Recent advances in the production of recombinant factor IX: bioprocessing and cell engineering

References

• Palta S, Saroa R, Palta A. Overview of the coagulation system. Indian J Anaesth. 2014;58(5):515–523.
   PubMedGoogle Scholar
• Mathur A, Zhong D, Sabharwal AK, et al. Interaction of factor IXa with factor VIIIa effects of protease domain Ca2+ binding site, proteolysis in the autolysis loop, phospholipid, and factor X. J Biol Chem. 1997;272(37):23418–23426.
   PubMed Web of Science ®Google Scholar
• Stenflo J. Contributions of gla and EGF-like domains to the function of vitamin K-dependent coagulation factors. Crit Rev Eukar Gene Exp. 1999;9(1):59–88.
   PubMed Web of Science ®Google Scholar
• Bowen DJ. Haemophilia a and haemophilia B: molecular insights. Mol Pathol. 2002;55(2):127–144.
   PubMedGoogle Scholar
• Yoshitake S, Schach BG, Foster DC, et al. Nucleotide sequence of the gene for human factor IX (antihemophilic factor B). Biochemistry. 1985;24(14):3736–3750.
   PubMed Web of Science ®Google Scholar
• Brownlee G. Haemophilia B: a review of patient defects, diagnosis with gene probes and prospects for gene therapy. Rec Adv Haematol. 1988;5:251–264.
   Google Scholar
• Li T, Miller CH, Payne AB, et al. The CDC hemophilia B mutation project mutation list: a new online resource. Mol Genet Genomic Med. 2013;1(4):238–245.
   PubMedGoogle Scholar
• Rallapalli P, Kemball-Cook G, Tuddenham E, et al. An interactive mutation database for human coagulation factor IX provides novel insights into the phenotypes and genetics of hemophilia B. J Thromb Haemost. 2013;11(7):1329–1340.
   PubMed Web of Science ®Google Scholar
• Morfini M, Coppola A, Franchini M, et al. Clinical use of factor VIII and factor IX concentrates. Blood Transfusion. 2013;11(Suppl 4):s55.
   PubMedGoogle Scholar
• Bolton-Maggs PH, Pasi KJ. Haemophilias a and b. The Lancet. 2003;361(9371):1801–1809.
   PubMed Web of Science ®Google Scholar
• Santagostino E, Martinowitz U, Lissitchkov T, et al. Long-acting recombinant coagulation factor IX albumin fusion protein (rIX-FP) in hemophilia B: results of a phase 3 trial. Blood. 2016;127(14):1761–1769.
   PubMed Web of Science ®Google Scholar
• Doshi B, Arruda V. Gene therapy for hemophilia: what does the future hold? Ther Adv Hematol. 2018;9(9):273–293.
   PubMed Web of Science ®Google Scholar
• Miesbach W, Meijer K, Coppens M, et al. Gene therapy with adeno-associated virus vector 5-human factor IX in adults with hemophilia B. Blood. 2018;131(9):1022–1031.
   PubMed Web of Science ®Google Scholar
• Redrup Y. New CSL gene therapy could trigger a stock rerating. Sydney: Australian Financial Review; 2020.
   Google Scholar
• Paul Perreault JL, CSL Limited. Half year results; 2021. Available from: https://www.csl.com/investors/financial-results-and-information2021.
   Google Scholar
• Jørgensen LF. Novo Nordisk annual report; 2020. Available from: https://www.novonordisk.com/investors/financial-results.html2021.
   Google Scholar
• Abbonizio F, Giampaolo A, Chelucci C, et al. Associazione italiana centri emofilia (AICE). registro nazionale coagulopatie congenite. Tech. Rep. Rapporti ISTISAN 14/12. Roma, Italy: Istituto Superiore di Sanita; 2012.
   Google Scholar
• Kelley B, Renshaw T, Kamarck M. Process and operations strategies to enable global access to antibody therapies. Biotechnol Progr. 2021;37(3):e3139.
   PubMed Web of Science ®Google Scholar
• Pandey S, Vyas GN. Adverse effects of plasma transfusion. Transfusion. 2012;52:65S–79S.
   PubMed Web of Science ®Google Scholar
• Klamroth R, Gröner A, Simon TL. Pathogen inactivation and removal methods for plasma-derived clotting factor concentrates. Transfusion. 2014;54(5):1406–1417.
   PubMed Web of Science ®Google Scholar
• Anson D, Choo K, Rees D, et al. The gene structure of human anti‐haemophilic factor IX. Embo J. 1984;3(5):1053–1060.
   PubMed Web of Science ®Google Scholar
• Bentley A, Rees D, Rizza C, et al. Defective propeptide processing of blood clotting factor IX caused by mutation of arginine to glutamine at position-4. Cell. 1986;45(3):343–348.
   PubMed Web of Science ®Google Scholar
• Kumar SR. Industrial production of clotting factors: challenges of expression, and choice of host cells. Biotechnol J. 2015;10(7):995–1004.
   PubMed Web of Science ®Google Scholar
• Pegg CL, Zacchi LF, Recinos DR, et al. Identification of novel glycosylation events on human serum-derived factor IX. Glycoconj J. 2020;37(4):471–483.
   PubMed Web of Science ®Google Scholar
• Hansson K, Stenflo J. Post-translational modifications in proteins involved in blood coagulation. J Thromb Haemost. 2005;3(12):2633–2648.
   PubMed Web of Science ®Google Scholar
• Bond M, Jankowski M, Patel H, et al., editors. Biochemical characterization of recombinant factor IX. Seminars in hematology. 1998;35(2 Suppl 2):11–17.
   Google Scholar
• Chevreux G, Faid V, Andre MH, et al. Differential investigations from plasma-derived and recombinant Factor IX revealed major differences in post-translational modifications of activation peptides. Vox Sang. 2013;104(2):171–174.
   PubMed Web of Science ®Google Scholar
• Arruda VR, Hagstrom JN, Deitch J, et al. Posttranslational modifications of recombinant myotube-synthesized human factor IX. Blood. 2001;97(1):130–138.
   PubMed Web of Science ®Google Scholar
• DiScipio RG, Davie EW. Characterization of protein S, a. gamma.-carboxyglutamic acid containing protein from bovine and human plasma. Biochemistry. 1979;18(5):899–904.
