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Thromb Haemost 2013; 110(05): 931-939
DOI: 10.1160/TH13-03-0213
Review Article
Schattauer GmbH

Extending the pharmacokinetic half-life of coagulation factors by fusion to recombinant albumin

Hubert J. Metzner
1   CSL Behring GmbH, Marburg, Germany
,
Steven W. Pipe
2   Departments of Pediatrics and Pathology, University of Michigan Medical Center, Ann Arbor, Michigan, USA
,
Thomas Weimer
1   CSL Behring GmbH, Marburg, Germany
,
Stefan Schulte
1   CSL Behring GmbH, Marburg, Germany
› Author Affiliations Financial support: This article was financially supported by CSL Behring, Germany.
Further Information

Publication History

Received: 12 March 2013

Accepted after major revision: 17 July 2013

Publication Date:
01 December 2017 (online)

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Summary

The prophylactic treatment of haemophilia B and the management of haemophilia A or B with inhibitors demand frequent administrations of coagulation factors due to the suboptimal half-lives of the products commercially available and currently in use, e.g. recombinant factor IX (rFIX) and recombinant factor VIIa (rFVIIa), respectively. The extension of the half-lives of rFIX and rFVIIa could allow for longer intervals between infusions and could thereby improve adherence and clinical outcomes and may improve quality of life. Albumin fusion is one of a number of different techniques currently being examined to prolong the half-life of rFIX and rFVIIa. Results from a phase I clinical trial demonstrated that the recombinant fusion protein linking FIX to albumin (rIX-FP) has a five-times longer half-life than rFIX, and preclinical studies with the recombinant fusion protein linking FVIIa to albumin (rVIIa-FP) suggest that rVIIa-FP possesses a significantly extended half-life versus rFVIIa. In this review, we describe albumin fusion technology and examine the recent progress in the development of rIX-FP and rVIIa-FP.

keywords

Coagulation factor IX - coagulation factor VIIa - half-life extension - albumin fusion
 

