Expression and characterization of a codon-optimized blood coagulation factor VIII

Journal of Thrombosis and Haemostasis

Volumn 15, Issue 4, 2017, Pages 709-720

  Shestopal, S A ^a   Hao, J J ^b   Karnaukhova, E ^a   Liang, Y ^a   Ovanesov, M V ^a   Lin, M ^a   Kurasawa, J H ^a   Lee, T K ^a   Mcvey, J H ^c   Sarafanov, A G ^a  

^a CENTER FOR DRUG EVALUATION AND RESEARCH   (United States)

^b Poochon Scientific   (United States)

^c UNIVERSITY OF SURREY   (United Kingdom)

Author keywords

coagulation factor VIII; hemophilia A; lentivirus; LRP1 protein, human; von Willebrand factor

Indexed keywords

BLOOD CLOTTING FACTOR 8; COMPLEMENTARY DNA; LOW DENSITY LIPOPROTEIN RECEPTOR RELATED PROTEIN; PROTEIN VARIANT; THROMBIN; B-DOMAIN-DELETED FACTOR VIII; PEPTIDE FRAGMENT; RECOMBINANT FACTOR VIII SQ; TYROSINE;

AFFINITY CHROMATOGRAPHY; AMINO ACID SEQUENCE; ANIMAL CELL; ARTICLE; BIOASSAY; CELL CULTURE; CHO CELL LINE; CIRCULAR DICHROISM; CONTROLLED STUDY; FEMALE; LIQUID CHROMATOGRAPHY; NONHUMAN; PROCESS OPTIMIZATION; PROTEIN ANALYSIS; PROTEIN CLEAVAGE; PROTEIN EXPRESSION; PROTEIN GLYCOSYLATION; PROTEIN PURIFICATION; SURFACE PLASMON RESONANCE; TANDEM MASS SPECTROMETRY; UPREGULATION; WESTERN BLOTTING; ANIMAL; CELL LINE; CHEMISTRY; CODON; CRICETULUS; GENE VECTOR; GENETICS; GLYCOSYLATION; HAMSTER; HUMAN; LENTIVIRUS; METABOLISM; MUTATION; PROTEIN ENGINEERING; PROTEIN SECONDARY STRUCTURE; STRUCTURE ACTIVITY RELATION;

ANIMALS; CELL LINE; CHO CELLS; CODON; CRICETINAE; CRICETULUS; DNA, COMPLEMENTARY; FACTOR VIII; GENETIC VECTORS; GLYCOSYLATION; HUMANS; LENTIVIRUS; MUTATION; PEPTIDE FRAGMENTS; PROTEIN ENGINEERING; PROTEIN STRUCTURE, SECONDARY; STRUCTURE-ACTIVITY RELATIONSHIP; TYROSINE;

EID: 85013498567     PISSN: 15387933     EISSN: 15387836     Source Type: Journal    
DOI: 10.1111/jth.13632     Document Type: Article

References (73)

