Recombinant clotting factors

Summary

The recombinant era for haemophilia began in the early 1980s with the cloning and subsequent expression of functional proteins for both factors VIII and IX. Efficient production of recombinant clotting factors in mammalian cell culture systems required overcoming significant challenges due to the complex post-translational modifications that were integral to their procoagulant function. The quick development and commercialization of recombinant clotting factors was, in part, facilitated by the catastrophic impact of viral contamination of plasma-derived clotting factor concentrates at the time. Since their transition into the clinic, the recombinant versions of both factor VIII and IX have proven to be remarkable facsimiles of their plasma-derived counterparts. The broad adoption of recombinant therapy throughout the developed world has significantly increased the supply of clotting factor concentrates and helped advance aggressive therapeutic interventions such as prophylaxis. The development of recombinant VIIa was a further advance bringing a recombinant option to haemophilia patients with inhibitors. Recombinant DNA technology remains the platform to address ongoing challenges in haemophilia care such as reducing the costs of therapy, increasing the availability to the developing world, and improving the functional properties of these proteins. In turn, the ongoing development of new recombinant clotting factor concentrates is providing alternatives for patients with other inherited bleeding disorders.

Keywords

Recombinant - factor VIII - factor IX - factor VIIa - von Willebrand factor

• References

• 1 Cohen SN, Chang AC, Boyer HW. et al. Construction of biologically functional bacterial plasmids in vitro. Proc Natl Acad Sci USA 1973; 70: 3240-3244.
• 2 Pisano GP. Can science be a business? Lessons from biotech. Harvard Business Rev 2006; 84: 114-124, 150.
• 3 Itakura K, Hirose T, Crea R. et al. Expression in Escherichia coli of a chemically synthesized gene for the hormone somatostatin. Science 1977; 198: 1056-1063.
• 4 Human insulin receives FDA approval. FDA drug bulletin 1982; 12: 18-19.
• 5 Genetics Institute, Inc. Company History.. Available at http://www.fundinguniverse.com/company-histori es/Genetics-Institute-Inc-Company-History.html. Accessed September 7, 2007.
• 6 Gitschier J. Remembrances of factor VIII. Part 1: the race to the gene. J Thromb Haemost 2004; 2: 383-387.
• 7 Pneumocystis carinii pneumonia among persons with haemophilia A. Morb Mortal Wkly Rep 1982; 31: 365-367.
• 8 Human immunodeficiency virus infection in the United States: a review of current knowledge. Morb Mortal Wkly Rep 1987; 36 (Suppl. 06) 1-48.
• 9 Gitschier J, Wood WI, Goralka TM. et al. Characterization of the human factor VIII gene. Nature 1984; 312: 326-330.
• 10 Wood WI, Capon DJ, Simonsen CC. et al. Expression of active human factor VIII from recombinant DNA clones. Nature 1984; 312: 330-337.
• 11 Vehar GA, Keyt B, Eaton D. et al. Structure of human factor VIII. Nature 1984; 312: 337-342.
• 12 Toole JJ, Knopf JL, Wozney JM. et al. Molecular cloning of a cDNA encoding human antihaemophilic factor. Nature 1984; 312: 342-347.
• 13 Kurachi K, Davie EW. Isolation and characterization of a cDNA coding for human factor IX. Proc Natl Acad Sci USA 1982; 79: 6461-6464.
• 14 White GC, 2nd Pickens EM, Liles DK. et al. Mammalian recombinant coagulation proteins: structure and function. Transfus Sci 1998; 19: 177-189.
• 15 Adamson R. Design and operation of a recombinant mammalian cell manufacturing process for rFVIII. Ann Hematol 1994; 68 (Suppl. 03) S9-14.
• 16 Koplove HM. Cell culture and purification process– purity and safety testing. Ann Hematol 1994; 68 (Suppl. 03) S15-20.
