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Bioprocess Challenges in Purification of Therapeutic Protein Charge Variants

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Abstract

Biopharmaceuticals are complex therapeutic protein molecules produced in living cells and have been a major driving force for drug development in the pharmaceutical sector in recent years. Monoclonal antibodies (mAbs) are biological macromolecules used for treating life-threatening and rare illnesses. mAbs with post-translation alterations can be observed during the assessment of charge variants. Controlling the charge variant profile of therapeutic protein is a regulatory requirement to confirm that the macromolecule complies with the quality parameters to ensure patient safety. Unfortunately, manufacturing these biopharmaceuticals is very expensive. However, the emergence of biosimilars has reduced developmental cost across the biopharmaceutical industry. The advent of biosimilars has constrained the development of more efficient downstream bioprocesses that are mainly considered the bottleneck of the manufacturing process. This review focuses on the existing methods for charge variants separation and process optimization and indicates new approaches for future developments. It also provides a comprehensive summary for the biological community about the impact of charge variants.

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References

  1. Oskouei, S. T. and A. R. Kusmierczyk (2021) Biosimilar uptake: the importance of healthcare provider education. Pharmaceut. Med. 35: 215–224.

    PubMed  PubMed Central  Google Scholar 

  2. Bhunia, B., B. Basak, T. Mandal, P. Bhattacharya, and A. Dey (2013) Effect of pH and temperature on stability and kinetics of novel extracellular serine alkaline protease (70kDa). Int. J. Biol. Macromol. 54: 1–8.

    CAS  PubMed  Google Scholar 

  3. Joshi, S., S. Kumari, and A. S. Rathore (2021) Identification and characterization of carbonylation sites in trastuzumab biosimilars. Int. J. Biol. Macromol. 169: 95–102.

    CAS  PubMed  Google Scholar 

  4. Reslan, M., V. Sifniotis, E. Cruz, Z. Sumer-Bayraktar, S. Cordwell, and V. Kayser (2020) Enhancing the stability of adalimumab by engineering additional glycosylation motifs. Int. J. Biol. Macromol. 158: 189–196.

    CAS  PubMed  Google Scholar 

  5. Beck, A., T. Wurch, C. Bailly, and N. Corvaia (2010) Strategies and challenges for the next generation of therapeutic antibodies. Nat. Rev. Immunol. 10: 345–352.

    CAS  PubMed  Google Scholar 

  6. Perobelli, R. F., B. Xavier, A. R. da Silveira, G. L. Remuzzi, L. G. J. Motta, and S. L. Dalmora (2018) Quantitation of the monoclonal antibody Denosumab by bioassay and validated LC methods. Int. J. Biol. Macromol. 119: 96–104.

    CAS  PubMed  Google Scholar 

  7. McAtee, C. P. and J. Hornbuckle (2012) Isolation of monoclonal antibody charge variants by displacement chromatography. Curr. Protoc. Protein Sci. 69: 8.10.1–8.10.13.

    Google Scholar 

  8. Kadkhoda, J., M. Akrami-Hasan-Kohal, M. R. Tohidkia, S. Khaledi, S. Davaran, and A. Aghanejad (2021) Advances in antibody nanoconjugates for diagnosis and therapy: A review of recent studies and trends. Int. J. Biol. Macromol. 185: 664–678.

    CAS  PubMed  Google Scholar 

  9. Lu, R.-M., Y.-C. Hwang, I.-J. Liu, C.-C. Lee, H.-Z. Tsai, H.-J. Li, and H.-C. Wu (2020) Development of therapeutic antibodies for the treatment of diseases. J. Biomed. Sci. 27: 1.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Berkowitz, S. A., J. R. Engen, J. R. Mazzeo, and G. B. Jones (2012) Analytical tools for characterizing biopharmaceuticals and the implications for biosimilars. Nat. Rev. Drug Discov. 11: 527–540.

