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Current Protein & Peptide Science

Editor-in-Chief

ISSN (Print): 1389-2037
ISSN (Online): 1875-5550

Review Article

Multimodal Chromatography for Purification of Biotherapeutics – A Review

Author(s): Vivek Halan, Sunit Maity, Rahul Bhambure and Anurag S. Rathore*

Volume 20, Issue 1, 2019

Page: [4 - 13] Pages: 10

DOI: 10.2174/1389203718666171020103559

Price: $65

Abstract

Process chromatography forms the core of purification of biotherapeutics. The unparalleled selectivity that it offers over other alternatives combined with the considerable robustness and scalability make it the unit operation of choice in downstream processing. It is typical to have three to five chromatography steps in a purification process for a biotherapeutic. Generally, these steps offer different modes of separation such as ion-exchange, reversed phase, size exclusion, and hydrophobic interaction. In the past decade, multimodal chromatography has emerged as an alternative to the traditional modes. It involves use of more than one mode of separation and typically combines ion-exchange and hydrophobic interactions to achieve selectivity and sensitivity. Over the last decade, numerous authors have demonstrated the significant potential that multimode chromatography offers as a protein purification tool. This review aims to present key recent developments that have occurred on this topic together with a perspective on future applications of multimodal chromatography.

Keywords: Multimodal chromatography/mixed-mode chromatography, MMC, mAb, Fab, antibody fragments, Biopharmaceuticals, therapeutic proteins, host cell proteins, product related impurities, process related impurities.

