jps.21566.
   Google Scholar
• Chi EY, Krishnan S, Randolph TW, Carpenter JF. Physical stability of proteins in aqueous solution: mechanism and driving forces in non-native protein aggregation. Pharm Res. 2003;20:1325–36. doi:https://doi.org/10.1023/A:1025771421906.
   PubMed Web of Science ®Google Scholar
• Alt N, Zhang TY, Motchnik P, Taticek R, Quarmby V, Tilman S, Beck H, Emrich T, Harris RJ. Determination of critical quality attributes for monoclonal antibodies using quality by design principles. Biologicals. 2016;44:291–305. doi:https://doi.org/10.1016/j.biologicals.2016.06.005.
   PubMed Web of Science ®Google Scholar
• Dingman R, Balu-Iyer Sathy V. Immunogenicity of protein pharmaceuticals. J of Pharm Sc. 2019;108:1637–54. doi:https://doi.org/10.1016/j.xphs.2018.12.014.
   PubMed Web of Science ®Google Scholar
• Ratanji KD, Derrick JP, Dearman RJ, Kimber I. Immunogenicity of therapeutic proteins: influence of aggregation. J Immunotoxicol. 2014;11:99–109. doi:https://doi.org/10.3109/1547691X.2013.821564.
   PubMed Web of Science ®Google Scholar
• Rosenberg AS. Effects of protein aggregates: an immunologic perspective. AAPS J. 2006;8:501–07. doi:https://doi.org/10.1208/aapsj080359.
   PubMed Web of Science ®Google Scholar
• Tran BN, Chan SL, Ng C, Shi J, Correia I, Radziejewski C, Matsudaira P. Higher order structures of Adalimumab, Infliximab and their complexes with TNFa revealed by electron microscopy. Protein Science. 2017;26:2392–98. doi:https://doi.org/10.1002/pro.3306.
   PubMed Web of Science ®Google Scholar
• Berkowitz SA. Role of analytical ultracentrifugation in assessing the aggregation of protein biopharmaceuticals. AAPS J. 2006;8:590–605. doi:https://doi.org/10.1208/aapsj080368.
   PubMed Web of Science ®Google Scholar
• Gabrielson JP, Arthur KK. Measuring low levels of protein aggregation by sedimentation velocity. Methods. 2011;54:83–91. doi:https://doi.org/10.1016/j.ymeth.2010.12.030.
   PubMed Web of Science ®Google Scholar
• Arakawa T, Philo JS, Ejima D. Aggregation analysis of therapeutic proteins, part 1. General Aspects and Techniques for Assessment. Bioprocess Int. 2006;4:42–43.
   Google Scholar
• Beck A, Wagner-Rousset E, Ayoub D, Van Dorsselaer A, Sanglier-Cianférani S. Characterization of therapeutic antibodies and related products. Anal Chem. 2013;85:715–36. doi:https://doi.org/10.1021/ac3032355.
   PubMed Web of Science ®Google Scholar
• Fekete S, Gassner AL, Rudaz S, Schappler J, Guillarme D. Analytical strategies for the characterization of therapeutic monoclonal antibodies. Trends Anal Chem. 2013;42:74–83. doi:https://doi.org/10.1016/j.trac.2012.09.012.
   Web of Science ®Google Scholar
• D’Atri V, Fekete S, Clarke A, Veuthey JL, Guillarme D. Recent advances in chromatography for pharmaceutical analysis. Anal Chem. 2019;91:210–39. 10.1021/acs.analchem.8b05026.
   PubMed Web of Science ®Google Scholar
• Goyon A, Fekete S, Beck A, Veuthey JL, Guillarme D. Unraveling the mysteries of modern size exclusion chromatography - the way to achieve confident characterization of therapeutic proteins. J Chrom B. 2018;1092:368–78. doi:https://doi.org/10.1016/j.jchromb.2018.06.029.
   PubMed Web of Science ®Google Scholar
• Arakawa T, Philo JS, Ejima D. Aggregation analysis of therapeutic proteins, part 3: principles and optimization of field-flow fractionation. Bioprocess Int. 2007;5:52–70.
   Google Scholar
• Arakawa T, Ejima D, Li T, Philo JS. The critical role of mobile phase composition in size exclusion chromatography of protein pharmaceuticals. J Pharm Sc. 2010;99(4):1674–92. doi:https://doi.org/10.1002/jps.21974.
   PubMed Web of Science ®Google Scholar
• Haselberg R, De Vijlder T, Heukers R, Smit MJ, Romijn EP, Somsen GW, Domínguez-Vega E. Heterogeneity assessment of antibody-derived therapeutics at the intact and middle-up level by low-flow sheathless capillary electrophoresis-mass spectrometry. Anal Chim Acta. 2018;1044:181–90. doi:https://doi.org/10.1016/j.aca.2018.08.024.