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Vlasak, J., M. C. Bussat, S. Wang, E. Wagner-Rousset, M. Schaefer, C. Klinguer-Hamour, M. Kirchmeier, N. Corvaïa, R. Ionescu, and A. Beck (2009) Identification and characterization of asparagine deamidation in the light chain CDR1 of a humanized IgG1 antibody. Anal. Biochem. 392: 145–154.

    CAS  PubMed  Google Scholar 

  12. Khawli, L. A., S. Goswami, R. Hutchinson, Z. W. Kwong, J. Yang, X. Wang, Z. Yao, A. Sreedhara, T. Cano, D. Tesar, I. Nijem, D. E. Allison, P. Y. Wong, Y.-H. Kao, C. Quan, A. Joshi, R. J. Harris, and P. Motchnik (2010) Charge variants in IgG1: Isolation, characterization, in vitro binding properties and pharmacokinetics in rats. mAbs. 2: 613–624.

    PubMed  PubMed Central  Google Scholar 

  13. Shen, Z., Y. Wang, H. Xu, Q. Zhang, C. Sha, B. Sun, and Q. Li (2021) Analytical comparability assessment on glycosylation of ziv-aflibercept and the biosimilar candidate. Int. J. Biol. Macromol. 180: 494–509.

    CAS  PubMed  Google Scholar 

  14. Simoens, S. and A. G. Vulto (2021) A health economic guide to market access of biosimilars. Expert Opin. Biol. Ther. 21: 9–17.

    PubMed  Google Scholar 

  15. Agbogbo, F. K., D. M. Ecker, A. Farrand, K. Han, A. Khoury, A. Martin, J. McCool, U. Rasche, T. D. Rau, D. Schmidt, M. Sha, and N. Treuheit (2019) Current perspectives on biosimilars. J. Ind. Microbiol. Biotechnol. 46: 1297–1311.

    CAS  PubMed  Google Scholar 

  16. Niazi, S. K. (2019) Comparability of Biotechnological/Biological Products Subject to Changes in Their Manufacturing Process. 3rd ed., pp. 95–100. CRC Press.

  17. Vanam, R. P., M. A. Schneider, and M. S. Marlow (2015) Rapid quantitative analysis of monoclonal antibody heavy and light chain charge heterogeneity. mAbs. 7: 1118–1127.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Neill, A., C. Nowak, R. Patel, G. Ponniah, N. Gonzalez, D. Miano, and H. Liu (2015) Characterization of recombinant monoclonal antibody charge variants using OFFGEL fractionation, weak anion exchange chromatography, and mass spectrometry. Anal. Chem. 87: 6204–6211.

    CAS  PubMed  Google Scholar 

  19. Zheng, J. Y. and L. J. Janis (2006) Influence of pH, buffer species, and storage temperature on physicochemical stability of a humanized monoclonal antibody LA298. Int. J. Pharm. 308: 46–51.

    CAS  PubMed  Google Scholar 

  20. Brown, K. A., S. Rajendran, J. Dowd, and D. J. Wilson (2019) Rapid characterization of structural and functional similarity for a candidate bevacizumab (Avastin) biosimilar using a multipronged mass-spectrometry-based approach. Drug Test Anal. 11: 1207–1217.

    CAS  PubMed  Google Scholar 

  21. Majumder, S. K., M. K. Sharma, and T. K. Gupta (2011) Liquid formulation of follicle stimulating hormone. European Patent EP2533800B1.

  22. Majumder, S. K., and T. K. Gupta (2014) Process for the purification of fc fusion. WIPO (PCT) WO2014102814A1.

  23. Du, Y., A. Walsh, R. Ehrick, W. Xu, K. May, and H. Liu (2012) Chromatographic analysis of the acidic and basic species of recombinant monoclonal antibodies. mAbs. 4: 578–585.

    PubMed  PubMed Central  Google Scholar 

  24. Cramer, S. M. and M. A. Holstein (2011) Downstream bioprocessing: recent advances and future promise. Curr. Opin. Chem. Eng. 1: 27–37.

    CAS  Google Scholar 

  25. Chon, J. H. and G. Zarbis-Papastoitsis (2011) Advances in the production and downstream processing of antibodies. New Biotechnol. 28: 458–463.