1. Vehar GA, Keyt B, Eaton D, Rodriguez H, O'Brien DP, Rotblat F, Oppermann H, Keck R, Wood WI, Harkins RN, Tuddenham EG, Lawn RM, Capon DJ. Structure of human factor VIII. Nature 1984; 312: 337–42.
2. Toole JJ, Knopf JL, Wozney JM, Sultzman LA, Buecker JL, Pittman DD, Kaufman RJ, Brown E, Shoemaker C, Orr EC. Molecular cloning of a cDNA encoding human antihaemophilic factor. Nature 1984; 312: 342–7.
3. Jankowski MA, Patel H, Rouse JC, Marzilli LA, Weston SB, Sharpe PJ. Defining ‘full-length’ recombinant factor VIII: a comparative structural analysis. Haemophilia 2007; 13: 30–7.
4. Fay PJ. Factor VIII structure and function. Int J Hematol 2006; 83: 103–8.
5. Bovenschen N, Mertens K, Hu L, Havekes LM, van Vlijmen BJ. LDL receptor cooperates with LDL receptor-related protein in regulating plasma levels of coagulation factor VIII in vivo. Blood 2005; 106: 906–12.
6. Kurasawa JH, Shestopal SA, Woodle SA, Ovanesov MV, Lee TK, Sarafanov AG. Cluster III of low-density lipoprotein receptor-related protein 1 binds activated blood coagulation factor VIII. Biochemistry 2015; 54: 481–9.
7. Lenting PJ, Neels JG, van Den Berg BM, Clijsters PP, Meijerman DW, Pannekoek H, van Mourik JA, Mertens K, van Zonneveld AJ. The light chain of factor VIII comprises a binding site for low density lipoprotein receptor-related protein. J Biol Chem 1999; 274: 23734–9.
8. Saenko EL, Yakhyaev AV, Mikhailenko I, Strickland DK, Sarafanov AG. Role of the low density lipoprotein-related protein receptor in mediation of factor VIII catabolism. J Biol Chem 1999; 274: 37685–92.
9. Pipe SW. Recombinant clotting factors. Thromb Haemost 2008; 99: 840–50.
10. Wood WI, Capon DJ, Simonsen CC, Eaton DL, Gitschier J, Keyt B, Seeburg PH, Smith DH, Hollingshead P, Wion KL, Delwart E, Tuddenham EG, Vehar GA, Lawn RM. Expression of active human factor VIII from recombinant DNA clones. Nature 1984; 312: 330–7.
11. Lynch CM, Israel DI, Kaufman RJ, Miller AD. Sequences in the coding region of clotting factor VIII act as dominant inhibitors of RNA accumulation and protein production. Hum Gene Ther 1993; 4: 259–72.
12. Hoeben RC, Fallaux FJ, Cramer SJ, van den Wollenberg DJ, van Ormondt H, Briet E, van Der Eb AJ. Expression of the blood-clotting factor-VIII cDNA is repressed by a transcriptional silencer located in its coding region. Blood 1995; 85: 2447–54.
13. Fallaux FJ, Hoeben RC, Cramer SJ, van den Wollenberg DJ, Briet E, van Ormondt H, van Der Eb AJ. The human clotting factor VIII cDNA contains an autonomously replicating sequence consensus- and matrix attachment region-like sequence that binds a nuclear factor, represses heterologous gene expression, and mediates the transcriptional effects of sodium butyrate. Mol Cell Biol 1996; 16: 4264–72.
14. Koeberl DD, Halbert CL, Krumm A, Miller AD. Sequences within the coding regions of clotting factor VIII and CFTR block transcriptional elongation. Hum Gene Ther 1995; 6: 469–79.
15. Marquette KA, Pittman DD, Kaufman RJ. A 110-amino acid region within the A1-domain of coagulation factor VIII inhibits secretion from mammalian cells. J Biol Chem 1995; 270: 10297–303.
16. Swaroop M, Moussalli M, Pipe SW, Kaufman RJ. Mutagenesis of a potential immunoglobulin-binding protein-binding site enhances secretion of coagulation factor VIII. J Biol Chem 1997; 272: 24121–4.
17. Kaufman RJ, Wasley LC, Dorner AJ. Synthesis, processing, and secretion of recombinant human factor VIII expressed in mammalian cells. J Biol Chem 1988; 263: 6352–62.
18. Dorner AJ, Bole DG, Kaufman RJ. The relationship of N-linked glycosylation and heavy chain-binding protein association with the secretion of glycoproteins. J Cell Biol 1987; 105: 2665–74.
19. Kaufman RJ. Selection and coamplification of heterologous genes in mammalian cells. Methods Enzymol 1990; 185: 537–66.
