Subscribe to RSS
DOI: 10.1160/TH14-04-0332
Half-life extension technologies for haemostatic agents
Publication History
Received:
11 April 2014
Accepted after minor revision:
27 August 2014
Publication Date:
27 November 2017 (online)
![](https://www.thieme-connect.de/media/10.1055-s-00035024/201501/lookinside/thumbnails/10-1160-th14-04-0332-1.jpg)
Summary
The use of plasma-derived and recombinant coagulation factors for the treatment of haemophilia A and B is well established and permits patients to live a relatively normal life. In order to improve treatment options, several products are in development, which have a prolonged duration of action, thus enabling less frequent prophylactic dosing and aiming to reduce the burden of treatment. Several innovative approaches are being pursued to extend the half-life of factor VIIa, factor VIII and factor IX, utilising technologies such as Fc fusion, recombinant albumin fusion and addition of polyethyleneglycol (PEG) (PEG ylation). These methods prolong the time in the circulation by reducing degradation and elimination. This review summarises the technologies and products in development and their stages of development, and also discusses their pros and cons.
-
References
- 1 Fischer K. et al. Prophylactic versus on-demand treatment strategies for severe haemophilia: a comparison of costs and long-term outcome. Haemophilia 2002; 08: 745-752.
- 2 Gringeri A. et al. Health status and health-related quality of life of children with haemophilia from six West European countries. Haemophilia 2004; 10 (Suppl. 01) 26-33.
- 3 Gringeri A. et al. A randomized clinical trial of prophylaxis in children with haemophilia A (the ESPRIT Study). J Thromb Haemost 2011; 09: 700-710.
- 4 Ljung R. Prophylactic therapy in haemophilia. Blood Rev 2009; 23: 267-274.
- 5 Mannucci PM. et al. How do we choose factor VIII to treat haemophilia. Blood 2012; 119: 4108-4114.
- 6 Guh S. et al. Healthcare expenditures for males with haemophilia and employer-sponsored insurance in the United States, 2008. Haemophilia 2012; 18: 268-275.
- 7 Guh S. et al. Health care expenditures for Medicaid-covered males with haemophilia in the United States, 2008. Haemophilia 2012; 18: 276-283.
- 8 Morfini M. Pharmacokinetics of factor VIII and factor IX. Haemophilia 2003; 09 (Suppl. 01) 94-99.
- 9 Pipe SW. The hope and reality of long-acting haemophilia products. Am J Hematol 2012; 87 (Suppl. 01) S33-S39.
- 10 Moher D. et al. Preferred reporting items for systematic reviews and metaanalyses: the PRISMA statement. Ann Intern Med 2009; 151: 264-269.
- 11 Dumont JA. et al. Prolonged activity of a recombinant factor VIII-Fc fusion protein in haemophilia A mice and dogs. Blood 2012; 119: 3024-3030.
- 12 van der Flier A. et al. VWF affects the clearance and biodistribution of recombinant factor VIII Fc fusion (rFVIIIFc). J Thromb Haemost 2013; 11 (Suppl. 02) 476 (Abstract PA 4.13-6).
- 13 Peters RT. et al. Biochemical and functional characterization of a recombinant monomeric factor VIII-Fc fusion protein. J Thromb Haemost 2013; 11: 132-141.
- 14 Powell JS. et al. Safety and prolonged activity of recombinant factor VIII Fc fusion protein in haemophilia A patients. Blood 2012; 119: 3031-3037.
- 15 Mahlangu J. et al. Phase 3 study of recombinant factor VIII Fc fusion protein in severe haemophilia A. Blood 2014; 123: 317-325.
- 16 Mahlangu J. et al. Long-lasting recombinant factor VIII Fc fusion (rFVIIIFc) for perioperative management of subjects with haemophilia A in the phase 3 A-LONG study. J Thromb Haemost 2013; 11 (Suppl. 02) 459 (Abstract PA 2.07-4).
- 17 Buyue Y. et al. Evaluation of the thrombin generation potential of a recombinant factor VIII Fc fusion protein (rFVIIIFc) in a phase III multi-national clinical trial. J Thromb Haemost 2013; 11 (Suppl. 02) 228 (Abstract OC 64.3).
- 18 Sommer J. et al. Evaluation of whole blood clotting activity of recombinant factor VIII Fc fusion protein by ROTEM analysis in a multi-center Phase 3 clinical trial. J Thromb Haemost 2013; 11 (Suppl. 02) 39 (Abstract AS 26.1).