    CAS  Google Scholar 

  26. Shukla, A. A. and J. Thömmes (2010) Recent advances in large-scale production of monoclonal antibodies and related proteins. Trends Biotechnol. 28: 253–261.

    CAS  PubMed  Google Scholar 

  27. Rathore, A. S., R. Bhambure, and V. Ghare (2010) Process analytical technology (PAT) for biopharmaceutical products. Anal. Bioanal. Chem. 398: 137–154.

    CAS  PubMed  Google Scholar 

  28. Li, F., Y. Hashimura, R. Pendleton, J. Harms, E. Collins, and B. Lee (2006) A systematic approach for scale-down model development and characterization of commercial cell culture processes. Biotechnol. Prog. 22: 696–703.

    PubMed  Google Scholar 

  29. Yoo, E. M., K. R. Chintalacharuvu, M. L. Penichet, and S. L. Morrison (2002) Myeloma expression systems. J. Immunol. Methods 261: 1–20.

    CAS  PubMed  Google Scholar 

  30. Costa, A. R., M. E. Rodrigues, M. Henriques, J. Azeredo, and R. Oliveira (2010) Guidelines to cell engineering for monoclonal antibody production. Eur. J. Pharm. Biopharm. 74: 127–138.

    Google Scholar 

  31. Jordan, M., D. Voisard, A. Berthoud, L. Tercier, B. Kleuser, G. Baer, and H. Broly (2013) Cell culture medium improvement by rigorous shuffling of components using media blending. Cytotechnology 65: 31–40.

    CAS  PubMed  Google Scholar 

  32. Li, F., N. Vijayasankaran, A. (Yijuan) Shen, R. Kiss, and A. Amanullah (2010) Cell culture processes for monoclonal antibody production. mAbs. 2: 466–479.

    PubMed  PubMed Central  Google Scholar 

  33. Liu, H. F., J. Ma, C. Winter, and R. Bayer (2010) Recovery and purification process development for monoclonal antibody production. mAbs. 2: 480–499.

    PubMed  PubMed Central  Google Scholar 

  34. Fahrner, R. L., H. L. Knudsen, C. D. Basey, W. Galan, D. Feuerhelm, M. Vanderlaan, and G. S. Blank (2001) Industrial purification of pharmaceutical antibodies: development, operation, and validation of chromatography processes. Biotechnol. Genet. Eng. Rev. 18: 301–327.

    CAS  PubMed  Google Scholar 

  35. Manning, M. C., D. K. Chou, B. M. Murphy, R. W. Payne, and D. S. Katayama (2010) Stability of protein pharmaceuticals: an update. Pharm. Res. 27: 544–575.

    PubMed  Google Scholar 

  36. Talebi, M., A. Nordborg, A. Gaspar, N. A. Lacher, Q. Wang, X. Z. He, P. R. Haddad, and E. F. Hilder (2013) Charge heterogeneity profiling of monoclonal antibodies using low ionic strength ion-exchange chromatography and well-controlled pH gradients on monolithic columns. J. Chromatogr. A 1317: 148–154.

    CAS  PubMed  Google Scholar 

  37. Wagner-Rousset, E., S. Fekete, L. Morel-Chevillet, O. Colas, N. Corvaïa, S. Cianférani, D. Guillarme, and A. Beck (2017) Development of a fast workflow to screen the charge variants of therapeutic antibodies. J. Chromatogr. A 1498: 147–154.

    CAS  PubMed  Google Scholar 

  38. Liu H., G. Gaza-Bulseco, D. Faldu, C. Chumsae, and J. Sun (2008) Heterogeneity of monoclonal antibodies. J. Pharm. Sci. 97: 2426–2447.

    CAS  PubMed  Google Scholar 

  39. Dick Jr, L. W., D. Qiu, D. Mahon, M. Adamo, and K.-C. Cheng (2008) C-terminal lysine variants in fully human monoclonal antibodies: investigation of test methods and possible causes. Biotechnol. Bioeng. 100: 1132–1143.