   PubMed Web of Science ®Google Scholar
• Belov AM, Viner R, Santos MR, Horn DM, Bern M, Karger BL, Ivanov AR. Analysis of proteins, protein complexes, and organellar proteomes using sheathless capillary zone electrophoresis - native mass spectrometry. J Am Soc Mass Spectr. 2017;28:2614–34. doi:https://doi.org/10.1007/s13361-017-1781-1.
   PubMed Web of Science ®Google Scholar
• Belov AM, Zang L, Sebastiano R, Santos MR, Bush DR, Karger BL, Ivanov AR. Complementary middle-down and intact monoclonal antibody proteoform characterization by capillary zone electrophoresis-mass spectrometry. Electrophoresis. 2018;39:2069–82. doi:https://doi.org/10.1002/elps.201800067.
   PubMed Web of Science ®Google Scholar
• Le-Minh V, Tran NT, Makky A, Rosilio V, Taverna M, Smadja C. Capillary zone electrophoresis-native mass spectrometry for the quality control of intact therapeutic monoclonal antibodies. J Chrom A. 2019;1601:375–84. doi:https://doi.org/10.1016/j.chroma.2019.05.050.
   PubMed Web of Science ®Google Scholar
• Marie AL, Dominguez-Vega E, Saller F, Plantier JL, Urbain R, Borgel D, Taverna M. Characterization of conformers and dimers of antithrombin by capillary electrophoresis-quadrupole-time-of-flight mass spectrometry. Analytica Chimica Acta. 2016;947:58–65. doi:https://doi.org/10.1016/j.aca.2016.10.016.
   PubMed Web of Science ®Google Scholar
• Haberger M, Leiss M, Heidenreich AK, Pester O, Hafenmair G, Hook M, Bonnington L, Wegele H, Haindl M, Reusch D, et al. Rapid characterization of biotherapeutic proteins by size-exclusion chromatography coupled to native mass spectrometry. MAbs. 2015;8:331–39. doi:https://doi.org/10.1080/19420862.2015.1122150.
   PubMed Web of Science ®Google Scholar
• Ventouri IK, Malheiro DBA, Voeten RLC, Kok S, Honing M, Somsen GW, Haselberg R. Probing protein denaturation during size-exclusion chromatography using native mass spectrometry’. Anal Chem. 2020;92:4292–300. doi:https://doi.org/10.1021/acs.analchem.9b04961.
   PubMed Web of Science ®Google Scholar
• Ehkirch A, Hernandez-Alba O, Colas O, Beck A, Guillarme D, Cianférani S. Hyphenation of Size exclusion chromatography to native ion mobility mass spectrometry for the analytical characterization of therapeutic antibodies and related product. J Chrom B. 2018;1086:176–83. doi:https://doi.org/10.1021/acs.analchem.8b03333.
   PubMed Web of Science ®Google Scholar
• Ehkirch A, Goyon A, Hernandez-Alba O, Rouviere F, D’Atri V, Dreyfus C, Cianferani S. A novel online four-dimensional SECxSEC-IMxMS methodology for characterization of monoclonal antibody size variants. Anal Chemis. 2018;23:13929–37. doi:https://doi.org/10.1021/acs.analchem.8b03333.
   Google Scholar
• Leblanc Y, Ramon C, Bihoreau N. Charge variants characterization of a monoclonal antibody by ion exchange chromatography coupled on-line to native mass spectrometry: case study after a long-term storage at+5 degrees C. J of Chrom B. 2017;1048:130–39. doi:https://doi.org/10.1016/j.jchromb.2017.02.017.
   PubMed Web of Science ®Google Scholar
• Yan Y, Liu AP, Wang S, Daly TJ, Li N. Ultrasensitive characterization of charge heterogeneity of therapeutic monoclonal antibodies using strong cation exchange chromatography coupled to native mass spectrometry. Anal Chem. 2018;90(21):13013–20. doi:https://doi.org/10.1021/acs.analchem.8b03773.
   PubMed Web of Science ®Google Scholar
• Lau H, Pace D, Yan B, McGrath T, Smallwood S, Patel K, Latypov RF. Investigation of degradation processes in IgG1 monoclonal antibodies by limited proteolysis coupled with weak cation-exchange HPLC. J chrom B. 2010;878(11–12):868–76. doi:https://doi.org/10.1016/j.jchromb.2010.02.003.
   PubMed Web of Science ®Google Scholar
• Chen B, Lin Z, Alpert AJ, Fu C, Zhang Q, Pritts WA, Ge Y. Online hydrophobic interaction chromatography–mass spectrometry for the analysis of intact monoclonal antibodies. Anal Chem. 2018;90:7135–38. doi:https://doi.org/10.1021/acs.analchem.8b01865.
   PubMed Web of Science ®Google Scholar
• Houde D, Arndt J, Domeier W, Berkowitz S, Engen JR. Characterization of IgG1 conformation and conformational dynamics by hydrogen/deuterium exchange mass spectrometry. Anal Chem. 2009;81:2644–51. doi:https://doi.org/10.1021/ac802575y.