   PubMed Web of Science ®Google Scholar
• Freedman SJ, Furie BC, Furie B, et al. Structure of the calcium ion-bound gamma-carboxyglutamic acid-rich domain of factor IX. Biochemistry. 1995;34(38):12126–12137.
   PubMed Web of Science ®Google Scholar
• Wacey AI, Krawczak M, Kakkar VV, et al. Determinants of the factor IX mutational spectrum in haemophilia B: an analysis of missense mutations using a multi-domain molecular model of the activated protein. Hum Genet. 1994;94(6):594–608.
   PubMed Web of Science ®Google Scholar
• Zhong D, Smith KJ, Birktoft JJ, et al. First epidermal growth factor-like domain of human blood coagulation factor IX is required for its activation by factor VIIa/tissue factor but not by factor XIa. Proc Natl Acad Sci. 1994;91(9):3574–3578.
   PubMed Web of Science ®Google Scholar
• Gillis S, Furie BC, Furie B, et al. gamma-Carboxyglutamic acids 36 and 40 do not contribute to human factor IX function . Protein Sci. 1997;6(1):185–196.
   PubMed Web of Science ®Google Scholar
• Mann KG, Nesheim ME, Church WR, et al. Surface-dependent reactions of the vitamin K-dependent enzyme complexes. Blood. 1990;176(1):1–16.
   PubMed Web of Science ®Google Scholar
• Tie JK, Stafford DW. Structural and functional insights into enzymes of the vitamin K cycle. J Thromb Haemost. 2016;14(2):236–247.
   PubMed Web of Science ®Google Scholar
• Stanley TB, Wu SM, Houben RJ, et al. Role of the propeptide and gamma-glutamic acid domain of factor IX for in vitro carboxylation by the vitamin K-dependent carboxylase. Biochemistry. 1998;37(38):13262–13268.
   PubMed Web of Science ®Google Scholar
• Stanley TB, Jin D-Y, Lin P-J, et al. The propeptides of the vitamin K-dependent proteins possess different affinities for the vitamin K-dependent carboxylase. J Biol Chem. 1999;274(24):16940–16944.
   PubMed Web of Science ®Google Scholar
• Wasley LC, Rehemtulla A, Bristol J, et al. PACE/furin can process the vitamin K-dependent pro-factor IX precursor within the secretory pathway. J Biol Chem. 1993;268(12):8458–8465.
   PubMed Web of Science ®Google Scholar
• Nelsestuen G. Role of gamma-carboxyglutamic acid. An unusual protein transition required for the calcium-dependent binding of prothrombin to phospholipid. J Biol Chem. 1976;251(18):5648–5656.
   PubMed Web of Science ®Google Scholar
• Gopinath SC, Shikamoto Y, Mizuno H, et al. Snake-venom-derived factor IX-binding protein specifically blocks the γ-carboxyglutamic acid-rich-domain-mediated membrane binding of human factors IX and X. Biochemical Journal. 2007;405(2):351–357.
   PubMedGoogle Scholar
• Shikamoto Y, Morita T, Fujimoto Z, et al. Crystal structure of Mg2+- and Ca2+-bound gla domain of factor IX complexed with binding protein. J Biol Chem. 2003;278(26):24090–24094.
   PubMed Web of Science ®Google Scholar
• Cheung W, Hamaguchi N, Smith K, et al. The binding of human factor IX to endothelial cells is mediated by residues 3-11. J Biol Chem. 1992;267(29):20529–20531.
   PubMed Web of Science ®Google Scholar
• Thompson AR. Structure, function, and molecular defects of factor IX. Blood. 1986;67(3):565–572.
   PubMed Web of Science ®Google Scholar
• Freedman SJ, Blostein MD, Baleja JD, et al. Identification of the phospholipid binding site in the vitamin K-dependent blood coagulation protein factor IX. J Biol Chem. 1996;271(27):16227–16236.
   PubMed Web of Science ®Google Scholar
• Sekiya F, Yoshida M, Yamashita T, et al. Magnesium(II) is a crucial constituent of the blood coagulation cascade. Potentiation of coagulant activities of factor IX by Mg2+ ions. J Biol Chem. 1996;271(15):8541–8544.
   PubMed Web of Science ®Google Scholar
• Venkateswarlu D. Structural insights into the interaction of blood coagulation co-factor VIIIa with factor IXa: a computational protein-protein docking and molecular dynamics refinement study. Biochem Biophys Res Commun. 2014;452(3):408–414.
   PubMed Web of Science ®Google Scholar
• Sekiya F, Yoshida M, Yamashita T, et al. Localization of the specific binding site for magnesium(II) ions in factor IX. FEBS Lett. 1996;392(3):205–208.
   PubMed Web of Science ®Google Scholar
• Knobe KE, Persson KE, Sjörin E, et al. Functional analysis of the factor IX epidermal growth factor-like domain mutation Ile66Thr associated with mild hemophilia B. Pathophysiol Haemost Thromb. 2006;35(5):370–375.
   PubMedGoogle Scholar
• Persson KE, Villoutreix BO, Thämlitz A-M, et al. The n-terminal epidermal growth factor-like domain of coagulation factor IX: probing its functions in the activation of factor ix and factor X with a monoclonal antibody. J Biol Chem. 2002;277(38):35616–35624.
   PubMed Web of Science ®Google Scholar
• Lenting PJ, Christophe OD, ter Maat H, et al. Ca2+ binding to the first epidermal growth factor-like domain of human blood coagulation factor IX promotes enzyme activity and factor VIII light chain binding. J Biol Chem. 1996;271(41):25332–25337.
   PubMed Web of Science ®Google Scholar
• Rao Z, Handford P, Mayhew M, et al. The structure of a Ca(2+)-binding epidermal growth factor-like domain: its role in protein-protein interactions . Cell. 1995;82(1):131–141.
   PubMed Web of Science ®Google Scholar
• Rees DJ, Jones IM, Handford PA, et al. The role of beta-hydroxyaspartate and adjacent carboxylate residues in the first EGF domain of human factor IX. Embo J. 1988;7(7):2053–2061.