    CAS  PubMed  Google Scholar 

  40. Yüce, M., F. Sert, M. Torabfam, A. Parlar, B. Gürel, N. Çakır, D. E. Dağlıkoca, M. A. Khan, and Y. Çapan (2021) Fractionated charge variants of biosimilars: a review of separation methods, structural and functional analysis. Anal. Chim. Acta 1152: 238189.

    PubMed  Google Scholar 

  41. Perkins, M., R. Theiler, S. Lunte, and M. Jeschke (2000) Determination of the origin of charge heterogeneity in a murine monoclonal antibody. Pharm. Res. 17: 1110–1117.

    CAS  PubMed  Google Scholar 

  42. Yan, B., S. Steen, D. Hambly, J. Valliere-Douglass, T. V. Bos, S. Smallwood, Z. Yates, T. Arroll, Y. Han, H. Gadgil, R. F. Latypov, A. Wallace, A. Lim, G. R. Kleemann, W. Wang, and A. Balland (2009) Succinimide formation at Asn 55 in the complementarity determining region of a recombinant monoclonal antibody IgG1 heavy chain. J. Pharm. Sci. 98: 3509–3521.

    CAS  PubMed  Google Scholar 

  43. Singh, S. K., G. Narula, and A. S. Rathore (2016) Should charge variants of monoclonal antibody therapeutics be considered critical quality attributes? Electrophoresis 37: 2338–2346.

    CAS  PubMed  Google Scholar 

  44. Saxena, A., M. Kumar, B. P. Tripathi, and V. K. Shahi (2010) Organic-inorganic hybrid charged membranes for proteins separation: isoelectric separation of proteins under coupled driving forces. Sep. Purif. Technol. 70: 280–290.

    CAS  Google Scholar 

  45. Fekete, S., A. Beck, J. Fekete, and D. Guillarme (2015) Method development for the separation of monoclonal antibody charge variants in cation exchange chromatography Part II: pH gradient approach. J. Pharm. Biomed. Anal. 102: 282–289.

    CAS  PubMed  Google Scholar 

  46. Fekete, S., A. Beck, J.-L. Veuthey, and D. Guillarme (2015) Ion-exchange chromatography for the characterization of biopharmaceuticals. J. Pharm. Biomed. Anal. 113: 43–55.

    CAS  PubMed  Google Scholar 

  47. Urmann, M., H. Graalfs, M. Joehnck, L. R. Jacob, and C. Frech (2010) Cation-exchange chromatography of monoclonal antibodies: characterisation of a novel stationary phase designed for production-scale purification. mAbs. 2: 395–404.

    PubMed  Google Scholar 

  48. Chung, S., J. Tian, Z. Tan, J. Chen, J. Lee, M. Borys, and Z. J. Li (2018) Industrial bioprocessing perspectives on managing therapeutic protein charge variant profiles. Biotechnol. Bioeng. 115: 1646–1665.

    CAS  PubMed  Google Scholar 

  49. Jing, S.-Y., J.-X. Gou, D. Gao, H.-B. Wang, S.-J. Yao, and D.-Q. Lin (2020) Separation of monoclonal antibody charge variants using cation exchange chromatography: resins and separation conditions optimization. Sep. Purif. Technol. 235: 116136.

    CAS  Google Scholar 

  50. Baek, J., A. B. Schwahn, S. Lin, C. A. Pohl, M. De Pra, S. M. Tremintin, and K. Cook (2020) New insights into the chromatography mechanisms of ion-exchange charge variant analysis: dispelling myths and providing guidance for robust method optimization. Anal. Chem. 92: 13411–13419.

    CAS  PubMed  Google Scholar 

  51. Svasti, J. and C. Milstein (1972) The disulphide bridges of a mouse immunoglobulin G1 protein. Biochem. J. 126: 837–850.

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Khanal, O., V. Kumar, K. Westerberg, F. Schlegel, and A. M. Lenhoff (2019) Multi-column displacement chromatography for separation of charge variants of monoclonal antibodies. J. Chromatogr. A 1586: 40–51.