• 17 Kaufman RJ. Selection and coamplification of heterologous genes in mammalian cells. Methods Enzymol 1990; 185: 537-566.
• 18 Kaufman RJ, Wasley LC, 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: 9622-9628.
• 19 Kaufman RJ, Wasley LC, Davies MV. et al. Effect of von Willebrand factor coexpression on the synthesis and secretion of factor VIII in Chinese hamster ovary cells. Mol Cell Biol 1989; 9: 1233-1242.
• 20 Ginsburg D, Handin RI, Bonthron DT. et al. Human von Willebrand factor (vWF): isolation of complementary DNA (cDNA) clones and chromosomal localization. Science 1985; 228: 1401-1406.
• 21 Lynch DC, Zimmerman TS, Collins CJ. et al. Molecular cloning of cDNA for human von Willebrand factor: authentication by a new method. Cell 1985; 41: 49-56.
• 22 Sadler JE, Shelton-Inloes BB, Sorace JM. et al. Cloning and characterization of two cDNAs coding for human von Willebrand factor. Proc Natl Acad Sci USA 1985; 82: 6394-6398.
• 23 Verweij CL, de Vries CJ, Distel B. et al. Construction of cDNA coding for human von Willebrand factor using antibody probes for colony-screening and mapping of the chromosomal gene. Nucleic Acids Res 1985; 13: 4699-4717.
• 24 Kamarck ME. Building biomanufacturing capacity– the chapter and verse. Nat Biotechnol 2006; 24: 503-505.
• 25 Jiang R, Monroe T, McRogers R. et al. Manufacturing challenges in the commercial production of recombinant coagulation factor VIII. Haemophilia 2002; 8 (Suppl. 02) 1-5.
• 26 Bray G. Inhibitor questions: plasma-derived factor VIII and recombinant factor VIII. Ann Hematol 1994; 68 (Suppl. 03) S29-34.
• 27 Abildgaard CF. Immunologic safety of recombinant factor VIII. The rFactor VIII Clinical Trial Group. Semin Hematol 1991; 28 (Suppl. 21) 44.
• 28 Aronson DL. The current status of recombinant human factor VIII. Semin Hematol 1991; 28 (Suppl. 21) 55-56.
• 29 White GC, 2nd McMillan CW, Kingdon HS. et al. Use of recombinant antihaemophilic factor in the treatment of two patients with classic haemophilia. N Engl J Med 1989; 320: 166-170.
• 30 Toole JJ, Pittman DD, Orr EC. et al. A large region (approximately equal to 95 kDa) of human factor VIII is dispensable for in vitro procoagulant activity. Proc Natl Acad Sci USA 1986; 83: 5939-5942.
• 31 Berntorp E. Second generation, B-domain deleted recombinant factor VIII. Thromb Haemost 1997; 78: 256-260.
• 32 Mikaelsson M, Oswaldsson U, Jankowski MA. Measurement of factor VIII activity of B-domain deleted recombinant factor VIII. Semin Hematol 2001; 38 (Suppl. 24) 13-23.
• 33 Mikaelsson M, Oswaldsson U, Sandberg H. Influence of phospholipids on the assessment of factor VIII activity. Haemophilia 1998; 4: 646-650.
• 34 Barrowcliffe TW, Raut S, Hubbard AR. Discrepancies in potency assessment of recombinant FVIII concentrates. Haemophilia 1998; 4: 634-640.
• 35 Stanley SL. Jr. The need for continuing vigilance: addressing the threat for transmission of blood-borne infectious disease. Semin Hematol 2006; 43 (Suppl. 23) S17-22.
• 36 White GC, 2nd Courter S, Bray GL. et al. A multicenter study of recombinant factor VIII (Recombinate) in previously treated patients with haemophilia A. The Recombinate Previously Treated Patient Study Group. Thromb Haemost 1997; 77: 660-667.