  • References

  • 1 Oldenburg J, Dolan G, Lemm G. Haemophilia care then, now and in the future. Haemophilia 2009; 15 (Suppl. 01) 2-7.
    CrossrefPubMedGoogle Scholar
  • 2 Nilsson IM, Berntorp E, Lofqvist T. et al. Twenty-five years’ experience of prophylactic treatment in severe haemophilia A and B. J Intern Med 1992; 232: 25-32.
    CrossrefPubMedGoogle Scholar
  • 3 Manco-Johnson MJ, Abshire TC, Shapiro AD. et al. Prophylaxis versus episodic treatment to prevent joint disease in boys with severe hemophilia. N Engl J Med 2007; 357: 535-544.
    CrossrefPubMedGoogle Scholar
  • 4 White 2nd GC, Beebe A, Nielsen B. Recombinant factor IX. Thromb Haemost 1997; 78: 261-265.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 5 Ewenstein BM, Joist JH, Shapiro AD. et al. Pharmacokinetic analysis of plasma-derived and recombinant F IX concentrates in previously treated patients with moderate or severe hemophilia B. Transfusion 2002; 42: 190-197.
    CrossrefPubMedGoogle Scholar
  • 6 Poon MC. Pharmacokinetics of factors IX, recombinant human activated factor VII and factor XIII. Haemophilia 2006; 12: S61-69.
    PubMedGoogle Scholar
  • 7 Björkman S, Ahlén V. Population pharmacokinetics of plasma-derived factor IX in adult patients with haemophilia B: implications for dosing in prophylaxis. Eur J Clin Pharmacol 2012; 68: 6969-6977.
    PubMedGoogle Scholar
  • 8 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.
    CrossrefPubMedGoogle Scholar
  • 9 DiMichele D. Inhibitor development in haemophilia B: an orphan disease in need of attention. Br J Haematol 2007; 138: 305-315.
    CrossrefPubMedGoogle Scholar
  • 10 Ehrenforth S, Kreuz W, Scharrer I. et al. Incidence of development of factor VIII and factor IX inhibitors in haemophiliacs. Lancet 1992; 339: 594-598.
    CrossrefPubMedGoogle Scholar
  • 11 Van’tVeer C, Golden NJ, Mann KG. Inhibition of thrombin generation by the zymogen factor VII: implications for the treatment of hemophilia A by factor VIIa. Blood 2000; 95: 1330-1335.
    PubMedGoogle Scholar
  • 12 Shibeko AM, Woodle SA, Lee TK. et al. Unifying the mechanism of recombinant FVIIa action: dose dependence is regulated differently by tissue factor and phospholipids. Blood 2012; 120: 891-899.
    CrossrefPubMedGoogle Scholar
  • 13 Erhardtsen E. Pharmacokinetics of recombinant activated factor VII (rFVIIa). Semin Thromb Hemost 2000; 26: 385-391.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 14 Jevsevar S, Kunstelj M, Porekar VG. PEGylation of therapeutic proteins. Biotechnol J 2010; 5: 113-128.
    CrossrefPubMedGoogle Scholar
  • 15 Karpf DM, Sørensen BB, Hermit MB. et al. Prolonged half-life of glycoPEGylated rFVIIa variants compared to native rFVIIa. Thromb Res 2011; 128: 191-195.
    CrossrefPubMedGoogle Scholar
  • 16 Negrier C, Knobe K, Tiede A. et al. Enhanced pharmacokinetic properties of a glycoPEGylated recombinant factor IX: a first human dose trial in patients with hemophilia B. Blood 2011; 118: 2695-2701.
    CrossrefPubMedGoogle Scholar
  • 17 Carter PJ. Introduction to current and future protein therapeutics: a protein engineering perspective. Exp Cell Res 2011; 317: 1261-1269.
    CrossrefPubMedGoogle Scholar
  • 18 Shapiro AD, Ragni MV, Valentino LA. et al. Recombinant factor IX-Fc fusion protein (rFIXFc) demonstrates safety and prolonged activity in a phase 1/2a study in hemophilia B patients. Blood 2012; 119: 666-672.
    CrossrefPubMedGoogle Scholar
  • 19 Kontermann RE. Strategies to extend plasma half-lives of recombinant antibodies. BioDrugs 2009; 23: 93-109.
    CrossrefPubMedGoogle Scholar
  • 20 Peters Jr. T. Serum albumin. Adv Protein Chem 1985; 37: 161-245.
    PubMedGoogle Scholar
  • 21 Kim J, Bronson CL, Hayton WL. Albumin turnover: FcRn-mediated recycling saves as much albumin from degradation as the liver produces. Am J Physiol Gastrointest Liver Physiol 2006; 290: G352-360.
    CrossrefPubMedGoogle Scholar
  • 22 Matthews JE, Stewart MW, De Boever EH. et al. Pharmacodynamics, pharmacokinetics, safety, and tolerability of albiglutide, a long-acting glucagon-like peptide-1 mimetic, in patients with type 2 diabetes. J Clin Endocrinol Metab 2008; 93: 4810-4817.
    CrossrefPubMedGoogle Scholar
  • 23 Huang YJ, Lundy PM, Lazaris A. et al. Substantially improved pharmacokinetics of recombinant human butyrylcholinesterase by fusion to human serum albumin. BMC Biotechnol 2008; 8: 50
    CrossrefPubMedGoogle Scholar
  • 24 Safety and Efficacy Study of Albiglutide in Type 2 Diabetes. NCT00849017. Available at: http://www.clinicaltrials.gov. Last accessed Jan 11 2013
    PubMedGoogle Scholar