Graphical Abstract
[1]
Bhambure, R.; Kumar, K.; Rathore, A.S. High-throughput process development for biopharmaceutical drug substances. Trends Biotechnol., 2011, 29(3), 127-135.
[2]
Zhao, G.; Dong, X.Y.; Sun, Y. Ligands for mixed-mode protein chromatography: Principles, characteristics and design. J. Biotechnol., 2009, 144, 3-11.
[5]
GE-healthcare product manual. http://wolfson.huji.ac.il/ purification/PDF/HCIC/GE_CaptoCore700DataFile.pdf (Accessed on January 29, 2016).
[6]
GE-healthcare multimodal chromatography handbook. https://proteins.gelifesciences.com/~/media/protein-purification-ib/documents/handbooks/multimodal_chromatography.pdf?la=en (Accessed on January 29, 2016).
[7]
Bio-Rad product manual. http://www.bio-rad.com/webroot/web/ pdf/lsr/literature/LIT611E.PDF (Accessed on January 29, 2016).
[8]
Pall Corporation product manual. http://www.pall.in/main/ biopharmaceuticals/product.page?id=43716 (Accessed on January 29, 2016).
[9]
Pall Corporation product http://www.pall.co.in/main/ biopharmaceuticals/product.page?id=35677 (Accessed on January 29, 2016).
[12]
Toueille, M.; Uzel, A.; Depoisier, J.; Gantiera, R. Designing new monoclonal antibody purification processes using mixed-mode chromatography sorbents. J. Chromatogr. , 2011, 879, 836-843.
[13]
Kaleas, K.A.; Tripodi, M.; Revelli, S.; Sharma, V.; Pizarro, S.A. Evaluation of a multimodal resin for selective capture of CHO-derived monoclonal antibodies directly from harvested cell culture fluid. J. Chromatogr. , 2014, 969, 256-263.
[14]
Schwart, W.; Judd, D.; Wysocki, M.; Guerrier, L.; Birck-Wilson, E.; Boschetti, E. Comparison of hydrophobic charge induction chromatography with affinity chromatography on protein A for harvest and purification of antibodies. J. Chromatogr. A, 2001, 908(1-2), 251-263.
[15]
Dos Santos, R.; Rosa, S.A.; Aires-Barros, M.R.; Tover, A.; Azevedo, A.M. Phenylboronic acid as a multi-modal ligand for the capture of monoclonal antibodies: development and optimization of a washing step. J. Chromatogr. A, 2014, 1355, 115-124.
[16]
Dong, G.; Li-Li, W.; Dong-Qiang, L.; Shan-Jing, Y. Evaluating antibody monomer separation from associated aggregates using mixed-mode chromatography. J. Chromatogr. A, 2013, 1294, 70-75.
[17]
Wolfe, L.S.; Barringer, C.P.; Mostafa, S.S.; Shukla, A.A. Multimodal chromatography: Characterization of protein binding and selectivity enhancement through mobile phase modulators. J. Chromatogr. A, 2014, 1340, 151-156.
[18]
Hirano, A.; Arakawa, T.; Kameda, T. Interaction of arginine with Capto MMC in multimodal chromatography. J. Chromatogr. A, 2014, 1338, 58-66.
[19]
Chmielowski, R.A.; Meissner, S.; Roush, D.; Linden, T.O.; Glowacki, E.; Konietzko, J.; Nti-Gyabaah, J. Resolution of heterogeneous charged antibody aggregates via multimodal chromatography: a comparison to conventional approaches. Biotechnol. Prog., 2014, 30(3), 636-645.
[20]
Mountford, S.J.; Daly, R.; Robinson, A.J.; Hearn, M.T. Design, synthesis and evaluation of pyridine based chromatographic adsorbents for antibody purification. J. Chromatogr. A, 2014, 1355, 15-25.
[21]
Bio-Rad product manual. http://www.bio-rad.com/webroot/web/ pdf/lsr/literature/Bulletin_6749.pdf (Accessed on January 29, 2016).
[22]
Voitl, A.; Müller-Spath, T.; Morbidelli, M. Application of mixed mode resins for the purification of antibodies. J. Chromatogr. A, 2010, 1217, 5753-5760.
[23]
Chen, J.; Tetrault, J.; Zhang, Y.; Wasserman, A.; Conley, G.; DiLeo, M.; Haimes, E.; Nixon, A.E.; Ley, A. The distinctive separation attributes of mixed-mode resins and their applicationin monoclonal antibody downstream purification process. J. Chromatogr. A, 2010, 1217, 216-224.
[24]
Pezzini, J.; Joucla, G.; Gantier, R.; Toueille, M.; Lomenech, A.M.; Le Sénéchal, C.; Garbay, B.; Santarelli, X.; Cabanne, C. Antibody capture by mixed-mode chromatography: A comprehensive study from determination of optimal purification conditions to identification of contaminating host cell proteins. J. Chromatogr. A, 2011, 1218, 8197-8208.
