Development of a plasma- and albumin -free recombinant von Willebrand factor

Summary

Baxter has developed a recombinant therapy for treating von Willebrand‘s disease. Recombinant VWF is co-expressed with the rFVIII in CHO cells used to produce the rFVIII product Advate. This rVWF is used as a drug component for a rVWF-rFVIII complex drug product. CHO cells produce partially processed and partially un-processed rVWF still containing the pro-peptide. In order to make a consistent preparation containing mature and processed rVWF only, rVWF is exposed to recombinant furin to remove the pro-peptide. Recombinant

Keywords

Recombinant von Willebrand factor - von Willebrand disease - hemophilia - substitution therapy

• References

• 1 Sadler JE. Biochemistry and genetics of von Willebrand factor. Annu Rev Biochem 1998; 67: 395-424.
• 2 Ofosu FA, Freedman J, Semple JW. Plasma-derived biological medicines used to promote haemostasis. Thromb Haemost 2008; 99: 851-862.
• 3 Franchini M, Targher G, Lippi G. Prophylaxis in von Willebrand disease. Ann Hematol 2007; 86: 699-704.
• 4 Gill JC. Treatment of urgent bleeding in von Willebrand disease. Thromb Res 2007; 120 (Suppl. 01) S21-S25.
• 5 Nichols WL, Hultin MB, James AH. et al. Von Willebrand disease (VWD): Evidence-based diagnosis and management guidelines, the National Heart, Lung, and Blood Institute (NHLBI) Expert Panel report (USA). Haemophilia 2008; 14: 171-232.
• 6 Ruggeri ZM, Zimmerman TS. The complex multi-meric composition of factor VIII/von Willebrand factor. Blood 1981; 57: 1140-1143.
• 7 Aihara M, Sawada Y, Ueno K. et al. Visualization of von Willebrand factor multimers by immunoenzymatic stain using avidin-biotin peroxidase complex. Thromb Haemost 1986; 55: 263-267.
• 8 Denis C, Methia N, Frenette PS. et al. A mouse model of severe von Willebrand disease: Defects in hemostasis and thrombosis. Proc Natl Acad Sci USA 1998; 95: 9524-9529.
• 9 Blanchette VS, Shapiro AD, Liesner RJ. et al. rAHFPFM Clinical Study Group. Plasma and albumin-free recombinant factor VIII: pharmacokinetics, efficacy and safety in previously treated pediatric patients. J Thromb Haemost 2008; 6: 1319-1326.
• 10 Turecek PL, Váradi K, Schlokat U. et al. In vivo and in vitro processing of recombinant pro-von Willebrand factor. Histochem Cell Biol 2002; 117: 123-129.
• 11 Turecek PL, Pichler L, Auer W. et al. Evidence for extracellular processing of pro-von Willebrand factor after infusion in animals with and without severe von Willebrand disease. Blood 1999; 94: 1637-1647.
• 12 Schlokat U, Fischer BE, Herlitschka S. et al. Production of highly homogeneous and structurally intact recombinant von Willebrand factor multimers by furin-mediated propeptide removal in vitro. Biotechnol Appl Biochem 1996; 24: 257-267.
• 13 Wise RJ, Dorner AJ, Krane M. et al. The role of von Willebrand factor multimers and propeptide cleavage in binding and stabilization of factor VIII. J Biol Chem 1991; 266: 21948-21955.
• 14 Varadi K, Rottensteiner H, Vejda S. et al. Species-dependent variability of ADAMTS13-mediated proteolysis of human recombinant von Willebrand factor. J Thromb Haemost 2009; 7: 1134-1142.
• 15 Hubbard AR, Heath AB. Standardization of factor VIII and von Willebrand factor in plasma: calibration of the WHO 5^th International Standard (02/150). J Thromb Haemost 2004; 2: 1380-1384.
• 16 Hubbard AR. Von Willebrand factor standards for plasma and concentrate testing. Semin Thromb He-most 2006; 32: 522-528.
• 17 Lethagen S, Carlson M, Hillarp A. A comparative in vitro evaluation of six von Willebrand factor concentrates. Haemophilia 2004; 10: 243-249.
• 18 Budde U, Metzner HJ, Müller HG. Comparative analysis and classification of von Willebrand factor/ factor VIII concentrates: impact on treatment of patients with von Willebrand disease. Semin Thromb Hemost 2006; 32: 626-635.
• 19 Federici AB. Management of von Willebrand disease with factor VIII/von Willebrand factor concentrates: results from current studies and surveys. Blood Coagul Fibrinolysis 2005; 16 (Suppl. 01) S17-S21.
• 20 Federici AB, Castaman G, Thompson A, Berntorp E. Von Willebrand‘s disease: clinical management. Haemophilia 2006; 12 (Suppl. 03) 152-158.
• 21 Parti R, Schoppmann A, Lee H, Yang L. Stability of lyophilized and reconstituted plasma/albumin-free recombinant human factor VIII (ADVATE rAHFPFM). Haemophilia 2005; 11: 492-496.
• 22 Shapiro AD. Anti-hemophilic factor (recombinant), plasma/albumin-free method (octocog-alpha; ADVATE) in the management of hemophilia A. Vasc Health Risk Manag 2007; 3: 555-565.
• 23 Fischer BE, Schlokat U, Mitterer A. et al. Structural analysis of recombinant von Willebrand factor produced at industrial scale fermentation of transformed CHO cells co-expressing recombinant furin. FEBS Lett 1995; 375: 259-262.
• 24 Preininger A, Schlokat U, Mohr G. et al. Strategies for recombinant Furin employment in a biotechnological process: complete target protein precursor cleavage. Cytotechnology 1999; 30: 1-16.
• 25 Turecek PL, Furlan M, Lämmle B. et al. Cleavage of recombinant von Willebrand factor by a VWF-depolymerizing protease. Poster presented at the 38th Annual Meeting of the American Society of Hematology (ASH), Orlando, FL/USA, Dec. 6–10, 1996. Blood 1996; 88 (Suppl. 01) 326a.
• 26 Roussi J, Turecek PL, André P. et al. Effects of human recombinant, plasma-derived and porcine von Willebrand factor in pigs with severe von Willebrand disease. Blood Coagul Fibrinolysis 1998; 9: 361-372.
• 27 Plaimauer B, Schlokat U, Turecek PL. et al. Recombinant von Willebrand factor: preclinical development. Semin Thromb Hemost 2001; 27: 395-403.
• 28 Schwarz HP, Dorner F, Mitterer A. et al. Evaluation of recombinant von Willebrand factor in a canine model of von Willebrand disease. Haemophilia 1998; 4 (Suppl. 03) 53-62.
• 29 Schwarz HP, Dorner F, Mitterer A. et al. Preclinical evaluation of recombinant von Willebrand factor in a canine model of von Willebrand disease. Wien Klin Wochenschr 1999; 111: 181-191.
• 30 Turecek PL, Gritsch H, Pichler L. et al. In vivo characterization of recombinant von Willebrand factor in dogs with von Willebrand disease. Blood 1997; 90: 3555-3567.
• 31 Schwarz HP, Schlokat U, Mitterer A. et al. Recombinant von Willebrand factor-insight into structure and function through infusion studies in animals with severe von Willebrand disease. Semin Thromb Hemost 2002; 28: 215-226.