- 19 Peters RT. et al. Prolonged activity of factor IX as a monomeric Fc fusion protein. Blood 2010; 115: 2057-2064.
- 20 Shapiro AD. et al. Recombinant factor IX-Fc fusion protein (rFIXFc) demonstrates safety and prolonged activity in a phase 1/2a study in haemophilia B patients. Blood 2012; 119: 666-672.
- 21 Powell JS. et al. Phase 3 study of recombinant factor IX Fc fusion protein in haemophilia B. N Engl J Med 2013; 369: 2313-2323.
- 22 Pasi J. et al. Treatment of bleeding episodes in subjects with haemophilia B with the long-lasting recombinant factor IX Fc fusion protein (rFIXFc) in the phase 3 B-LONG study. J Thromb Haemost 2013; 11 (Suppl. 02) 359 (Abstract PA 2.07-6).
- 23 Powell J. et al. Long-lasting recombinant factor FIX Fc fusion (rFIXFc) for perioperative management of subjects with haemophilia B in the phase 3 B-LONG study. J Thromb Haemost 2013; 11 (Suppl. 02) 358 (Abstract PA 2.07-4).
- 24 Li S. et al. Clinical implications of population pharmacokinetics of rFIXFc in routine prophylaxis, control of bleeding and perioperative management for haemophilia B patients. J Thromb Haemost 2013; 11 (Suppl. 02) 358 (Abstract PA 2.07-5).
- 25 Salas J. et al. Enhanced pharmacokinetics of factor VIIA as a monomeric FC fusion. J Thromb Haemost 2011; 09 (Suppl. 02) 268 (Abstract O-TU-026).
- 26 Bain VG. et al. A phase 2 study to evaluate the antiviral activity, safety, and phar-macokinetics of recombinant human albumin-interferon alfa fusion protein in genotype 1 chronic hepatitis C patients. J Hepatol 2006; 44: 671-678.
- 27 Sheffield WP. et al. Effects of genetic fusion of factor IX to albumin on in vivo clearance in mice and rabbits. Br J Haematol 2004; 126: 565-573.
- 28 Metzner HJ. et al. Genetic fusion to albumin improves the pharmacokinetic properties of factor IX. Thromb Haemost 2009; 102: 634-644.
- 29 Nolte MW. et al. Improved kinetics of rIX-FP, a recombinant fusion protein linking factor IX with albumin, in cynomolgus monkeys and haemophilia B dogs. J Thromb Haemost 2012; 10: 1591-1599.
- 30 Herzog E, Harris S, Hensen C. et al. Biodistribution of recombinant fusion protein linking recombinant factor IX with albumin (rIX-FP) in rats. Thromb Res 2014; 133: 900-907.
- 31 Santagostino E. et al. Safety and pharmacokinetics of a novel recombinant fusion protein linking coagulation factor IX with albumin (rIX-FP) in haemophilia B patients. Blood 2012; 120: 2405-2411.
- 32 Santagostino E. PROLONG-9FP clinical development program--phase I results of recombinant fusion protein linking coagulation factor IX with recombinant albumin (rIX-FP). Thromb Res 2013; 131 (Suppl. 02) S7-10.
- 33 Martinowitz U, Lubetsky A. Phase I/II, open-label, multicenter, safety, efficacy and PK study of a recombinant coagulation factor IX albumin fusion protein (rIX-FP) in subjects with haemophilia B. Thromb Res 2013; 131 (Suppl. 02) S11-14.
- 34 Martinowitz U. et al. Efficacy, PK and safety results of a Phase I/II clinical study of recombinant fusion protein linking coagulation factor IX with albumin (rIX-FP) in previously treated patients with haemophilia B. J Thromb Haemost 2013; 11 (Suppl. 02) 240-241 (Abstract OC 70.2).
- 35 Horn C. et al. Concept and structure model of factor VIIa albumin fusion proteins. Haemophilia 2010; 16 (Suppl. 04) 37 (Abstract 08P19).
- 36 Schulte S. Use of albumin fusion technology to prolong the half-life of recombi-nant factor VIIa. Thromb Res 2008; 122 (Suppl. 04) S14-S19.
- 37 Weimer T. et al. Prolonged in-vivo half-life of factor VIIa by fusion to albumin. Thromb Haemost 2008; 99: 659-667.
- 38 Zollner S. et al. Pharmacological characteristics of a novel, recombinant fusion protein linking coagulation factor VIIa with albumin (rVIIa-FP). J Thromb Haemost 2014; 12: 220-228.