• 37 Tarantino MD, Collins PW, Hay CR. et al. Clinical evaluation of an advanced category antihaemophilic factor prepared using a plasma/albumin-free method: pharmacokinetics, efficacy, and safety in previously treated patients with haemophilia A. Haemophilia 2004; 10: 428-437.
• 38 Lusher JM, Lee CA, Kessler CM. et al. The safety and efficacy of B-domain deleted recombinant factor VIII concentrate in patients with severe haemophilia A. Haemophilia 2003; 9: 38-49.
• 39 Abshire TC, Brackmann HH, Scharrer I. et al. Sucrose formulated recombinant human antihaemophilic factor VIII is safe and efficacious for treatment of haemophilia A in home therapy–International Kogenate- FS Study Group. Thromb Haemost 2000; 83: 811-816.
• 40 Bray GL, Gomperts ED, Courter S. et al. A multicenter study of recombinant factor VIII (recombinate): safety, efficacy, and inhibitor risk in previously untreated patients with haemophilia A. The Recombinate Study Group. Blood 1994; 83: 2428-2435.
• 41 Lusher JM. First and second generation recombinant factor VIII concentrates in previously untreated patients: recovery, safety, efficacy, and inhibitor development. Semin Thromb Haemost 2002; 28: 273-276.
• 42 Bayer HealthCare LLC.. Bayer HealthCare Pharmaceuticals: Kogenate FS efficacy. Available at http://www.kogenatefs.com/patients_K_Efficacy.cfm. Accessed on September 29, 2007.
• 43 Lusher JM. Is the incidence and prevalence of inhibitors greater with recombinant products? No. J Thromb Haemost 2004; 2: 863-865.
• 44 Aledort LM. Is the incidence and prevalence of inhibitors greater with recombinant products? Yes. J Thromb Haemost 2004; 2: 861-862.
• 45 Wight J, Paisley S. The epidemiology of inhibitors in haemophilia A: a systematic review. Haemophilia 2003; 9: 418-435.
• 46 Goudemand J, Rothschild C, Demiguel V. et al. Influence of the type of factor VIII concentrate on the incidence of factor VIII inhibitors in previously untreated patients with severe haemophilia A. Blood 2006; 107: 46-51.
• 47 Gouw SC, van der Bom JG, Auerswald G. et al. Recombinant versus plasma-derived factor VIII products and the development of inhibitors in previously untreated patients with severe haemophilia A: the CANAL cohort study. Blood 2007; 109: 4693-4697.
• 48 Chalmers EA, Brown SA, Keeling D. et al. Early factor VIII exposure and subsequent inhibitor development in children with severe haemophilia A. Haemophilia 2007; 13: 149-155.
• 49 Goudemand J, Calvez T. Link between recombinants and inhibitor risk. Available from http://www. wfh.org/2/docs/Events/Global-Forum2007/Monday/GF2007-Goudemand_recombinants-inhibitor.ppt. Accessed on November 14, 2007.
• 50 Guerois C, Laurian Y, Rothschild C. et al. Incidence of factor VIII inhibitor development in severe haemophilia A patients treated only with one brand of highly purified plasma-derived concentrate. Thromb Haemost 1995; 73: 215-218.
• 51 Rothschild C, Laurian Y, Satre EP. et al. French previously untreated patients with severe haemophilia A after exposure to recombinant factor VIII : incidence of inhibitor and evaluation of immune tolerance. Thromb Haemost 1998; 80: 779-783.
• 52 McMillan CW, Shapiro SS, Whitehurst D. et al. The natural history of factor VIII:C inhibitors in patients with haemophilia A: a national cooperative study. II. Observations on the initial development of factor VIII:C inhibitors. Blood 1988; 71: 344-348.
• 53 Giles AR, Rivard GE, Teitel J. et al. Surveillance for factor VIII inhibitor development in the Canadian Haemophilia A population following the widespread introduction of recombinant factor VIII replacement therapy. Transfus Sci 1998; 19: 139-148.