    CAS  PubMed  Google Scholar 

  53. Zhang, L., T. Patapoff, D. Farnan, and B. Zhang (2013) Improving pH gradient cation-exchange chromatography of monoclonal antibodies by controlling ionic strength. J. Chromatogr. A 1272: 56–64.

    CAS  PubMed  Google Scholar 

  54. Lee, Y. F., M. Jöhnck, and C. Frech (2018) Evaluation of differences between dual salt-pH gradient elution and mono gradient elution using a thermodynamic model: Simultaneous separation of six monoclonal antibody charge and size variants on preparative-scale ion exchange chromatographic resin. Biotechnol. Prog. 34: 973–986.

    CAS  PubMed  Google Scholar 

  55. Liu, Z., S. R. Wickramasinghe, and X. Qian (2017) Membrane chromatography for protein purifications from ligand design to functionalization. Sep. Sci. Technol. 52: 299–319.

    CAS  Google Scholar 

  56. Hintersteiner, B., N. Lingg, E. Janzek, O. Mutschlechner, H. Loibner, and A. Jungbauer (2016) Microheterogeneity of therapeutic monoclonal antibodies is governed by changes in the surface charge of the protein. Biotechnol. J. 11: 1617–1627.

    CAS  PubMed  Google Scholar 

  57. Huang, L., J. Lu, V. J. Wroblewski, J. M. Beals, and R. M. Riggin (2005) In vivo deamidation characterization of monoclonal antibody by LC/MS/MS. Anal. Chem. 77: 1432–1439.

    CAS  PubMed  Google Scholar 

  58. Gaza-Bulseco, G., S. Faldu, K. Hurkmans, C. Chumsae, and H. Liu (2008) Effect of methionine oxidation of a recombinant monoclonal antibody on the binding affinity to protein A and protein G. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci. 870: 55–62.

    CAS  PubMed  Google Scholar 

  59. Rehder, D. S., D. Chelius, A. McAuley, T. M. Dillon, G. Xiao, J. Crouse-Zeineddini, L. Vardanyan, N. Perico, V. Mukku, D. N. Brems, M. Matsumura, and P. V. Bondarenko (2008) Isomerization of a single aspartyl residue of anti-epidermal growth factor receptor immunoglobulin gamma2 antibody highlights the role avidity plays in antibody activity. Biochemistry 47: 2518–2530.

    CAS  PubMed  Google Scholar 

  60. Alt, N., T. Y. Zhang, P. Motchnik, R. Taticek, V. Quarmby, T. Schlothauer, H. Beck, T. Emrich, and R. J. Harris (2016) Determination of critical quality attributes for monoclonal antibodies using quality by design principles. Biologicals 44: 291–305.

    CAS  PubMed  Google Scholar 

  61. Lee, N., J. J. Lee, H. Yang, S. Baek, S. Kim, S. Kim, T. Lee, D. Song, and G. Park (2019) Evaluation of similar quality attribute characteristics in SB5 and reference product of adalimumab. mAbs. 11: 129–144.

    CAS  PubMed  Google Scholar 

  62. Singh, S. K., D. Kumar, H. Malani, and A. S. Rathore (2021) LC-MS based case-by-case analysis of the impact of acidic and basic charge variants of bevacizumab on stability and biological activity. Sci. Rep. 11: 2487.

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Sule, S. V., J. E. Fernandez, V. J. Mecozzi, Y. Kravets, W. C. Yang, P. Feng, S. Liu, L. Zang, A. D. Capili, T. B. Estey, and K. Gupta (2017) Assessing the impact of charge variants on stability and viscosity of a high concentration antibody formulation. J. Pharm. Sci. 106: 3507–3514.

    CAS  PubMed  Google Scholar 

  64. Linke, T., J. Feng, K. Yu, H. J. Kim, Z. Wei, Y. Wang, W. K. Wang, and A. K. Hunter (2012) Process scale separation of an anti-CD22 immunotoxin charge variant. J. Chromatogr. A 1260: 120–125.

    CAS  PubMed  Google Scholar 

  65. Kumar, R., D. Vikramachakravarthi, and P. Pal (2014) Production and purification of glutamic acid: a critical review towards process intensification. Chem. Eng. Process. 81: 59–71.