20. Boedeker BG. Production processes of licensed recombinant factor VIII preparations. Semin Thromb Hemost 2001; 27: 385–94.
21. Baranyi L, Doering CB, Denning G, Gautney RE, Harris KT, Spencer HT, Roy A, Zayed H, Dropulic B. Rapid generation of stable cell lines expressing high levels of erythropoietin, factor VIII, and an antihuman CD20 antibody using lentiviral vectors. Hum Gene Ther Methods 2013; 24: 214–27.
22. Spencer HT, Denning G, Gautney RE, Dropulic B, Roy AJ, Baranyi L, Gangadharan B, Parker ET, Lollar P, Doering CB. Lentiviral vector platform for production of bioengineered recombinant coagulation factor VIII. Mol Ther 2011; 19: 302–9.
23. Schroder AR, Shinn P, Chen H, Berry C, Ecker JR, Bushman F. HIV-1 integration in the human genome favors active genes and local hotspots. Cell 2002; 110: 521–9.
24. Oberbek A, Matasci M, Hacker DL, Wurm FM. Generation of stable, high-producing CHO cell lines by lentiviral vector-mediated gene transfer in serum-free suspension culture. Biotechnol Bioeng 2011; 108: 600–10.
25. Miao HZ, Sirachainan N, Palmer L, Kucab P, Cunningham MA, Kaufman RJ, Pipe SW. Bioengineering of coagulation factor VIII for improved secretion. Blood 2004; 103: 3412–9.
26. Pipe SW. Functional roles of the factor VIII B domain. Haemophilia 2009; 15: 1187–96.
27. Sandberg H, Almstedt A, Brandt J, Gray E, Holmquist L, Oswaldsson U, Sebring S, Mikaelsson M. Structural and functional characteristics of the B-domain-deleted recombinant factor VIII protein, r-VIII SQ. Thromb Haemost 2001; 85: 93–100.
28. Winge S, Yderland L, Kannicht C, Hermans P, Adema S, Schmidt T, Gilljam G, Linhult M, Tiemeyer M, Belyanskaya L, Walter O. Development, upscaling and validation of the purification process for human-cl rhFVIII (Nuwiq(R)), a new generation recombinant factor VIII produced in a human cell-line. Protein Expr Purif 2015; 115: 165–75.
29. Berntorp E. Second generation, B-domain deleted recombinant factor VIII. Thromb Haemost 1997; 78: 256–60.
30. Thim L, Vandahl B, Karlsson J, Klausen NK, Pedersen J, Krogh TN, Kjalke M, Petersen JM, Johnsen LB, Bolt G, Norby PL, Steenstrup TD. Purification and characterization of a new recombinant factor VIII (N8). Haemophilia 2010; 16: 349–59.
31. Sandberg H, Kannicht C, Stenlund P, Dadaian M, Oswaldsson U, Cordula C, Walter O. Functional characteristics of the novel, human-derived recombinant FVIII protein product, human-cl rhFVIII. Thromb Res 2012; 130: 808–17.
32. Peters RT, Toby G, Lu Q, Liu T, Kulman JD, Low SC, Bitonti AJ, Pierce GF. Biochemical and functional characterization of a recombinant monomeric factor VIII-Fc fusion protein. J Thromb Haemost 2013; 11: 132–41.
33. Pabinger-Fasching I. The story of a unique molecule in hemophilia A: recombinant single-chain factor VIII. Thromb Res 2016; 141: S2–4.
34. Kolind MP, Norby PL, Flintegaard TV, Berchtold MW, Johnsen LB. The B-domain of Factor VIII reduces cell membrane attachment to host cells under serum free conditions. J Biotechnol 2010; 147: 198–204.
35. Kaufman RJ, Wasley LC, Davies MV, Wise RJ, Israel DI, Dorner AJ. Effect of von Willebrand factor coexpression on the synthesis and secretion of factor VIII in Chinese hamster ovary cells. Mol Cell Biol 1989; 9: 1233–42.
36. Adamson R. Design and operation of a recombinant mammalian cell manufacturing process for rFVIII. Ann Hematol 1994; 68: S9–14.
37. Fath S, Bauer AP, Liss M, Spriestersbach A, Maertens B, Hahn P, Ludwig C, Schafer F, Graf M, Wagner R. Multiparameter RNA and codon optimization: a standardized tool to assess and enhance autologous mammalian gene expression. PLoS ONE 2011; 6: e17596.
38. Ward NJ, Buckley SM, Waddington SN, Vandendriessche T, Chuah MK, Nathwani AC, McIntosh J, Tuddenham EG, Kinnon C, Thrasher AJ, McVey JH. Codon optimization of human factor VIII cDNAs leads to high-level expression. Blood 2011; 117: 798–807.