• 54 Scharrer I, Ehrlich HJ. Lack of evidence for increased inhibitor incidence in patients switched from plasma-derived to recombinant factor VIII. Haemophilia 2001; 7: 346-348.
• 55 Goudemand J, Laurian Y, Calvez T. Risk of inhibitors in haemophilia and the type of factor replacement. Curr Opin Hematol 2006; 13: 316-322.
• 56 van der Bom JG, Gouw SC, van den Berg HM. Immunogenicity of factor VIII concentrates in patients with haemophilia: the next sensible step. Blood 2007; 110: 3085.
• 57 Ettingshausen CE, Kreuz W. Recombinant vs. plasma- derived products, especially those with intact VWF, regarding inhibitor development. Haemophilia 2006; 12 (Suppl. 06) 102-106.
• 58 Hodge G, Saxon B, Revesz T. Effect of factor VIII concentrate on leucocyte cytokine receptor expression in vitro: relevance to inhibitor formation and tolerance induction. Haemophilia 2006; 12: 133-139.
• 59 Kallas A, Kuuse S, Maimets T. et al. von Willebrand factor and transforming growth factor-beta modulate immune response against coagulation factor VIII in FVIII-deficient mice. Thromb Res 2007; 120: 911-919.
• 60 Lin Y, Yang X, Chevrier MC. et al. Relationships between factor VIII:Ag and factor VIII in recombinant and plasma-derived factor VIII concentrates. Haemophilia 2004; 10: 459-469.
• 61 White GC, 2nd Beebe A, Nielsen B. Recombinant factor IX. Thromb Haemost 1997; 78: 261-265.
• 62 Wasley LC, Rehemtulla A, Bristol JA. et al. PACE/ furin can process the vitamin K-dependent pro-factor IX precursor within the secretory pathway. J Biol Chem 1993; 268: 8458-8465.
• 63 Bond M, Jankowski M, Patel H. et al. Biochemical characterization of recombinant factor IX. Semin Hematol 1998; 35 (Suppl. 22) 11-17.
• 64 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: 185-196.
• 65 White G, Shapiro A, Ragni M. et al. Clinical evaluation of recombinant factor IX. Semin Hematol 1998; 35 (Suppl. 22) 33-38.
• 66 Shapiro AD, Di Paola J, Cohen A. et al. The safety and efficacy of recombinant human blood coagulation factor IX in previously untreated patients with severe or moderately severe haemophilia B. Blood 2005; 105: 518-525.
• 67 Shapiro AD, Ragni MV, Lusher JM. et al. Safety and efficacy of monoclonal antibody purified factor IX concentrate in previously untreated patients with haemophilia B. Thromb Haemost 1996; 75: 30-35.
• 68 Sultan Y. Prevalence of inhibitors in a population of 3435 haemophilia patients in France. French Haemophilia Study Group. Thromb Haemost 1992; 67: 600-602.
• 69 Hedner U. Recombinant factor VIIa: its background, development and clinical use. Curr Opin Hematol 2007; 14: 225-229.
• 70 Hedner U. Mechanism of action, development and clinical experience of recombinant FVIIa. J Biotechnol 2006; 124: 747-757.
• 71 Hedner U, Kisiel W. Use of human factor VIIa in the treatment of two haemophilia A patients with high-titer inhibitors. J Clin Invest 1983; 71: 1836-1841.
• 72 Hagen FS, Gray CL, O’Hara P. et al. Characterization of a cDNA coding for human factor VII. Proc Natl Acad Sci USA 1986; 83: 2412-2416.
• 73 O’Hara PJ, Grant FJ, Haldeman BA. et al. Nucleotide sequence of the gene coding for human factor VII, a vitamin K-dependent protein participating in blood coagulation. Proc Natl Acad Sci USA 1987; 84: 5158-5162.