    CAS  Google Scholar 

  66. Frost Ebersold, M. and A. L. Zydney (2004) Separation of protein charge variants by ultrafiltration. Biotechnol. Prog. 20: 543–549.

    Google Scholar 

  67. Madadkar, P., U. Umatheva, G. Hale, Y. Durocher, and R. Ghosh (2017) Ultrafast separation and analysis of monoclonal antibody aggregates using membrane chromatography. Anal. Chem. 89: 4716–4720.

    CAS  PubMed  Google Scholar 

  68. Wang, J., J. Zhou, Y. K. Gowtham, S. W. Harcum, and S. M. Husson (2017) Antibody purification from CHO cell supernatant using new multimodal membranes. Biotechnol. Prog. 33: 658–665.

    CAS  PubMed  Google Scholar 

  69. Orr, V., L. Zhong, M. Moo-Young, and C. P. Chou (2013) Recent advances in bioprocessing application of membrane chromatography. Biotechnol. Adv. 31: 450–465.

    CAS  PubMed  Google Scholar 

  70. Hart, D. S., C. Harinarayan, G. Malmquist, A. Axén, M. Sharma, and R. van Reis (2009) Surface extenders and an optimal pore size promote high dynamic binding capacities of antibodies on cation exchange resins. J. Chromatogr. A 1216: 4372–4376.

    CAS  PubMed  Google Scholar 

  71. Ichihara, T., T. Ito, and C. Gillespie (2018) Polishing approach with fully connected flow-through purification for therapeutic monoclonal antibody. Eng. Life Sci. 19: 31–36.

    PubMed  PubMed Central  Google Scholar 

  72. Somasundaram, B., K. Pleitt, E. Shave, K. Baker, and L. H. L. Lua (2018) Progression of continuous downstream processing of monoclonal antibodies: current trends and challenges. Biotechnol. Bioeng. 115: 2893–2907.

    CAS  PubMed  Google Scholar 

  73. FDA (2017) Modernizing the way drugs are made: a transition to continuous manufacturing. https://www.fda.gov/drugs/news-events-human-drugs/modernizing-way-drugs-are-made-transition-continuous-manufacturing.

  74. Zhang, J., L. Conley, J. Pieracci, and S. Ghose (2016) Pool-less processing to streamline downstream purification of monoclonal antibodies. Eng. Life Sci. 17: 117–124.

    PubMed  PubMed Central  Google Scholar 

  75. Klutz, S., L. Holtmann, M. Lobedann, and G. Schembecker (2016) Cost evaluation of antibody production processes in different operation modes. Chem. Eng. Sci. 141: 63–74.

    CAS  Google Scholar 

  76. Kateja, N., D. Kumar, A. Godara, V. Kumar, and A. S. Rathore (2017) Integrated chromatographic platform for simultaneous separation of charge variants and aggregates from monoclonal antibody therapeutic products. Biotechnol. J.https://doi.org/10.1002/biot.201700133.

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Acknowledgements

The authors are thankful to Kashiv BioSciences Pvt. Ltd. and Institute of Science, Nirma University, Ahmedabad, Gujarat for providing us with the necessary facilities and guidance for the completion of the review article.

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  1. Institute of Science, Nirma University, Ahmedabad, 382481, Gujarat, India

    Tarun Gupta & Sriram Seshadri

  2. Downstream Process Development, Kashiv BioSciences Pvt Ltd., Ahmedabad, 382210, Gujarat, India

    Tarun Gupta & Anuj Kumar

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Tarun Gupta, Anuj Kumar and Sriram Seshadri performed the initial literature search, all authors contributed to the writing and final editing of the paper. Sriram Seshadri designed the paper and supervised the writing.

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Gupta, T., Kumar, A. & Seshadri, S. Bioprocess Challenges in Purification of Therapeutic Protein Charge Variants. Biotechnol Bioproc E 28, 493–506 (2023). https://doi.org/10.1007/s12257-023-0078-4

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