39. Mauro VP, Chappell SA. A critical analysis of codon optimization in human therapeutics. Trends Mol Med 2014; 20: 604–13.
40. Hunt RC, Simhadri VL, Iandoli M, Sauna ZE, Kimchi-Sarfaty C. Exposing synonymous mutations. Trends Genet 2014; 30: 308–21.
41. Marin M. Folding at the rhythm of the rare codon beat. Biotechnol J 2008; 3: 1047–57.
42. Tsai CJ, Sauna ZE, Kimchi-Sarfaty C, Ambudkar SV, Gottesman MM, Nussinov R. Synonymous mutations and ribosome stalling can lead to altered folding pathways and distinct minima. J Mol Biol 2008; 383: 281–91.
43. Kimchi-Sarfaty C, Schiller T, Hamasaki-Katagiri N, Khan MA, Yanover C, Sauna ZE. Building better drugs: developing and regulating engineered therapeutic proteins. Trends Pharmacol Sci 2013; 34: 534–48.
44. Demaison C, Parsley K, Brouns G, Scherr M, Battmer K, Kinnon C, Grez M, Thrasher AJ. High-level transduction and gene expression in hematopoietic repopulating cells using a human immunodeficiency [correction of imunodeficiency] virus type 1-based lentiviral vector containing an internal spleen focus forming virus promoter. Hum Gene Ther 2002; 13: 803–13.
45. Butenas S, Parhami-Seren B, Gissel MT, Gomperts ED, Fass DN, Mann KG. Potency and mass of factor VIII in FVIII products. Haemophilia 2009; 15: 63–72.
46. McCue JT, Selvitelli K, Walker J. Application of a novel affinity adsorbent for the capture and purification of recombinant factor VIII compounds. J Chromatogr A 2009; 1216: 7824–30.
47. Hellman U, Wernstedt C, Gonez J, Heldin CH. Improvement of an “In-Gel” digestion procedure for the micropreparation of internal protein fragments for amino acid sequencing. Anal Biochem 1995; 224: 451–5.
48. Jha NK, Shestopal SA, Gourley MJ, Woodle SA, Liang Y, Sarafanov AG, Weinstein M, Ovanesov MV. Optimization of the thrombin generation test components to measure potency of factor VIII concentrates. Haemophilia 2016; 22: 780–9.
49. Sandberg H, Almstedt A, Brandt J, Castro VM, Gray E, Holmquist L, Lewin M, Oswaldsson U, Mikaelsson M, Jankowski MA, Bond M, Scoble HA. Structural and functional characterization of B-domain deleted recombinant factor VIII. Semin Hematol 2001; 38: 4–12.
50. Fay PJ, Mastri M, Koszelak ME, Wakabayashi H. Cleavage of factor VIII heavy chain is required for the functional interaction of a2 subunit with factor IXA. J Biol Chem 2001; 276: 12434–9.
51. Kannicht C, Ramstrom M, Kohla G, Tiemeyer M, Casademunt E, Walter O, Sandberg H. Characterisation of the post-translational modifications of a novel, human cell line-derived recombinant human factor VIII. Thromb Res 2013; 131: 78–88.
52. Grushin K, Miller J, Dalm D, Parker ET, Healey JF, Lollar P, Stoilova-McPhie S. Lack of recombinant factor VIII B-domain induces phospholipid vesicle aggregation: implications for the immunogenicity of factor VIII. Haemophilia 2014; 20: 723–31.
53. Kosloski MP, Shetty KA, Wakabayashi H, Fay PJ, Balu-Iyer SV. Effects of replacement of factor VIII amino acids Asp519 and Glu665 with Val on plasma survival and efficacy in vivo. AAPS J 2014; 16: 1038–45.
54. Purohit VS, Balasubramanian SV. Interaction of dicaproyl phosphatidylserine with recombinant factor VIII and its impact on immunogenicity. AAPS J 2006; 8: E362–70.
55. Paik SH, Kim YJ, Han SK, Kim JY, Park H, Park YI. Comparability studies of new 3rd generation recombinant human factor VIII GreenGene F after improvement of formulation and viral inactivation/removal process. Biologicals 2012; 40: 405–14.
56. Ingerslev J, Jankowski MA, Weston SB, Charles LA. Collaborative field study on the utility of a BDD factor VIII concentrate standard in the estimation of BDDr Factor VIII: C activity in hemophilic plasma using one-stage clotting assays. J Thromb Haemost 2004; 2: 623–8.
57. Saenko EL, Scandella D. The acidic region of the factor VIII light chain and the C2 domain together form the high affinity binding site for von willebrand factor. J Biol Chem 1997; 272: 18007–14.