- 39 Herzog E. et al. Quantitative whole body autoradiography (QWBA) study on the biodistribution of a recombinant factor rVIIa linked to human albumin. J Thromb Haemost 2103 11 (Suppl. 02) 587 (Abstract PB 1.58-3).
- 40 Golor G. et al. Safety and Pharmacokinetics of a Recombinant Fusion Protein Linking Coagulation Factor VIIa with Albumin (rVIIa-FP) in Healthy Volunteers. J Thromb Haemost 2013; 11: 1977-1985.
- 41 Schulte S. Innovative coagulation factors: albumin fusion technology and rec-ombinant single-chain factor VIII. Thromb Res 2013; 131 (Suppl. 02) S2-S6.
- 42 Stennicke HR. et al. A novel B-domain O-glycoPEGylated FVIII (N8-GP) demonstrates full efficacy and prolonged effect in haemophilic mice models. Blood 2013; 121: 2108-2116.
- 43 Krogh-Meibom T. et al. The activity of glycoPEGylated recombinant FVIII (N8-GP) can be measured in both two-stage chromogenic and one-stage clotting assays. J Thromb Haemost 2013; 11 (Suppl. 02) 1042 (Abstract PO 059).
- 44 Agerso H. et al. Pharmacokinetics and pharmacodynamics of turoctocog alfa and N8-GP in haemophilia A dogs. Haemophilia 2012; 18: 941-947.
- 45 Johansen PB. et al. Dose response relationship and duration of effect of a PEGy-lated recombinant FVIII conjugate, N8-GP, in a new tail vein transection bleeding model in anaesthetized FVIII k/o mice. J Thromb Haemost 2013; 11 (Suppl. 02) 475 (Abstract PA 4.13-3).
- 46 Tiede A. et al. Enhancing the pharmacokinetic properties of recombinant factor VIII: first-in-human trial of glycoPEGylated recombinant factor VIII in patients with haemophilia A. J Thromb Haemost 2013; 11: 670-678.
- 47 Mei B. et al. Rational design of a fully active, long-acting PEGylated factor VIII for haemophilia A treatment. Blood 2010; 116: 270-279.
- 48 Coyle T. et al. An open-label phase I study to evaluate the pharmacokinetics and safety profile of Bay 94-9027, a PEGylated B-domain-deleted recombinant factor VIII, in previously treated patients with severe haemophilia A. Haemophilia 2012; 18 (Suppl. 03) 22 (Abstract FP-MO-03.2-3).
- 49 Paz P. et al. PEGylated FVIII Exhibits Reduced Immunogenicity in Haemophilia A Mice and In Vitro in Human Cells. Haemophilia 2012; 18 (Suppl. 03) 93 (Abstract PO-WE-125).
- 50 Turecek PL. et al. BAX 855, a PEGylated rFVIII product with prolonged halflife. Development, functional and structural characterisation. Hamostaseologie 2012; 32 (Suppl. 01) S29-S38.
- 51 Dietrich B. et al. Preclinical safety of a longer acting recombinant factor VIII (BAX 855). J Thromb Haemost 2013; 11 (Suppl. 02) 844 (Abstract PB 3.55-4).
- 52 Stidl R. et al. PEGylated biopharmaceuticals and safety evaluation of polyethylene glycol (PEG) with focus on PEG-rFVIII. J Thromb Haemost 2013; 11 (Suppl. 02) 845 (Abstract PB 3.55-6).
- 53 Horlin F. et al. The use of novel models for preclinical immunogenicity assessment of a longer-acting FVIII candidate. Haemophilia 2012; 18 (Suppl. 03) 90 (Abstract PO-WE-107).
- 54 Turecek PL. et al. Structural and functional characterization of clinical phase 1 and phase 2/3 material of BAX 855, a PEGylated recombinant FVIII. J Thromb Haemost 2013; 11 (Suppl. 02) 922-923 (Abstract PB 4.35-2).
- 55 Negrier C. et al. Enhanced pharmacokinetic properties of a glycoPEGylated rec-ombinant factor IX: a first human dose trial in patients with haemophilia B. Blood 2011; 118: 2695-2701.
- 56 Ostergaard H. et al. Prolonged half-life and preserved enzymatic properties of factor IX selectively PEGylated on native N-glycans in the activation peptide. Blood 2011; 118: 2333-2341.
- 57 Collins PW. et al. Population pharmacokinetic modeling for dose setting of non-acog beta pegol (N9-GP), a glycoPEGylated recombinant factor IX. J Thromb Haemost 2012; 10: 2305-2312.