[25]
Yang, X.; Zhang, Y.; Wang, F.; Wang, L.; Richardson, D.; Shameem, M.; Ambrogelly, A. Analysis and purification of IgG4 bispecific antibodies by a mixed-mode chromatography. Anal. Biochem., 2015, 484, 173-179.
[26]
Mountford, S.J.; Dal, R.; Robinson, A.J.; Hearn, M.T.W. Design, synthesis and evaluation of pyridine-based chromatographic adsorbents for antibody purification. J. Chromatogr. A, 2014, 1355, 15-25.
[27]
Kaleas, K.A.; Tripodi, M.; Revelli, S.; Sharma, V.; Pizarro, S.A. Evaluation of a multimodal resin for selective capture of CHOderived monoclonal antibodies directly from harvested cell culture fluid. J. Chromatogr. B, 2014. 969, 256-263.
[28]
Chen, J.; Tetrault, J.; Ley, A. Comparison of standard and new generation hydrophobic interaction chromatography resins in the monoclonal antibody purification process. J. Chromatogr. A, 2008, 1177(2), 272-281.
[29]
Maria, S.; Joucla, G.; Garbay, B.; Dieryck, W.; Lomenech, A.M.; Santarelli, X.; Cabanne, C. Purification process of recombinant monoclonal antibodies with mixed mode chromatography. J. Chromatogr. A, 2015, 1393, 57-64.
[30]
Vajda, J.; Mueller, E.; Bahret, E. Dual salt mixtures in mixed mode chromatography with an immobilized tryptophan ligand influence the removal of aggregated monoclonal antibodies. Biotechnol. J., 2014, 9, 555-565.
[31]
Zhang, C.; Fredericks, D.; Campi, E.M.; Florio, P.; Jespersgaard, C.; Schiødt, C.B.; Hearn, M.T.W. Purification of monoclonal antibodies by chemical affinity mixed mode chromatography. Separ. Purif. Tech., 2015, 142, 332-339.
[32]
Shi, Q.H.; Cheng, Z.; Sun, Y. 4-(1H-imidazol-1-yl) aniline: A new ligand of mixed-mode chromatography for antibody purification. J. Chromatogr. A, 2009, 1216, 6081-6087.
[33]
Zhang, C.; Fredericks, D.P.; Camoyupi, E.M.; Hearn, M.T.W. Application of 4′-terpyridinylsulfanylethylamine resins for the purification of monoclonal antibodies by mixed-mode chromatography. Protein Expr. Purif., 2014, 104, 34-40.
[34]
Lindner, R.; Moosmann, A.; Dietrich, A.; Böttinger, H.; Kontermann, R.; Siemann-Herzberg, M. Process development of periplasmatically produced single chain fragment variable against epidermal growth factor receptor in Escherichia coli. J. Biotechnol., 2014, 192, 136-145.
[35]
Karkov, H.S.; Krogh, B.O.; Woo, J.; Parimal, S.; Ahmadian, H.; Cramer, S.M. Investigation of protein selectivity in multimodal chromatography using in silico designed Fab fragment variants. Biotechnol. Bioeng., 2015, 112, 2305-2315.
[36]
Damasceno, L.M.; Pla, I.; Chang, H.J.; Cohen, L.; Ritter, G.; Old, L.J.; Batt, C.A. An optimized fermentation process for high-level production of a single-chain Fv antibody fragment in Pichia pastoris. Protein Expr. Purif., 2004, 37(1), 18-26.
[37]
Gagnon, P.; Cheung, C.W.; Lepin, E.J.; Wu, A.M.; Sherman, M.A.; Raubitschek, A.A.; Yazaki, P.J. Minibodies and multimodal chromatography methods: a convergence of challenge and opportunity. Bioprocess Int., 2010, 8(2), 26-35.
[38]
Thundimadathil, J. Cancer treatment using peptides: Current therapies and future prospects. J. Amino Acids, 2012, 2, 1-13.
[39]
Gilar, M.; Yu, Y.Q.; Ahn, J.; Fournier, J.; Gebler, J.C. Mixed-mode chromatography for fractionation of peptides, phosphopeptides, and sialylated glycopeptides. J. Chromatogr. A, 2008, 1191, 162-170.
[40]
Bernardia, S.; Gétazb, D.; Forrerc, N.; Morbidellia, M. Modeling of mixed-mode chromatography of peptides. J. Chromatogr. A, 2013, 1283, 46-52.
[41]
Chilamkurthi, S.; Sevillano, D.M.; Albers, L.H.G.; Sahoo, M.R.; Verheijen, P.J.T.; van der Wielen, L.A.M.; den Hollander, J.L.; Ottens, M. Thermodynamic description of peptide adsorption on mixed-mode resins. J. Chromatogr. A, 2014, 1341, 41-49.
[42]
Shen, A.; Li, X.; Dong, X.; Wei, J.; Guo, Z.; Liang, X. Glutathione-based zwitterionic stationary phase for hydropilic interaction/cation-exchange mixed-mode chromatography. J. Chromatogr. A, 2013, 1314, 63-69.