  • 25 Rosenstock J, Reusch J, Bush M. et al. Potential of albiglutide, a long-acting GLP-1 receptor agonist, in type 2 diabetes: a randomized controlled trial exploring weekly, biweekly, and monthly dosing. Diabetes Care 2009; 32: 1880-1886.
    CrossrefPubMedGoogle Scholar
  • 26 Halpern W, Riccobene TA, Agostini H. et al. AlbugraninTM, a recombinant human granulocyte colony stimulating factor (G-CSF) genetically fused to recombinant human albumin induces prolonged myelopoietic effects in mice and monkeys. Pharm Res 2002; 19: 1720-1724.
    CrossrefPubMedGoogle Scholar
  • 27 Neugranin in Breast Cancer Patients Receiving Doxorubicin/Docetaxel (NEUGR-002). NCT00837265. Available at: http://www.clinicaltrials.gov. Last accessed Jan 11 2013
    PubMedGoogle Scholar
  • 28 Neugranin in Breast Cancer Patients Receiving Doxorubicin/Docetaxel (NEUGR-003). NCT01126190. Available at: http://www.clinicaltrials.gov. Last accessed Jan 11 2013
    PubMedGoogle Scholar
  • 29 Batorova A, High KA, Gringeri A. Special lectures in haemophilia management. Haemophilia 2010; 16 (Suppl. 05) 22-28.
    CrossrefPubMedGoogle Scholar
  • 30 Thornburg CD, Pipe SW. Adherence to prophylactic infusions of factor VIII or factor IX for haemophilia. Haemophilia 2006; 12: 198-199.
    CrossrefPubMedGoogle Scholar
  • 31 Metzner HJ, Weimer T, Kronthaler U. et al. Genetic fusion to albumin improves the pharmacokinetic properties of factor IX. Thromb Haemost 2009; 102: 634-644.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 32 Schulte S. Half-life extension through albumin fusion technologies. Thromb Res 2009; 124 (Suppl. 02) S6-8.
    CrossrefPubMedGoogle Scholar
  • 33 Horn C, Steuber H, Metzner HJ. et al. Concept and structure model of factor IX albumin fusion proteins. Haemophilia. 2010 16. 04 Abstract 08P18.
    PubMedGoogle Scholar
  • 34 Metzner HJ, Weimer T, Zollner S. et al. Pharmacokinetics of activated recombinant factor IX albumin fusion proteins. J Thromb Haemost 2011; 9 (Suppl. 02) 354
    PubMedGoogle Scholar
  • 35 Nolte MW, Nichols T, Mueller-Cohrs J. et al. Improved kinetics of rIX-FP, a recombinant fusion protein linking factor IX with albumin in cynomolgus monkeys and hemophilia B dogs. J Thromb Haemost 2012; 10: 1591-1599.
    CrossrefPubMedGoogle Scholar
  • 36 Santagostino E, Negrier C, Klamroth R. et al. Safety and pharmacokinetics of a novel recombinant fusion protein linking coagulation factor IX with albumin (rIX-FP) in hemophilia B patients. Blood 2012; 120: 2405-2411.
    CrossrefPubMedGoogle Scholar
  • 37 A Safety and Efficacy Study of a Recombinant Fusion Protein Linking Coagulation Factor IX with Albumin (rIX-FP) in Patients with HemophiliaB. NCT01496274. Available at: http://www.clinicaltrials.gov. Last accessed Jan 11 2013
    PubMedGoogle Scholar
  • 38 Lusher JM. Early treatment with recombinant factor VIIa results in greater efficacy with less product. Eur J Haematol Suppl 1998; 63: 7-10.
    PubMedGoogle Scholar
  • 39 Weimer T, Wormsbächer W, Kronthaler U. et al. Prolonged in-vivo half-life of factor VIIa by fusion to albumin. Thromb Haemost 2008; 99: 659-667.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 40 Schulte S. Use of albumin fusion technology to prolong the half-life of recombinant factor VIIa. Thromb Res 2008; 122 (Suppl. 04) S14-19.
    PubMedGoogle Scholar
  • 41 Zollner S, Weimer T, Schmidbauer S. et al. Pharmacokinetics of a recombinant albumin-fused human coagulation factor VIIa (rVIIa-FP) exhibiting prolonged serum half-life in different animal species. Haemophilia 2010; 16 (Suppl. 04) 33
    CrossrefPubMedGoogle Scholar
  • 42 Kronthaler U, Schmidbauer S, Liebing U. et al. Prolonged half-life of recombinant factor VIIa fusion protein – single dose study in rabbits. XXII Congress of ISTH. June 2–6 2009 Boston USA.: Abstract PP-TH-561. Available at http://abstract.mci-group.com/cgi-bin/mc/delquery.pl?APP=ISTH2009ABS-abstract&ccode=ISTH2009ABS&tpcgr.
    PubMedGoogle Scholar
  • 43 Kazmier FJ, Spittell JA, Thompson JJ. et al. Effect of oral anticoagulants on factors VII, IX, X and II. Arch Intern Med 1965; 115: 667-673.
    CrossrefPubMedGoogle Scholar
  • 44 Zollner S, Schuermann D, Raquet E. et al. Prolonged plasma half-life and hemostatic efficacy of a recombinant fusion protein linking activated coagulation factor VII with albumin (rVIIa-FP). Haemophilia 2012; 18 (Suppl. 03) 97
    PubMedGoogle Scholar
  • 45 A Safety and Pharmacokinetics Study of a Recombinant Fusion Protein Linking Coagulation Factor VIIa with Albumin (rVIIa-FP) in Healthy Male Volunteers. NCT01542619. Available at: http://www.clinicaltrials.gov. Last accessed Jan 11 2013
    PubMedGoogle Scholar
  • 46 Schulte S. Innovative coagulation factors: albumin fusion technology and recombinant single-chain factor VIII. Thromb Res 2013; 131S2: S2-6.
    PubMedGoogle Scholar