- 58 Collins PW. et al. Safety, efficacy and pharmacokinetics of nonacog beta pegol (N9-GP) for prophylaxis and treatment of bleeding episodes in patients with haemophilia B. J Thromb Haemost 2013; 11 (Suppl. 02) 19 (Abstract AS 12.4).
- 59 Novo Nordisk.. Novo Nordisk press release. 17 May 2013. Available at http://www.novonordisk.com/include/asp/exe_news_attachment.asp?sAttachmentGUID=BD0FD957-1FD8-4B8E-A8CE-07BCB7E23A33 Accessed March 2014.
- 60 Novo Nordisk.. Novo Nordisk press release. Available at: http://www.novonordisk.com/images/investors/investor_presentations2011/Q3/PR111027_9M_2011_UK.pdf Accessed July 2013.
- 61 Stennicke HR. et al. Generation and biochemical characterization of glyco-PEGylated factor VIIa derivatives. Thromb Haemost 2008; 100: 920-928.
- 62 Sen P. et al. Effect of glycoPEGylation on factor VIIa binding and internaliz-ation. Haemophilia 2010; 16: 339-348.
- 63 Holmberg H. et al. GlycoPEGylated rFVIIa (N7-GP) has a prolonged hemos-tatic effect in haemophilic mice compared with rFVIIa. J Thromb Haemost 2011; 09: 1070-1072.
- 64 Johansen PB. et al. Prolonged effect of GlycoPEGylated rFVIIa (40k-PEGrFVIIa) in rabbits correlates to activity in plasma. Thromb Haemost 2010; 104: 157-164.
- 65 Karpf DM, Sorensen BB, Hermit MB. et al. Prolonged half-life of glycoPEGylated rFVIIa variants compared to native rFVIIa. Thromb Res 2011; 128: 191-195.
- 66 Moss J. et al. Safety and pharmacokinetics of a glycoPEGylated recombinant activated factor VII derivative: a randomized first human dose trial in healthy subjects. J Thromb Haemost 2011; 09: 1368-1374.
- 67 Ljung R. et al. 40K glycoPEGylated, recombinant FVIIa: 3-month, double-blind, randomized trial of safety, pharmacokinetics and preliminary efficacy in haemophilia patients with inhibitors. J Thromb Haemost 2013; 11: 1260-1268.
- 68 Yatuv R. et al. The use of PEGylated liposomes in the development of drug delivery applications for the treatment of haemophilia. Int J Nanomedicine 2010; 05: 581-591.
- 69 Barenholz Y. Doxil(R)--the first FDA-approved nano-drug: lessons learned. J Control Release 2012; 160: 117-134.
- 70 Lacerda JF, Oliveira CM. Diagnosis and treatment of invasive fungal infections focus on liposomal amphotericin B. Clin Drug Investig 2013; 33 (Suppl. 01) S5-14.
- 71 Baru M. et al. Factor VIII efficient and specific non-covalent binding to PEGy-lated liposomes enables prolongation of its circulation time and haemostatic efficacy. Thromb Haemost 2005; 93: 1061-1068.
- 72 Dayan I. et al. Enhancement of haemostatic efficacy of plasma-derived FVIII by formulation with PEGylated liposomes. Haemophilia 2009; 15: 1006-1013.
- 73 Pan J. et al. Enhanced efficacy of recombinant FVIII in noncovalent complex with PEGylated liposome in haemophilia A mice. Blood 2009; 114: 2802-2811.
- 74 Peng A. et al. PEGylation of a factor VIII-phosphatidylinositol complex: phar-macokinetics and immunogenicity in haemophilia A mice. AAPS J 2012; 14: 35-42.
- 75 Ramani K. et al. Passive transfer of polyethylene glycol to liposomal-recombi-nant human FVIII enhances its efficacy in a murine model for haemophilia A. J Pharm Sci 2008; 97: 3753-3764.
- 76 Martinowitz U. et al. Infusion rates of recombinant FVIII-FS with PEGylated liposomes in haemophilia A. Haemophilia 2008; 14: 1122-1124.
- 77 Spira J. et al. Prolonged bleeding-free period following prophylactic infusion of recombinant factor VIII reconstituted with pegylated liposomes. Blood 2006; 108: 3668-3673.
- 78 Powell JS. et al. Safety and pharmacokinetics of a recombinant factor VIII with pegylated liposomes in severe haemophilia A. J Thromb Haemost 2008; 06: 277-283.