   PubMed Web of Science ®Google Scholar
• Handford P, Mayhew M, Baron M, et al. Key residues involved in calcium-binding motifs in EGF-like domains. Nature. 1991;351(6322):164–167.
   PubMed Web of Science ®Google Scholar
• Brown MA, Stenberg LM. Biopharmaceuticals: post‐translational modification carboxylation and hydroxylation. In Gary Walsh, editor. Post-Translational Modification of Protein Biopharmaceuticals. New Jersey: Wiley; 2009. p. 209–252.
   Google Scholar
• Strynadka NC, James MN. Crystal structures of the helix-loop-helix calcium-binding proteins. Annu Rev Biochem. 1989;58(1):951–999.
   PubMedGoogle Scholar
• Rees DC, Lewis M, Lipscomb WN. Refined crystal structure of carboxypeptidase A at 1.54 A resolution. J Mol Biol. 1983;168(2):367–387.
   PubMed Web of Science ®Google Scholar
• Stenflo J, Lundwall A, Dahlbäck B. beta-Hydroxyasparagine in domains homologous to the epidermal growth factor precursor in vitamin K-dependent protein S. Proc Natl Acad Sci. 1987;84(2):368–372.
   PubMed Web of Science ®Google Scholar
• Handford P, Baron M, Mayhew M, et al. The first EGF‐like domain from human factor IX contains a high‐affinity calcium binding site. Embo J. 1990;9(2):475–480.
   PubMed Web of Science ®Google Scholar
• Hughes PE, Morgan G, Rooney EK, et al. Tyrosine 69 of the first epidermal growth factor-like domain of human factor IX is essential for clotting activity. J Biol Chem. 1993;268(24):17727–17733.
   PubMed Web of Science ®Google Scholar
• Ohlin AK, Linse S, Stenflo J. Calcium binding to the epidermal growth factor homology region of bovine protein C. J Biol Chem. 1988;263(15):7411–7417.
   PubMed Web of Science ®Google Scholar
• Giannelli F, Green P, Sommer S, et al. Haemophilia B: database of point mutations and short additions and deletions—eighth edition. Nucleic Acids Res. 1998;26(1):265–268.
   PubMed Web of Science ®Google Scholar
• Cooke RM, Wilkinson AJ, Baron M, et al. The solution structure of human epidermal growth factor. Nature. 1987;327(6120):339–341.
   PubMed Web of Science ®Google Scholar
• Mathur A, Bajaj SP. Protease and egf1 domains of factor ixa play distinct roles in binding to factor VIIIa importance of helix 330 (helix 162 in chymotrypsin) of protease domain of factor IXa in its interaction with factoR VIIIa. J Biol Chem. 1999;274(26):18477–18486.
   PubMed Web of Science ®Google Scholar
• Knobe K, Persson K, Sjörin E, et al. Functional analysis of the EGF-like domain mutations Pro55Ser and Pro55Leu, which cause mild hemophilia B. J Thromb Haemost. 2003;1(4):782–790.
   PubMed Web of Science ®Google Scholar
• Appella E, Weber IT, Blasi F. Structure and function of epidermal growth factor-like regions in proteins. FEBS Lett. 1988;231(1):1–4.
   PubMed Web of Science ®Google Scholar
• Yang Y, Sweeney WV, Schneider K, et al. Two-step selective formation of three disulfide bridges in the synthesis of the C-terminal epidermal growth factor-like domain in human blood coagulation factor IX. Protein Sci. 1994;3(8):1267–1275.
   PubMed Web of Science ®Google Scholar
• Wilkinson FH, Ahmad SS, Walsh PN. The factor IXa second epidermal growth factor (EGF2) domain mediates platelet binding and assembly of the factor X activating complex. J Biol Chem. 2002;277(8):5734–5741.
   PubMed Web of Science ®Google Scholar
• Fribourg C, Meijer AB, Mertens K. The interface between the EGF2 domain and the protease domain in blood coagulation factor IX contributes to factor VIII binding and factor X activation. Biochemistry. 2006;45(35):10777–10785.
   PubMed Web of Science ®Google Scholar
• Christophe OD, Lenting PJ, Kolkman JA, et al. Blood coagulation factor IX residues Glu78 and Arg94 provide a link between both epidermal growth factor-like domains that is crucial in the interaction with factor VIII light chain. J Biol Chem. 1998;273(1):222–227.
   PubMed Web of Science ®Google Scholar
• Hertzberg MS, Facey SL, Hogg PJ. An arg/ser substitution in the second epidermal growth factor–like module of factor IX introduces an O-Linked carbohydrate and markedly impairs activation by factor XIa and factor VIIa/tissue factor and catalytic efficiency of factor IXa. Blood. 1999;94(1):156–163.
   PubMed Web of Science ®Google Scholar
• Zögg T, Brandstetter H. Activation mechanisms of coagulation factor IX. Biol Chem. 2009;390(5–6):391–400.
   PubMed Web of Science ®Google Scholar
• Fujikawa K, Legaz ME, Kato H, et al. The mechanism of activation of bovine factor IX (Christmas factor) by bovine factor XIa (activated plasma thromboplastin antecedent). Biochemistry. 1974;13(22):4508–4516.
   PubMed Web of Science ®Google Scholar
• Orlova NA, Kovnir SV, Vorobiev II, et al. Coagulation factor IX for hemophilia B therapy. Acta Naturae. 2012;4(2):62–73.
   PubMed Web of Science ®Google Scholar
• Monahan PE, Velander WH, Bajaj SP. Coagulation factor IXa. Handbook of proteolytic enzymes. Amsterdam: Elsevier; 2013. p. 2898–2905.
   Google Scholar
• Di Scipio RG, Kurachi K, Davie EW. Activation of human factor IX (Christmas factor). J Clin Invest. 1978;61(6):1528–1538.
   PubMed Web of Science ®Google Scholar
• Komar AA. The art of gene redesign and recombinant protein production: approaches and perspectives. Protein therapeutics. New York City: Springer; 2016. p. 161–177.
   Google Scholar
• Mertens K, Van Wijngaarden A, Bertina R. The role of factor VIII in the activation of human blood coagulation factor X by activated factor IX. Thromb Haemost. 1985;53(03):654–660.