• 74 Roddie PH, Ludlam CA. Recombinant coagulation factors. Blood Rev 1997; 11: 169-177.
• 75 Parameswaran R, Shapiro AD, Gill JC. et al. Dose effect and efficacy of rFVIIa in the treatment of haemophilia patients with inhibitors: Analysis from the Haemophilia and Thrombosis Research Society Registry. Haemophilia 2005; 11: 100-106.
• 76 Monroe DM, Hoffman M, Oliver JA. et al. A possible mechanism of action of activated factor VII independent of tissue factor. Blood Coagul Fibrinolysis 1998; 9 (Suppl. 01) S15-20.
• 77 Santagostino E, Mancuso ME, Rocino A. et al. A prospective randomized trial of high and standard dosages of recombinant factor VIIa for treatment of hemarthroses in haemophiliacs with inhibitors. J Thromb Haemost 2006; 4: 367-371.
• 78 Astermark J, Donfield SM, DiMichele DM. et al. A randomized comparison of bypassing agents in haemophilia complicated by an inhibitor: the FEIBA NovoSeven Comparative (FENOC) Study. Blood 2007; 109: 546-551.
• 79 O’Connell KA, Wood JJ, Wise RP. et al. Thromboembolic adverse events after use of recombinant human coagulation factor VIIa. J Am Med Assoc 2006; 295: 293-298.
• 80 Abshire T, Kenet G. Recombinant factor VIIa: review of efficacy, dosing regimens and safety in patients with congenital and acquired factor VIII or IX inhibitors. J Thromb Haemost 2004; 2: 899-909.
• 81 Weiskopf RB. Recombinant-activated coagulation factor VIIa (NovoSeven): current development. Vox Sang 2007; 92: 281-288.
• 82 Hilgartner MW. The need for recombinant factor VIII: historical background and rationale. Semin Hematol 1991; 28 (Suppl. 21) 6-9.
• 83 VanAken WG. The potential impact of recombinant factor VIII on haemophilia care and the demand for blood and blood products. Transfus Med Rev 1997; 11: 6-14.
• 84 Mannucci PM, Gringeri A. The use of recombinant factor VIII in the management of haemophilia. La Ricerca Clin Lab 1991; 21: 1-7.
• 85 Lippert B, Berger K, Berntorp E. et al. Cost effectiveness of haemophilia treatment: a cross-national assessment. Blood Coagul Fibrinolysis 2005; 16: 477-485.
• 86 Manco-Johnson MJ, Abshire TC, Shapiro AD. et al. Prophylaxis versus episodic treatment to prevent joint disease in boys with severe haemophilia. N Engl J Med 2007; 357: 535-544.
• 87 Mannucci P. Trends in the Plasma-derived and recombinant markets – clinician’s perspective. Available at http://www.wfh.org/2/6/6_2_Link1_Forum.htm. Accessed September 29, 2007.
• 88 Garber K. rFactor VIII deficit questioned. Nat Biotechnol 2000; 18: 1133.
• 89 Centers for Disease Control. Report on the Universal Data Collection Program. 6. 2 2004 Available at: http://www.cdc.gov.ncbddd/hbd/documents/UDC6(2).pdf. Accessed September 29, 2007.
• 90 Mauser-Bunschoten EP, Roosendaal G, van den Berg HM. Product choice and haemophilia treatment in the Netherlands. Haemophilia 2001; 7: 96-98.
• 91 Mantovani LG, Monzini MS, Mannucci PM. et al. Differences between patients’, physicians’ and pharmacists’ preferences for treatment products in haemophilia: a discrete choice experiment. Haemophilia 2005; 11: 589-597.
• 92 Brown SA. Issues in making a therapeutic choice: recombinant and/or human-derived products. Haemophilia 2000; 6: 125-129.
• 93 Bonthron DT, Handin RI, Kaufman RJ. et al. Structure of pre-pro-von Willebrand factor and its expression in heterologous cells. Nature 1986; 324: 270-273.