[43]
Islam, T.; Aguilar-Yanez, J.M.; Simental-Martínez, J.; Ortiz-Alcaraz, C.I.; Rito-Palomares, M.; Fernandez-Lahore, M. A novel strategy for the purification of a recombinant protein using ceramic fluorapatite-binding peptides as affinity tags. J. Chromatogr. A, 2014, 1339, 26-33.
[44]
Cabanne, C.; Pezzini, J.; Joucla, G.; Hocquellet, A.; Barbot, C.; Garbay, B.; Santarelli, X. Efficient purification of recombinant proteins fused to maltose-binding protein by mixed-mode chromatography. J. Chromatogr. A, 2009. 1216(20), 4451-4456.
[45]
Pizarro, S.A.; Gunson, J.; Field, M.J.; Dinges, R.; Khoo, S.; Dalal, M.; Lee, M.; Kaleas, K.A.; Moiseff, K.; Garnick, S.; Reilly, D.E.; Laird, M.W.; Schmelzer, C.H. High-yield expression of human vascular endothelial growth factor VEGF165 in Escherichia coli and purification for therapeutic applications. Protein Expr. Purif., 2010, 72, 184-193.
[46]
Lu, H.; Huang, J.; Li, G.; Ge, K.; Wu, H.; Huang, Q. Expression, purification and characterization of recombinant human serine proteinase inhibitor Kazal-type 6 (SPINK6) in Pichia pastoris. Protein Expr. Purif., 2012, 82, 144-149.
[47]
Arakawa, T.; Tsumoto, K.; Ejima, D. Alternative downstream processes for production of antibodies and antibody fragments. Biochim. Biophys. Acta, 2014, 1844, 2032-2040.
[48]
Xiuwen , Tang C.; Downes, P. Purification and characterization of gβγ –responsive phosphoinositide 3-kinases from pig platelet cytosol. J. Biol. Chem., 1997, 272(22), 14193-14199.
[49]
Palczewski, K.; McDowell, J.H.; Hargrave, P.A. Purification and characterization of rhodopsin kinase. J. Biol. Chem., 1998, 263(28), 14067-14073.
[50]
Paul, J.; Jensen, S.; Dukart, A.; Cornelissen, G. Optimization of a preparative multimodal ion exchange step for purification of a potential malaria vaccine. J. Chromatogr. A, , 2014, 1366,, 38-44.
[51]
Liu, N.; Wang, Z.; Liu, X.; Yu, L.; Sun, Y. Characterization of novel mixed-mode protein adsorbents fabricated from benzoyl-modified polyethyleneimine-grafted Sepharose. J. Chromatogr. A, 2014, 1372, 157-165.
[52]
Sheth, R.D.; Morrison, C.J.; Cramer, S.M. Selective displacement chromatography in multimodal cation exchange systems. J. Chromatogr. A, 2011, 1218, 9250-9259.
[53]
Holsteina, M.A.; Nikfetrata, A.A.M.; Gagea, M.; Hirshb, A.G.; Cramer, S.M. Improving selectivity in multimodal chromatography using controlled pH gradient elution. J. Chromatogr. A, 2012, 1233, 152-155.
[54]
Kaleas, K.A.; Schmelzer, C.H.; Pizarro, S.A. Industrial case study: Evaluation of a mixed-mode resin for selective capture of a human growth factor recombinantly expressed in E. coli. J. Chromatogr. A, 2010, 1217, 235-242.
[55]
Spadiut, O.; Rossetti, L.; Dietzsch, C.; Herwig, C. Purification of a recombinant plant peroxidase produced in Pichia pastoris by a simple 2-step strategy. Protein Expr. Purif., 2012, 86, 89-97.
[56]
Bayramoglua, G.; Cengiz Ozalpc, V.; Begum Altintasa, M.; Arica, Y. Preparation and characterization of mixed-mode magnetic adsorbent with p-amino-benzamidine ligand: Operated in a magnetically stabilized fluidized bed reactor for purification of trypsin from bovine pancreas. Process Biochem., 2014, 49, 520-528.
[57]
Brenac Brochier, V.; Chabre, H.; Lautrette, A.; Ravault, V.; Couret, M.N.; Didierlaurent, A.; Moingeon, P. High throughput screening of mixed-mode sorbents and optimisation using pre-packed lab-scale columns for the purification of the recombinant allergen rBet v 1a. J. Chromatogr. B., 2009, 877, 2420-2427.
[58]
Pezzini, J.; Brenac Brochier, V.; Barrouillet, M.P.; Cerruti, M.; Clofent-Sanchez, G.; Schapman, A.; Topol, A.; Robert, R.; Cabanne, C.; Cerruti, P.; Santarelli, X. Rapid screening of purification strategies for the capture of a human recombinant F(ab′)2 expressed in baculovirus-infected cells using a micro-plate approach and SELDI-MS. J. Chromatogr. B ., 2009, 877, 2428-2434.