   Google Scholar
• Zacchi LF, Roche-Recinos D, Pegg CL, et al. Coagulation factor IX analysis in bioreactor cell culture supernatant predicts quality of the purified product. Commun Biol. 2021;4(1):1–19.
   PubMed Web of Science ®Google Scholar
• Kurachi K, Davie EW. Isolation and characterization of a cDNA coding for human factor IX. Proc Natl Acad Sci. 1982;79(21):6461–6464.
   PubMed Web of Science ®Google Scholar
• Katayama K, Ericsson LH, Enfield DL, et al. Comparison of amino acid sequence of bovine coagulation factor IX (Christmas factor) with that of other vitamin K-dependent plasma proteins. Proc Natl Acad Sci USA. 1979;76(10):4990–4994.
   PubMed Web of Science ®Google Scholar
• Huang LJ, Lin JH, Tsai JH, et al. Identification of protein O-glycosylation site and corresponding glycans using liquid chromatography-tandem mass spectrometry via mapping accurate mass and retention time shift. J Chromatogr A. 2014;1371:136–145.
   PubMed Web of Science ®Google Scholar
• Seo Y, Park GM, Oh MJ, et al. Investigation of O-glycosylation heterogeneity of recombinant coagulation factor IX using LC-MS/MS. Bioanalysis. 2017;9(18):1361–1372.
   PubMed Web of Science ®Google Scholar
• Nishimura H, Takao T, Hase S, et al. Human factor IX has a tetrasaccharide O-glycosidically linked to serine 61 through the fucose residue. J Biol Chem. 1992;267(25):17520–17525.
   PubMed Web of Science ®Google Scholar
• Nishimura H, Kawabata S, Kisiel W, et al. Identification of a disaccharide (Xyl-Glc) and a trisaccharide (Xyl2-Glc) O-glycosidically linked to a serine residue in the first epidermal growth factor-like domain of human factors VII and IX and protein Z and bovine protein Z. J Biol Chem. 1989;264(34):20320–20325.
   PubMed Web of Science ®Google Scholar
• Monroe DM, Jenny RJ, Van Cott KE, et al. Characterization of IXINITY® (trenonacog alfa), a recombinant factor IX with primary sequence corresponding to the threonine-148 polymorph. Advances in Hematology. 2016;2016:7678901.
   PubMedGoogle Scholar
• Rouse JC, McClellan JE, Patel HK, et al. Top-down characterization of protein pharmaceuticals by liquid chromatography/mass spectrometry: application to recombinant factor IX comparability- a case study. Methods Mol Biol. 2005;308:435–460.
   PubMedGoogle Scholar
• Harris RJ, Spellman MW. O-linked fucose and other post-translational modifications unique to EGF modules. Glycobiology. 1993;3(3):219–224.
   PubMed Web of Science ®Google Scholar
• Harris RJ, van Halbeek H, Glushka J, et al. Identification and structural analysis of the tetrasaccharide NeuAc alpha(2->6)Gal beta(1->4)GlcNAc beta(1->3)Fuc alpha 1->O-linked to serine 61 of human factor IX. Biochemistry. 1993;32(26):6539–6547.
   PubMed Web of Science ®Google Scholar
• Furie B, Furie BC. The molecular basis of blood coagulation. Cell. 1988;53(4):505–518.
   PubMed Web of Science ®Google Scholar
• McMullen B, Fujikawa K, Kisiel W. The occurrence of beta-hydroxyaspartic acid in the vitamin K-dependent blood coagulation zymogens. Biochem Biophys Res Commun. 1983;115(1):8–14.
   PubMed Web of Science ®Google Scholar
• Rabiet M-J, Jorgensen MJ, Furie B, et al. Effect of propeptide mutations on post-translational processing of factor IX. Evidence that beta-hydroxylation and gamma-carboxylation are independent events. J Biol Chem. 1987;262(31):14895–14898.
   PubMed Web of Science ®Google Scholar
• Harris R, PDI TL, Smith K, editors. Partial phosphorylation of serine-68 in EGF-1 of human factor IX. Proceedings of XIth International Conference on Methods in Protein Structure Analysis, Annecy; 1996. p. 106.
   Google Scholar
• Gil G-C, Velander WH, Van Cott KE. Analysis of the N-glycans of recombinant human factor IX purified from transgenic pig milk. Glycobiology. 2008;18(7):526–539.
   PubMed Web of Science ®Google Scholar
• Makino Y, Omichi K, Kuraya N, et al. Structural analysis of N-linked sugar chains of human blood clotting factor IX. J Biochem. 2000;128(2):175–180.
   PubMed Web of Science ®Google Scholar
• Agarwala KL, Kawabata S, Takao T, et al. Activation peptide of human factor IX has oligosaccharides O-glycosidically linked to threonine residues at 159 and 169. Biochemistry. 1994;33(17):5167–5171.
   PubMed Web of Science ®Google Scholar
• Cook KM, Butera D, Hogg PJ. Evaluation of a potential redox switch in blood coagulation tenase. BioRxiv. 2019;:515718.
   Google Scholar
• Brandstetter H, Bauer M, Huber R, et al. X-ray structure of clotting factor IXa: active site and module structure related to xase activity and hemophilia B. Proc Natl Acad Sci. 1995;92(21):9796–9800.
   PubMed Web of Science ®Google Scholar
• Bajaj SP, Sabharwal AK, Gorka J, et al. Antibody-probed conformational transitions in the protease domain of human factor IX upon calcium binding and zymogen activation: putative high-affinity Ca (2+)-binding site in the protease domain. Proc Natl Acad Sci. 1992;89(1):152–156.
   PubMed Web of Science ®Google Scholar
• Kolkman JA, Christophe OD, Lenting PJ, et al. Surface loop 199–204 in blood coagulation factor IX is a cofactor-dependent site involved in macromolecular substrate interaction. J Biol Chem. 1999;274(41):29087–29093.
   PubMed Web of Science ®Google Scholar
• Kaufman R, Wasley L, Furie BC, et al. Expression, purification, and characterization of recombinant gamma-carboxylated factor IX synthesized in Chinese hamster ovary cells. J Biol Chem. 1986;261(21):9622–9628.