58. Christiansen ML, Balling KW, Persson E, Hilden I, Bagger-Sorensen A, Sorensen BB, Viuff D, Segel S, Klausen NK, Ezban M, Lethagen S, Steenstrup TD, Kjalke M. Functional characteristics of N8, a new recombinant FVIII. Haemophilia 2010; 16: 878–87.
59. van den Biggelaar M, Madsen JJ, Faber JH, Zuurveld MG, van der Zwaan C, Olsen OH, Stennicke HR, Mertens K, Meijer AB. Factor VIII interacts with the endocytic receptor low-density lipoprotein receptor-related protein 1 via an extended surface comprising “hot-spot” lysine residues. J Biol Chem 2015; 290: 16463–76.
60. Young PA, Migliorini M, Strickland DK. Evidence that factor VIII forms a bivalent complex with the LDL receptor-related protein 1 (LRP1): identification of cluster IV on LRP1 as the major binding site. J Biol Chem 2016; 291: 26035–44.
61. Meijer AB, Rohlena J, van der ZC, van Zonneveld AJ, Boertjes RC, Lenting PJ, Mertens K. Functional duplication of ligand-binding domains within low-density lipoprotein receptor-related protein for interaction with receptor associated protein, alpha2-macroglobulin, factor IXa and factor VIII. Biochim Biophys Acta 2007; 1774: 714–22.
62. Schwarz F, Aebi M. Mechanisms and principles of N-linked protein glycosylation. Curr Opin Struct Biol 2011; 21: 576–82.
63. Hossler P, Khattak SF, Li ZJ. Optimal and consistent protein glycosylation in mammalian cell culture. Glycobiology 2009; 19: 936–49.
64. Zhong X, Wright JF. Biological insights into therapeutic protein modifications throughout trafficking and their biopharmaceutical applications. Int J Cell Biol 2013; 2013: 273086.
65. Leyte A, Van Schijndel HB, Niehrs C, Huttner WB, Verbeet MP, Mertens K, van Mourik JA. Sulfation of Tyr1680 of human blood coagulation factor VIII is essential for the interaction of factor VIII with von Willebrand factor. J Biol Chem 1991; 266: 740–6.
66. Buyue Y, Liu T, Kulman JD, Toby GG, Kamphaus GD, Patarroyo-White S, Lu Q, Reidy TJ, Mei B, Jiang H, Pierce GF, Sommer JM, Peters RT. A single chain variant of factor VIII Fc fusion protein retains normal in vivo efficacy but exhibits altered in vitro activity. PLoS ONE 2014; 9: e113600.
67. Nathwani AC, Ward NJ, Thrasher AJ, Tuddenham E, McVey JH, Gray J, Davidoff A, inventors. Optimised coding sequence and promoter. US Patent, US20150273082 A1. 2015.
68. Tan S, Peters RT, inventors. Optimized factor VIII gene. US Patent, US20150361158 A1. 2015.
69. McIntosh J, Lenting PJ, Rosales C, Lee D, Rabbanian S, Raj D, Patel N, Tuddenham EG, Christophe OD, McVey JH, Waddington S, Nienhuis AW, Gray JT, Fagone P, Mingozzi F, Zhou SZ, High KA, Cancio M, Ng CY, Zhou J, et al. Therapeutic levels of FVIII following a single peripheral vein administration of rAAV vector encoding a novel human factor VIII variant. Blood 2013; 121: 3335–44.
70. Hoellriegl W, Weiller M, Kopic A, Gritsch H, Gangadharan B, Falkner FG, Monahan PE, Rottensteiner H, Scheiflinger F, Turecek M. Biopotency and efficacy of a FVIII gene therapy construct in hemophilia A mice. Haemophilia 2016; 22(Suppl. 4): 34.
71. Falkner FG, Horling F, Lengler F, Willer M, Mayrhofer J, Turecek M, Monahan PE, Hoellriegl W, Rottensteiner H, Scheiflinger F. Development of a lead candidate for Baxalta's AAV8-based FVIII gene therapy program BAX 888. Haemophilia 2016; 22(Suppl. 4): 34.
72. Martinowitz U, Lissitchkov T, Lubetsky A, Jotov G, Barazani-Brutman T, Voigt C, Jacobs I, Wuerfel T, Santagostino E. Results of a phase I/II open-label, safety and efficacy trial of coagulation factor IX (recombinant), albumin fusion protein in haemophilia B patients. Haemophilia 2015; 21: 784–90.
73. Metzner HJ, Weimer T, Kronthaler U, Lang W, Schulte S. Genetic fusion to albumin improves the pharmacokinetic properties of factor IX. Thromb Haemost 2009; 102: 634–44.