   PubMed Web of Science ®Google Scholar
• Iacob RE, Bou-Assaf GM, Makowski L, Engen JR, Berkowitz SA, Houde D. Investigating monoclonal antibody aggregation using a combination of H/DX-MS and other biophysical measurements. J Pharm Sci. 2013;102:4315–29. doi:https://doi.org/10.1002/jps.23754.
   PubMed Web of Science ®Google Scholar
• Zhang A, Singh SK, Shirts MR, Kumar S, Fernandez EJ. Fernandez distinct aggregation mechanisms of monoclonal antibody under thermal and freeze-thaw stresses revealed by hydrogen exchange. Pharm Res. 2012;29:236–50. doi:https://doi.org/10.1007/s11095-011-0538-y.
   PubMed Web of Science ®Google Scholar
• Kiese S, Papppenberger A, Friess W, Mahler HC. Shaken, not stirred: mechanical stress testing of an IgG1 antibody. J Pharm Sci. 2008;97(10):4347–66. doi:https://doi.org/10.1002/jps.21328.
   PubMed Web of Science ®Google Scholar
• Hawe A, Kasper JC, Friess W, Jiskoot W. Structural properties of monoclonal antibody aggregates induced by freeze thawing and thermal stress. Eur J Pharm Sc. 2009;38:79–87. doi:https://doi.org/10.1016/j.ejps.2009.06.001.
   PubMed Web of Science ®Google Scholar
• Joubert MK, Luo Q, Nashed-Samuel Y, Wypych J, Narhi LO. Classification and characterization of therapeutic antibody aggregates. J Biol Chem. 2011;286:25118–33. doi:https://doi.org/10.1074/jbc.M110.160457.
   PubMed Web of Science ®Google Scholar
• Paul R, Graff-Meyer A, Stahlberg H, Lauer ME, Rufer AC, Beck H, Briguet A, Schnaible V, Buckel T, Boeckle S. Structure and function of purified monoclonal antibody dimers induced by different stress conditions. Pharm Res. 2012;29:2047–59. doi:https://doi.org/10.1007/s11095-012-0732-6.
   PubMed Web of Science ®Google Scholar
• Remmele RL, Callahan WJ, Krishnan S, Zhou LD, Bondarenko PV, Nichols AC, Kleemann GR, Pipes GD, Park S, Fodor S, et al. Active dimer of epratuzumab provides insight into the complex nature of an antibody aggregate. J Pharm Sci. 2007;98:126–45. doi:https://doi.org/10.1002/jps.20515.
   Google Scholar
• Iwura T, Fukuda J, Yamazaki K, Kanamaru S, Arisaka F. Intermolecular interactions and conformation of antibody dimers present in igG1 biopharmaceuticals. J Biochem. 2013;155:63–71. doi:https://doi.org/10.1093/jb/mvt095.
   PubMed Web of Science ®Google Scholar
• Deperalta G, Alvarez M, Bechtel C, Dong K, McDonald R, Ling V. Structural analysis of a therapeutic monoclonal antibody dimer by hydroxyl radical footprinting. MAbs. 2013;5:86–101. doi:https://doi.org/10.4161/mabs.22964.
   PubMed Web of Science ®Google Scholar
• Plath F, Ringler P, Graff-Meyer A, Stahlberg H, Lauer ME, Rufer Arne C, Graewert MA, Svergun D, Gellermann G, Finkler C, et al. Characterization of mAb dimers reveals predominant dimer forms common in therapeutic. MAbs. 2016;8:928–40. doi:https://doi.org/10.1080/19420862.2016.1168960.
   PubMed Web of Science ®Google Scholar
• Liu H, Chumsae C, Gaza-Bulseco G, Hurkmans K, Radziejewski CH. Ranking the susceptibility of disulfide bonds in human IgG1 antibodies by reduction, differential alkylation, and LC-MS analysis’. Anal Chem. 2010;82(12):5219–26. doi:https://doi.org/10.1021/ac100575n.
   PubMed Web of Science ®Google Scholar
• Chevreux G, Tilly N, Bihoreau N. Fast analysis of recombinant monoclonal antibodies using IdeS proteolytic digestion and electrospray mass spectrometry. Anal Biochem. 2011;415:212–14. doi:https://doi.org/10.1016/j.ab.2011.04.030.
   PubMed Web of Science ®Google Scholar
• Spoerry C, Seele J, Valentin-Weigand P, Baums CG, Von Pawel-Rammingen U. Identification and characterization of IgdE, a novel IgG-degrading protease of streptococcus suis with unique specificity for porcine IgG. J Biol Chem. 2016;291(15):7915–25. doi:https://doi.org/10.1074/jbc.M115.711440.
   PubMed Web of Science ®Google Scholar