   PubMed Web of Science ®Google Scholar
• Food and Drug Administrator (FDA). Approval letter – Benefix 1997; 1997 February 11 [cited 2020 May 4]. Available from: http://wayback.archive-it.org/7993/20170723024338/https://www.fda.gov/BiologicsBloodVaccines/BloodBloodProducts/ApprovedProducts/LicensedProductsBLAs/FractionatedPlasmaProducts/ucm057039.htm.
   Google Scholar
• Swiech K, Picanço-Castro V, Covas DT. Production of recombinant coagulation factors: are humans the best host cells? Bioengineered. 2017;8(5):462–470.
   PubMed Web of Science ®Google Scholar
• Food and Drug Administrator (FDA). Approval letter – REBINYN 2017; 2017, May 31 [cited 2020 May 5]. Available from: https://www.fda.gov/media/105612/download.
   Google Scholar
• Desai SG. Continuous and semi-continuous cell culture for production of blood clotting factors. J Biotechnol. 2015;213:20–27.
   PubMed Web of Science ®Google Scholar
• Collins PW, Young G, Knobe K, et al. Recombinant long-acting glycoPEGylated factor IX in hemophilia B: a multinational randomized phase 3 trial. Blood. 2014;124(26):3880–3886.
   PubMed Web of Science ®Google Scholar
• Pipe SW. Recombinant clotting factors. Thromb Haemost. 2008;99(5):840–850.
   PubMed Web of Science ®Google Scholar
• White GC, II Beebe A, Nielsen B. Recombinant factor IX. Thromb Haemost. 1997;78(1):261–265.
   PubMed Web of Science ®Google Scholar
• Roth DA, Kessler CM, Pasi KJ, et al. Human recombinant factor IX: safety and efficacy studies in hemophilia B patients previously treated with plasma-derived factor IX concentrates. Blood. 2001;98(13):3600–3606.
   PubMed Web of Science ®Google Scholar
• Rup B. Immune responses to recombinant factor IX (BeneFIX®) and recombinant B domain deleted factor VIII (ReFacto®). Develop Biol. 2002;109:103–106.
   Google Scholar
• Kaufman RJ. Post-translational modifications required for coagulation factor secretion and function. Thromb Haemost. 1998;79(6):1068–1079.
   PubMed Web of Science ®Google Scholar
• Berkner KL. Expression of recombinant vitamin K-dependent proteins in mammalian cells: factors IX and VII. Methods Enzymol. 1993;222:450–477.
   PubMed Web of Science ®Google Scholar
• Goh JB, Ng SK. Impact of host cell line choice on glycan profile. Crit Rev Biotechnol. 2018;38(6):851–867.
   PubMed Web of Science ®Google Scholar
• de Castilho Fernandes A, Fontes A, Gonsales N, et al. Stable and high-level production of recombinant factor IX in human hepatic cell line. Biotechnol Appl Biochem. 2011;58(4):243–249.
   PubMed Web of Science ®Google Scholar
• Enjolras N, Dargaud Y, Pérot E, et al. Human hepatoma cell line HuH-7 is an effective cellular system to produce recombinant factor IX with improved post-translational modifications. Thromb Res. 2012;130(5):e266–e273.
   PubMed Web of Science ®Google Scholar
• Dumont J, Euwart D, Mei B, et al. Human cell lines for biopharmaceutical manufacturing: history, status, and future perspectives. Crit Rev Biotechnol. 2016;36(6):1110–1122.
   PubMed Web of Science ®Google Scholar
• Vatandoost J, Zomorodipour A, Sadeghizadeh M, et al. Expression of biologically active human clotting factor IX in drosophila S2 cells: γ-carboxylation of a human vitamin K-dependent protein by the insect enzyme. Biotechnol Prog. 2012;28(1):45–51.
   PubMed Web of Science ®Google Scholar
• Yee CM, Zak AJ, Hill BD, et al. The coming age of insect cells for manufacturing and development of protein therapeutics. Ind Eng Chem Res. 2018;57(31):10061–10070.
   PubMed Web of Science ®Google Scholar
• Khorshidi S, Zomorodipour A, Behmanesh M, et al. Functional expression of the human coagulation factor IX using heterologous signal peptide and propeptide sequences in mammalian cell line. Biotechnol Lett. 2015;37(9):1773–1781.
   PubMed Web of Science ®Google Scholar
• Masterton RJ, Smales CM. The impact of process temperature on mammalian cell lines and the implications for the production of recombinant proteins in CHO cells. Pharm Bioprocess. 2014;2(1):49–61.
   Google Scholar
• Dean J, Reddy P. Metabolic analysis of antibody producing CHO cells in fed-batch production. Biotechnol Bioeng. 2013;110(6):1735–1747.
   PubMed Web of Science ®Google Scholar
• Ehret J, Zimmermann M, Eichhorn T, et al. Impact of cell culture media additives on IgG glycosylation produced in Chinese hamster ovary cells. Biotechnol Bioeng. 2019;116(4):816–830.
   PubMed Web of Science ®Google Scholar
• Backliwal G, Hildinger M, Kuettel I, et al. Valproic acid: a viable alternative to sodium butyrate for enhancing protein expression in mammalian cell cultures. Biotechnol Bioeng. 2008;101(1):182–189.
   PubMed Web of Science ®Google Scholar
• Ritacco FV, Wu Y, Khetan A. Cell culture media for recombinant protein expression in Chinese hamster ovary (CHO) cells: history, key components, and optimization strategies. Biotechnol Prog. 2018;34(6):1407–1426.
   PubMed Web of Science ®Google Scholar
• Sung YH, Song YJ, Lim SW, et al. Effect of sodium butyrate on the production, heterogeneity and biological activity of human thrombopoietin by recombinant Chinese hamster ovary cells. J Biotechnol. 2004;112(3):323–335.
   PubMed Web of Science ®Google Scholar
• Takagi Y, Kikuchi T, Wada R, et al. The enhancement of antibody concentration and achievement of high cell density CHO cell cultivation by adding nucleoside. Cytotechnology. 2017;69(3):511–521.
   PubMed Web of Science ®Google Scholar
• Pereira S, Kildegaard HF, Andersen MR. Impact of CHO metabolism on cell growth and protein production: an overview of toxic and inhibiting metabolites and nutrients. Biotechnol J. 2018;13(3):1700499.