• 94 Plaimauer B, Schlokat U, Turecek PL. et al. Recombinant von Willebrand factor: preclinical development. Semin Thromb Haemost 2001; 27: 395-403.
• 95 Saenko EL, Pipe SW. Strategies towards a longer acting factor VIII. Haemophilia 2006; 12 (Suppl. 03) 42-51.
• 96 Turecek PL, Scheiflinger F, Siekmann J. et al. Biochemical and functional characterization of chemically modified recombinant von Willebrand factor (rvWF) as a carrier prolonging survival of rFVIII in haemophilia A knock-out mice. J Thromb Haemost. 2007 O-M-018 (Abstract).
• 97 Lovejoy AE, Reynolds TC, Visich JE. et al. Safety and pharmacokinetics of recombinant factor XIII-A2 administration in patients with congenital factor XIII deficiency. Blood 2006; 108: 57-62.
• 98 Ichinose A, Davie EW. Characterization of the gene for the a subunit of human factor XIII (plasma transglutaminase), a blood coagulation factor. Proc Natl Acad Sci USA 1988; 85: 5829-5833.
• 99 Reynolds TC, Butine MD, Visich JE. et al. Safety, pharmacokinetics, and immunogenicity of single-dose rFXIII administration to healthy volunteers. J Thromb Haemost 2005; 3: 922-928.
• 100 Schaal-Jensen R, Kiehr B, Boesen HT. et al. Characterization of high molecular weight plasma protein complexes induced by clotting factor rFXIII-treatment in the cynomolgus monkey. J Thromb Haemost 2007; 5: 2070-2078.
• 101 Pipe SW. The promise and challenges of bioengineered recombinant clotting factors. J Thromb Haemost 2005; 3: 1692-1701.
• 102 Pipe SW, Saint-Remy JM, Walsh CE. New hightechnology products for the treatment of haemophilia. Haemophilia 2004; 10 (Suppl. 04) 55-63.
• 103 Key NS, Negrier C. Coagulation factor concentrates: past, present, and future. Lancet 2007; 370: 439-448.
• 104 Hsueh JL. Clinical protocol of human gene transfer for haemophilia B. Hum Gene Ther 1992; 3: 543-552.
• 105 Lillicrap D, VandenDriessche T, High K. Cellular and genetic therapies for haemophilia. Haemophilia 2006; 12 (Suppl. 03) 36-41.
• 106 Roth DA, Tawa NE, Jr. O’Brien JM. et al. Nonviral transfer of the gene encoding coagulation factor VIII in patients with severe haemophilia A. N Engl J Med 2001; 344: 1735-1742.
• 107 Pierce GF, Lillicrap D, Pipe SW. et al. Gene therapy, bioengineered clotting factors and novel technologies for haemophilia treatment. J Thromb Haemost 2007; 5: 901-906.
• 108 Running Deer J, Allison DS. High-level expression of proteins in mammalian cells using transcription regulatory sequences from the Chinese hamster EF-1alpha gene. Biotechnology progress 2004; 20: 880-889.
• 109 Van Cott KE, Monahan PE, Nichols TC. et al. Haemophilic factors produced by transgenic livestock: abundance that can enable alternative therapies worldwide. Haemophilia 2004; 10 (Suppl. 04) 70-76.
• 110 Pipe SW, Miao HZ, Butler ST. et al. Efficient secretion of bioengineered coagulation factor VIII into the milk of transgenic animals. J Thromb Haemost 2007: O-T-013 (Abstract).
• 111 National Haemophilia Foundation.. MASAC Document #151: MASAC recommendations concerning the treatment of haemophilia and other bleeding disorders. Available at: http://www.haemophilia.org/research/masac/masac151.pdf. Accessed September 29, 2007.
• 112 Niemann H, Kues WA. Transgenic farm animals: an update. Reprod Fertil Dev 2007; 19: 762-770.