- 79 Spira J. et al. Evaluation of liposomal dose in recombinant factor VIII reconstituted with pegylated liposomes for the treatment of patients with severe haemophilia A. Thromb Haemost 2008; 100: 429-434.
- 80 Powell J. et al. Efficacy and safety of prophylaxis with once-weekly BAY 79-4980 compared with thrice-weekly rFVIII-FS in haemophilia A patients. A randomised, active-controlled, double-blind study. Thromb Haemost 2012; 108: 913-922.
- 81 Yatuv R. et al. Enhancement of factor VIIa haemostatic efficacy by formulation with PEGylated liposomes. Haemophilia 2008; 14: 476-483.
- 82 Spira J. et al. Safety, pharmacokinetics and efficacy of factor VIIa formulated with PEGylated liposomes in haemophilia A patients with inhibitors to factor VIII--an open label, exploratory, cross-over, phase I/II study. Haemophilia 2010; 16: 910-918.
- 83 Dasgupta S. et al. VWF protects FVIII from endocytosis by dendritic cells and subsequent presentation to immune effectors. Blood 2007; 109: 610-612.
- 84 Schmidbauer S. et al. N-Glycosylation of rVIII-SingleChain, a novel recombi-nant single-chain factor VIII. J Thromb Haemost 2013; 11 (Suppl. 02) 713 (Abstract PB 2.55-6).
- 85 Zollner S. et al. Non-clinical pharmacokinetics and pharmacodynamics of rVIII-SingleChain, a novel recombinant single-chain factor VIII. Thromb Res 2014; 134: 125-131.
- 86 Zollner SB. et al. Preclinical efficacy and safety of rVIII-SingleChain (CSL627), a novel recombinant single-chain factor VIII. Thromb Res 2013; 132: 280-287.
- 87 Pabinger I. et al. Pharmacokinetics results of a phase I/III study of a novel rec-ombinant single chain factor VIII (rVIII-SingleChain) compared to octocog alfa in severe haemophilia A patients. J Thromb Haemost 2013; 11 (Suppl. 02) 712 (Abstract PB 2.55-4).
- 88 Hart G. et al. FVIIa-CTP and FIX-CTP are novel long-acting coagulation factors with prolonged hemopstatic activity in haemophilic animal models. Haemophilia 2012; 18 (Suppl. 03) 32 (Abstract PO-TU-025).
- 89 Hart G. et al. A long-acting FVIIa-CTP proposing an improved prophylactic and on demand treatment for haemophilic patients following SC and IV administration-evaluation in animal models. J Thromb Haemost 2013; 11 (Suppl. 02) 268 (Abstract OC 83.6).
- 90 Van der Linden P. et al. Safety of modern starches used during surgery. Anesth Analg 2013; 116: 35-48.
- 91 Sommer J. et al. Preservation of activity and prolonged efficacy of rFVIII after site-specific modification with high molecular weight hydroxyethyl starch. Haemophilia 2010; 16 (Suppl. 04) 39 (Abstract 08P35).
- 92 Hey T, Hackett F. Prolonged circulatory half life for rFVIIa after conjugation to hydroxyethyl starch. Haemophilia 2010; 16 (Suppl. 04) 36 (Abstract 08P16).
- 93 Liu T. et al. A combinatorial library approach to generate rFVIII variants with multiple XTEN insertions and improved pharmacokinetic properties. J Thromb Haemost 2013; 11 (Suppl. 02) 371 (Abstract PA 2.12-5).
- 94 Tan S. et al. A platelet-targeted factor VIIa. XTEN fusion protein with increased circulating half-life and improved clotting activity. J Thromb Haemost 2013; 11 (Suppl. 02) 586 (Abstract PB 1.58-1).
- 95 Dallabrida S. et al. Recombinant FVIIa-XTEN as a long-lasting form of rFVIIa with an enhanced PK profile. Haemophilia 2012; 18 (Suppl. 03) 28 (Abstract FPTU-01.1-2).
- 96 Flintegaard TV. et al. N-glycosylation increases the circulatory half-life of human growth hormone. Endocrinology 2010; 151: 5326-5336.
- 97 Bolt G. et al. Hyperglycosylation prolongs the circulation of coagulation factor IX. J Thromb Haemost 2012; 10: 2397-2398..
- 98 Andersen JT. et al. Structure-based mutagenesis reveals the albumin-binding site of the neonatal Fc receptor. Nat Commun 2012; 03: 610.