   Web of Science ®Google Scholar
• Kim WH, Kim J-S, Yoon Y, et al. Effect of Ca2+ and Mg2+ concentration in culture medium on the activation of recombinant factor IX produced in Chinese hamster ovary cells. J Biotechnol. 2009;142(3-4):275–278.
   PubMed Web of Science ®Google Scholar
• Hossler P, Racicot C, Chumsae C, et al. Cell culture media supplementation of infrequently used sugars for the targeted shifting of protein glycosylation profiles. Biotechnol Prog. 2017;33(2):511–522.
   PubMed Web of Science ®Google Scholar
• Restelli V, Wang MD, Huzel N, et al. The effect of dissolved oxygen on the production and the glycosylation profile of recombinant human erythropoietin produced from CHO cells. Biotechnol Bioeng. 2006;94(3):481–494.
   PubMed Web of Science ®Google Scholar
• Kaufmann H, Mazur X, Fussenegger M, et al. Influence of low temperature on productivity, proteome and protein phosphorylation of CHO cells. Biotechnol Bioeng. 1999;63(5):573–582.
   PubMed Web of Science ®Google Scholar
• Jiang R, Chen H, Xu S. pH excursions impact CHO cell culture performance and antibody N-linked glycosylation. Bioprocess Biosyst Eng. 2018;41(12):1731–1741.
   PubMed Web of Science ®Google Scholar
• Kunkel JP, Jan DC, Jamieson JC, et al. Dissolved oxygen concentration in serum-free continuous culture affects N-linked glycosylation of a monoclonal antibody. J Biotechnol. 1998;62(1):55–71.
   PubMed Web of Science ®Google Scholar
• Wang SB, Lee-Goldman A, Ravikrishnan J, et al. Manipulation of the sodium-potassium ratio as a lever for controlling cell growth and improving cell specific productivity in perfusion CHO cell cultures. Biotechnol Bioeng. 2018;115(4):921–931.
   PubMed Web of Science ®Google Scholar
• Sekiya F, Yamashita T, Atoda H, et al. Regulation of the tertiary structure and function of coagulation factor IX by magnesium (II) ions. J Biol Chem. 1995;270(24):14325–14331.
   PubMed Web of Science ®Google Scholar
• Hallgren KW, Hommema EL, McNally BA, et al. Carboxylase overexpression effects full carboxylation but poor release and secretion of factor IX: Implications for the release of vitamin K-Dependent proteins. Biochemistry. 2002;41(50):15045–15055.
   PubMed Web of Science ®Google Scholar
• Aghamohseni H, Ohadi K, Spearman M, et al. Effects of nutrient levels and average culture pH on the glycosylation pattern of camelid-humanized monoclonal antibody. J Biotechnol. 2014;186:98–109.
   PubMed Web of Science ®Google Scholar
• Butler M. Optimisation of the cellular metabolism of glycosylation for recombinant proteins produced by mammalian cell systems. Cytotechnology. 2006;50(1–3):57–76.
   PubMed Web of Science ®Google Scholar
• Borys MC, Linzer DI, Papoutsakis ET. Culture pH affects expression rates and glycosylation of recombinant mouse placental lactogen proteins by Chinese hamster ovary (CHO) cells. Bio/technology. 1993;11(6):720–724.
   PubMedGoogle Scholar
• Trummer E, Fauland K, Seidinger S, et al. Process parameter shifting: part I. Effect of DOT, pH, and temperature on the performance of Epo-Fc expressing CHO cells cultivated in controlled batch bioreactors . Biotechnol Bioeng. 2006;94(6):1033–1044.
   PubMed Web of Science ®Google Scholar
• Ahn WS, Jeon JJ, Jeong YR, et al. Effect of culture temperature on erythropoietin production and glycosylation in a perfusion culture of recombinant CHO cells. Biotechnol Bioeng. 2008;101(6):1234–1244.
   PubMed Web of Science ®Google Scholar
• Rodriguez J, Spearman M, Huzel N, et al. Enhanced production of monomeric interferon-beta by CHO cells through the control of culture conditions. Biotechnol Prog. 2005;21(1):22–30.
   PubMed Web of Science ®Google Scholar
• Avello V, Tapia B, Vergara M, et al. Impact of sodium butyrate and mild hypothermia on metabolic and physiological behaviour of CHO TF 70R cells. Electron J Biotechnol. 2017;27:55–62.
   Web of Science ®Google Scholar
• Sunley K, Tharmalingam T, Butler M. CHO cells adapted to hypothermic growth produce high yields of recombinant beta-interferon. Biotechnol Prog. 2008;24(4):898–906.
   PubMed Web of Science ®Google Scholar
• Hossler P, Khattak SF, Li ZJ. Optimal and consistent protein glycosylation in mammalian cell culture. Glycobiology. 2009;19(9):936–949.
   PubMed Web of Science ®Google Scholar
• Chotigeat W, Watanapokasin Y, Mahler S, et al. Role of environmental conditions on the expression levels, glycoform pattern and levels of sialyltransferase for hFSH produced by recombinant CHO cells. Cytotechnology. 1994;15(1–3):217–221.
   PubMed Web of Science ®Google Scholar
• Brühlmann D, Muhr A, Parker R, et al. Cell culture media supplemented with raffinose reproducibly enhances high mannose glycan formation. J Biotechnol. 2017 Jun 20;252:32–42.
   PubMed Web of Science ®Google Scholar
• Slade PG, Caspary RG, Nargund S, et al. Mannose metabolism in recombinant CHO cells and its effect on IgG glycosylation. Biotechnol Bioeng. 2016;113(7):1468–1480.
   PubMed Web of Science ®Google Scholar
• Onitsuka M, Tatsuzawa M, Asano R, et al. Trehalose suppresses antibody aggregation during the culture of Chinese hamster ovary cells. J Biosci Bioeng. 2014;117(5):632–638.
   PubMed Web of Science ®Google Scholar
• Liu B, Spearman M, Doering J, et al. The availability of glucose to CHO cells affects the intracellular lipid-linked oligosaccharide distribution, site occupancy and the N-glycosylation profile of a monoclonal antibody. J Biotechnol. 2014;170:17–27.