[59]
Heldin, E.; Grönlund, S.; Shanagar, J.; Hallgren, E.; Eriksson, K.; Xavier, M.; Tune, H.; Vilela, L. Development of an intermediate chromatography step in an insulin purification process. The use of a High Throughput Process Development approach based on selectivity parameters. J. Chromatogr. B ., 2014, 973, 126-132.
[60]
Bhambure, R.; Gupta, D.; Rathore, A.S. A novel multimodal chromatography based single step purification process for efficient manufacturing of an E.coli based biotherapeutic protein product. J. Chromatogr. A, 2013, 1314, 188-198.
[61]
Pezzini, J.; Cabanne, C.; Gantier, R.; Janakiraman, V.N.; Santarelli, X. A comprehensive evaluation of mixed mode interactions of HEA and PPA HyperCel™ chromatographic media. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci., 2015, 976-977, 68-77.
[62]
Buyel, J.F.; Twyman, R.M.; Fischer, R. Extraction and downstream processing of plant-derived recombinant proteins. Biotechnol. Adv., 2015, 33, 902-913.
[63]
Arakawa, T.; Ponce, S.; Young, G. Isoform separation of proteins by mixed-mode chromatography. Protein Expr. Purif., 2015, 116, 144-151.
[64]
Yon, R.J. Chromatography of lipophilic proteins on adsorbents containing mixed hydrophobic and ionic groups. Biochem. J., 1972, 126, 765-767.
[65]
Sivapragasam, M.; Norhafizah, A. Purification of Glutathione Stransferase (GST) using mixed mode chromatography. Int. J. Eng. Res. Technol., (IJERT), 2014. , 1, 1292-9
[66]
Zimmermann, A.; Greco, R.; Walker, I.; Horak, J.; Cavazzini, A.; Lämmerhofer, M. Synthetic oligonucleotide separations by mixed-mode reversed-phase/weak anion-exchange liquid chromatography. J. Chromatogr. A, 2014, 1354, 43-55.
[67]
Floyd, T.R.; Cicero, S.E.; Fazio, S.D.; Raglione, T.V.; Hsu, S.H.; Winkle, S.A.; Hartwick, R.A. Mixed-mode hydrophobic ion exchange for the separation of oligonucleotides and DNA fragments using HPLC., Anal. Biochem.1986. , 154(2), 570-577.
[68]
Biba M.; Jiang, E.; Mao, B.; Zewge, D.; Foley, J.P.; Welch, C.J. Factors influencing the separation of oligonucleotides using reversed-phase/ion-exchange mixed-mode high performance liquid chromatography columns. J. Chromatogr. A, 2013, 1304, 69-77.
[69]
Matos, T.; Queiroz, J.A.; Bülow, L. Binding and elution behavior of small deoxyribonucleic acid fragments on a strong anion-exchanger multimodal chromatography resin. J. Chromatogr. A, 2013, 1302, 40-44.
[70]
Matos, T.; Queiroz, J.A. Bülow, L.J. Plasmid DNA purification using a multimodal chromatography resin. Mol. Recognit.,, 2014, 27(4), 184-189.
[71]
Dong, X.; Shen, A.; Gou, Z.; Chen, D.; Liang, X. Hydrophilic interaction/weak cation-exchange mixed-mode chromatography for chitooligosaccharides separation. Carbohydr. Res., 2012, 361, 195-199.
[72]
Eastwood, H.; Xia, F.; Lo, M.C.; Zhou, J.; Jordan, J.B.; McCarter, J.; Barnhart, W.W.; Gahm, K.H. Development of a nucleotide sugar purification method using a mixed mode column & mass spectrometry detection. J. Pharm. Biomed. Anal., 2015, 115, 402-409.
[73]
Matos, T.; Silva, G.; Queiroz, J.A.; Bülow, L. Preparative isolation of polymerase chain reaction products using mixed-mode chromatography. Anal. Biochem., 2015, 489, 73-75.
[74]
Dai, L.; Wigman, L.; Zhang, K. Sensitive and direct determination of lithium by mixed-mode chromatography and charged aerosol detection. J. Chromatogr. A, 2015, 1408, 87-92.
[75]
Wang, Q.; Long, Y.; Yao, L.; Xu, L.; Shi, Z.G.; Xu, L. Preparation, characterization and application of a reversed phase liquid chromatography/hydrophilic interaction chromatography mixed-mode C18-DTT stationary phase. Talanta, 2016, 146, 442-451.
[76]
Qiao, X.; Zhang, L.; Zhang, N.; Wang, X.; Qin, X.; Yan, H.; Liu, H. Imidazolium embedded C8 based stationary phase for simultaneous reversed-phase/hydrophilic interaction mixed-mode chromatography. J. Chromatogr. A, 2015, 1400, 107-116.
[79]

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