- 99 Krishnan S, Miners A. Comparing projected prophylactic consumption and effects of recombinant factor VIII Fc Fusion (rFVIIIFc) and shorter half-life FVIII products in haemophilia. J Thromb Haemost 2013; 11 (Suppl. 01) 844-845 (Abstract PB 3.55-5).
- 100 Houde D, Berkowitz SA. Conformational comparability of factor IX-Fc fusion protein, factor IX, and purified Fc fragment in the absence and presence of calcium. J Pharm Sci 2012; 101: 1688-1700.
- 101 Collins PW. et al. Factor VIII requirement to maintain a target plasma level in the prophylactic treatment of severe haemophilia A: influences of variance in pharmacokinetics and treatment regimens. J Thromb Haemost 2009; 08: 269-275.
- 102 Ahnström J. et al. A 6-year follow-up of dosing, coagulation factor levels and bleedings in relation to joint status in the prophylactic treatment of haemophilia. Haemophilia 2004; 10: 689-697.
- 103 Hubbard AR. International biological standards for coagulation factors and inhibitors. Semin Thromb Hemost 2007; 33: 283-289.
- 104 Hubbard AR. et al. Recommendations on the potency labelling of factor VIII and factor IX concentrates. J Thromb Haemost 2013; 11: 988-989.
- 105 Flori N. et al. Pegylated interferon-alpha2a and ribavirin versus pegylated in-terferon-alpha2b and ribavirin in chronic hepatitis C: a meta-analysis. Drugs 2013; 73: 263-277.
- 106 Rizzari C. et al. Optimizing asparaginase therapy for acute lymphoblastic leukemia. Curr Opin Oncol 2013; 25 (Suppl. 01) S1-S9.
- 107 Schmidt SR. Fusion-proteins as biopharmaceuticals--applications and challenges. Curr Opin Drug Discov Devel 2009; 12: 284-295.
- 108 European Medicines Agency.. PRAC recommends suspending marketing authorisations for infusion solutions containing hydroxyethyl startch. 14 June 2013. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/Referrals_document/Solutions_for_infusion_containing_hydroxyethyl_starch/Rec-ommendation_provided_by_Pharmacovigilance_Risk_Assessment_Committee/WC500144448.pdf Last accessed January 2014.
- 109 Metzner HJ. et al. Extending the pharmacokinetic half-life of coagulation factors by fusion to recombinant albumin. Thromb Haemost 2013; 110: 931-939.
- 110 van der Flier A. et al. Different Contribution of Hematopoietic and Somatic Cell Types Expressing FcRn to the Prolonged Half-Life of Recombinant Factor VIII Fc and Recombinant FIX Fc. ASH Annual Meeting Abstracts 2012; 120: 1103.
- 111 Ivens IA. et al. PEGylated therapeutic proteins for haemophilia treatment: a review for haemophilia caregivers. Haemophilia 2013; 19: 11-20.
- 112 Bjoernsdottir I. et al. Excretion and pharmacokinetics of glycopegylated rFVIII (N8-GP) after single intravenous dose administration to rats. J Thromb Hae-most 2013; 11 (Suppl. 02) 579 (Abstract PB 1.55-2).
- 113 Kang JS. et al. Emerging PEGylated drugs. Expert Opin Emerg Drugs 2009; 14: 363-380.
- 114 Armstrong JK. et al. Antibody against poly(ethylene glycol) adversely affects PEG-asparaginase therapy in acute lymphoblastic leukemia patients. Cancer 2007; 110: 103-111.
- 115 Garay RP. et al. Antibodies against polyethylene glycol in healthy subjects and in patients treated with PEG-conjugated agents. Expert Opin Drug Deliv 2012; 09: 1319-1323.
- 116 Reipert B. et al. Does PEGylated factor VIII induce antibodies against PEG?. Haemophilia 2012; 18 (Suppl. 03) 28-29 (Abstract FP-MO-03.2-5).
- 117 Bendele A. et al. Short communication: renal tubular vacuolation in animals treated with polyethylene-glycol-conjugated proteins. Toxicol Sci 1998; 42: 152-157.
- 118 Rudmann DG. et al. High molecular weight polyethylene glycol cellular distribution and PEG-associated cytoplasmic vacuolation is molecular weight dependent and does not require conjugation to proteins. Toxicol Pathol 2013; 41: 970-983.
- 119 EMA assessment report for Cimzia.. Available at: http://www.ema.europa.eudocs/en_GB/document_library/EPAR_-_Public_assessment_report/human/001037/WC500069735.pdf Accessed June 2014.