   PubMed Web of Science ®Google Scholar
• Liu J, Wang J, Fan L, et al. Galactose supplementation enhance sialylation of recombinant Fc-fusion protein in CHO cell: an insight into the role of galactosylation in sialylation. World J Microbiol Biotechnol. 2015;31(7):1147–1156.
   PubMed Web of Science ®Google Scholar
• Leong DSZ, Teo BKH, Tan JGL, et al. Application of maltose as energy source in protein-free CHO-K1 culture to improve the production of recombinant monoclonal antibody. Sci Rep. 2018;8(1):4037.
   PubMedGoogle Scholar
• Leong DSZ, Tan JGL, Chin CL, et al. Evaluation and use of disaccharides as energy source in protein-free mammalian cell cultures. Sci Rep. 2017;7(1):45216.
   PubMedGoogle Scholar
• Das TK, Narhi LO, Sreedhara A, et al. Stress factors in mAb drug substance production processes: critical assessment of impact on product quality and control strategy. J Pharm Sci. 2020;109(1):116–133.
   PubMed Web of Science ®Google Scholar
• Park JH, Noh SM, Woo JR, et al. Valeric acid induces cell cycle arrest at G1 phase in CHO cell cultures and improves recombinant antibody productivity. Biotechnol J. 2016;11(4):487–496.
   PubMed Web of Science ®Google Scholar
• Kim NS, Lee GM. Overexpression of bcl‐2 inhibits sodium butyrate‐induced apoptosis in chinese hamster ovary cells resulting in enhanced humanized antibody production. Biotechnol Bioeng. 2000;71(3):184–193.
   PubMed Web of Science ®Google Scholar
• Chen F, Kou T, Fan L, et al. The combined effect of sodium butyrate and low culture temperature on the production, sialylation, and biological activity of an antibody produced in CHO cells. Biotechnol Bioproc E. 2011;16(6):1157–1165.
   Web of Science ®Google Scholar
• Yang M, Butler M. Effects of ammonia and glucosamine on the heterogeneity of erythropoietin glycoforms. Biotechnol Prog. 2002;18(1):129–138.
   PubMed Web of Science ®Google Scholar
• Baker KN, Rendall MH, Hills AE, et al. Metabolic control of recombinant protein N‐glycan processing in NS0 and CHO cells. Biotechnol Bioeng. 2001;73(3):188–202.
   PubMed Web of Science ®Google Scholar
• Hills AE, Patel A, Boyd P, et al. Metabolic control of recombinant monoclonal antibody N-glycosylation in GS-NS0 cells . Biotechnol Bioeng. 2001;75(2):239–251.
   PubMed Web of Science ®Google Scholar
• Doyle C, Butler M. The effect of pH on the toxicity of ammonia to a murine hybridoma. J Biotechnol. 1990;15(1–2):91–100.
   PubMed Web of Science ®Google Scholar
• Andersen DC, Goochee CF. The effect of ammonia on the O-linked glycosylation of granulocyte colony-stimulating factor produced by Chinese hamster ovary cells. Biotechnol Bioeng. 1995;47(1):96–105.
   PubMed Web of Science ®Google Scholar
• Andersen DC, Goochee CF. The effect of cell-culture conditions on the oligosaccharide structures of secreted glycoproteins. Curr Opin Biotechnol. 1994;5(5):546–549.
   PubMedGoogle Scholar
• Wahrheit J, Nicolae A, Heinzle E. Dynamics of growth and metabolism controlled by glutamine availability in Chinese hamster ovary cells. Appl Microbiol Biotechnol. 2014;98(4):1771–1783.
   PubMed Web of Science ®Google Scholar
• Graham RJ, Bhatia H, Yoon S. Consequences of trace metal variability and supplementation on chinese hamster ovary (CHO) cell culture performance: a review of key mechanisms and considerations. Biotechnol Bioeng. 2019;116(12):3446–3456.
   PubMed Web of Science ®Google Scholar
• Sumit M, Dolatshahi S, Chu A-HA, et al. Dissecting N-Glycosylation dynamics in Chinese hamster ovary cells fed-batch cultures using time course omics analyses. iScience. 2019;12:102–120.
   PubMed Web of Science ®Google Scholar
• Kaufman RJ, Swaroop M, Murtha-Riel P. Depletion of manganese within the secretory pathway inhibits O-linked glycosylation in mammalian cells. Biochemistry. 1994;33(33):9813–9819.
   PubMed Web of Science ®Google Scholar
• Crowell CK, Grampp GE, Rogers GN, et al. Amino acid and manganese supplementation modulates the glycosylation state of erythropoietin in a CHO culture system. Biotechnol Bioeng. 2007;96(3):538–549.
   PubMed Web of Science ®Google Scholar
• Alves CS, Prajapati S. Optimizing Chinese hamster ovary cell line development via targeted control of N-glycosylation. Pharm Bioprocess. 2015;3(7):443–461.
   Google Scholar
• Gawlitzek M, Estacio M, Fürch T, et al. Identification of cell culture conditions to control N‐glycosylation site‐occupancy of recombinant glycoproteins expressed in CHO cells. Biotechnol Bioeng. 2009;103(6):1164–1175.
   PubMed Web of Science ®Google Scholar
• Niu H, Wang J, Liu M, et al. Uridine modulates monoclonal antibody charge heterogeneity in Chinese hamster ovary cell fed-batch cultures. Bioresour Bioprocess. 2018;5(1):1–8.
   Google Scholar
• Gramer MJ, Eckblad JJ, Donahue R, et al. Modulation of antibody galactosylation through feeding of uridine, manganese chloride, and galactose. Biotechnol Bioeng. 2011;108(7):1591–1602.
   PubMed Web of Science ®Google Scholar
• Lee JH, Jeong YR, Kim YG, et al. Understanding of decreased sialylation of Fc-fusion protein in hyperosmotic recombinant Chinese hamster ovary cell culture: N-glycosylation gene expression and N-linked glycan antennary profile. Biotechnol Bioeng. 2017;114(8):1721–1732.
   PubMed Web of Science ®Google Scholar
• Gu X, Wang DI. Improvement of interferon‐γ sialylation in Chinese hamster ovary cell culture by feeding of N‐acetylmannosamine. Biotechnol Bioeng. 1998;58(6):642–648.
   PubMedGoogle Scholar
• Fiore M, Degrassi F. Dimethyl sulfoxide restores contact inhibition-induced growth arrest and inhibits cell density-dependent apoptosis in hamster cells. Exp Cell Res. 1999;251(1):102–110.
   PubMed Web of Science ®Google Scholar
• Liu J, Yoshikawa H, Nakajima Y, et al. Involvement of mitochondrial permeability transition and caspase-9 activation in dimethyl sulfoxide-induced apoptosis of EL-4 lymphoma cells. Int Immunopharmacol. 2001;1(1):63–74.
   PubMed Web of Science ®Google Scholar
• Coronel J, Klausing S, Heinrich C, et al. Valeric acid supplementation combined to mild hypothermia increases productivity in CHO cell cultivations. Biochem Eng J. 2016;114:101–109.
   Web of Science ®Google Scholar
• Coronel J, Heinrich C, Klausing S, et al. Perfusion process combining low temperature and valeric acid for enhanced recombinant factor VIII production. Biotechnol Prog. 2020;36(1):e2915.
   PubMed Web of Science ®Google Scholar
• Wallin R, Hutson SM. Warfarin and the vitamin K-dependent gamma-carboxylation system. Trends Mol Med. 2004;10(7):299–302.
   PubMed Web of Science ®Google Scholar
• Tie J-K, Jin D-Y, Straight DL, et al. Functional study of the vitamin K cycle in mammalian cells. Blood. 2011;117(10):2967–2974.
   PubMed Web of Science ®Google Scholar
• Wajih N, Hutson SM, Owen J, et al. Increased production of functional recombinant human clotting factor IX by baby hamster kidney cells engineered to overexpress VKORC1, the vitamin K 2, 3-epoxide-reducing enzyme of the vitamin K cycle. J Biol Chem. 2005;280(36):31603–31607.
   PubMed Web of Science ®Google Scholar
• Wallin R, Sane DC, Hutson SM. Vitamin K 2,3-epoxide reductase and the vitamin K-dependent gamma-carboxylation system. Thromb Res. 2002;108(4):221–226.
   PubMed Web of Science ®Google Scholar
• Liu J, Jonebring A, Hagström J, et al. Improved expression of recombinant human factor IX by co-expression of GGCX, VKOR and furin. Protein J. 2014;33(2):174–183.
   PubMed Web of Science ®Google Scholar
• Kovnir SV, Orlova NA, Shakhparonov MI, et al. A highly productive CHO cell line secreting human blood clotting factor IX. Acta Naturae. 2018;10(1):51–65.
   PubMed Web of Science ®Google Scholar
• Bolt G, D Steenstrup T, Kristensen C. All post-translational modifications except propeptide cleavage are required for optimal secretion of coagulation factor VII. 2007;98:988–997.
   Google Scholar
• Bolt G, Kristensen C, Steenstrup TD. More than one intracellular processing bottleneck delays the secretion of coagulation factor VII. Thromb Haemost. 2008;99(02):204–210.
   Google Scholar
• Kober L, Zehe C, Bode J. Optimized signal peptides for the development of high expressing CHO cell lines. Biotechnol Bioeng. 2013;110(4):1164–1173.
   PubMed Web of Science ®Google Scholar
• Camire RM, Larson PJ, Stafford DW, et al. Enhanced gamma-carboxylation of recombinant factor X using a chimeric construct containing the prothrombin propeptide . Biochemistry. 2000;39(46):14322–14329.
   PubMed Web of Science ®Google Scholar
• Vatandoost J, Sani Z. O. Effect of propeptide amino acid substitution in γ‐carboxylation, activity and expression of recombinant human coagulation factor IX. Biotechnol Progress. 2018;34(2):515–520.
   PubMed Web of Science ®Google Scholar
• Solá RJ, Griebenow K. Glycosylation of therapeutic proteins: an effective strategy to optimize efficacy. BioDrugs. 2010;24(1):9–21.
   PubMed Web of Science ®Google Scholar
• Aebi M. N-linked protein glycosylation in the ER. Biochimica et Biophysica Acta. 2013;1833(11):2430–2437.
   PubMed Web of Science ®Google Scholar
• Lowenthal MS, Davis KS, Formolo T, et al. Identification of novel N-glycosylation sites at noncanonical protein consensus motifs. J Proteome Res. 2016;15(7):2087–2101.
   PubMed Web of Science ®Google Scholar
• Valliere-Douglass JF, Kodama P, Mujacic M, et al. Asparagine-linked oligosaccharides present on a non-consensus amino acid sequence in the CH1 domain of human antibodies. J Biol Chem. 2009;284(47):32493–32506.
   PubMed Web of Science ®Google Scholar
• Varki A. Biological roles of oligosaccharides: all of the theories are correct. Glycobiology. 1993;3(2):97–130.
   PubMed Web of Science ®Google Scholar
• Lee HS, Qi Y, Im W. Effects of N-glycosylation on protein conformation and dynamics: protein data bank analysis and molecular dynamics simulation study. Sci Rep. 2015;5:8926.
   PubMed Web of Science ®Google Scholar
• Begbie ME, Mamdani A, Gataiance S, et al. An important role for the activation peptide domain in controlling factor IX levels in the blood of haemophilia B mice. Thromb Haemost. 2005;94(6):1138–1147.
   PubMed Web of Science ®Google Scholar
• Bolt G, Bjelke J, Hermit M, et al. Hyperglycosylation prolongs the circulation of coagulation factor IX. J Thromb Haemost. 2012;10(11):2397–2398.
   PubMed Web of Science ®Google Scholar
• Brooks AR, Sim D, Gritzan U, et al. Glycoengineered factor IX variants with improved pharmacokinetics and subcutaneous efficacy. J Thromb Haemost. 2013;11(9):1699–1706.
   PubMed Web of Science ®Google Scholar
• Bork K, Horstkorte R, Weidemann W. Increasing the sialylation of therapeutic glycoproteins: the potential of the sialic acid biosynthetic pathway. J Pharm Sci. 2009;98(10):3499–3508.
   PubMed Web of Science ®Google Scholar