FVIII Half-life Extension by Coadministration of a D'D3 Albumin Fusion Protein in Mice, Rabbits, Rats, and Monkeys

Overview

Journal Blood Adv

Specialty Hematology

Date 2020 May 7

PMID 32374879

Authors

Sabine Pestel

Hans-Wilhelm Beltz

Philipp Claar

Holger Lind

Marcel Mischnik

Elmar Raquet

Arna Andrews

Jason Simmonds

Vesna Tomasetig

Steven K Dower

Anna Tjarnlund-Wolf

Stefan Schulte

Peter M Schmidt

Thomas Weimer

Affiliations

Soon will be listed here.

Abstract

A novel mechanism for extending the circulatory half-life of coagulation factor VIII (FVIII) has been established and evaluated preclinically. The FVIII binding domain of von Willebrand factor (D'D3) fused to human albumin (rD'D3-FP) dose dependently improved pharmacokinetics parameters of coadministered FVIII in all animal species tested, from mouse to cynomolgus monkey, after IV injection. At higher doses, the half-life of recombinant FVIII (rVIII-SingleChain) was calculated to be increased 2.6-fold to fivefold compared with rVIII-SingleChain administered alone in rats, rabbits, and cynomolgus monkeys, and it was increased 3.1-fold to 9.1-fold in mice. Sustained pharmacodynamics effects were observed (ie, activated partial thromboplastin time and thrombin generation measured ex vivo). No increased risk of thrombosis was observed with coadministration of rVIII-SingleChain and rD'D3-FP compared with rVIII-SingleChain alone. At concentrations beyond the anticipated therapeutic range, rD'D3-FP reduced the hemostatic efficacy of coadministered rVIII-SingleChain. This finding might be due to scavenging of activated FVIII by the excessive amount of rD'D3-FP which, in turn, might result in a reduced probability of the formation of the tenase complex. This observation underlines the importance of a fine-tuned balance between FVIII and its binding partner, von Willebrand factor, for hemostasis in general.

References

Pipe S, Montgomery R, Pratt K, Lenting P, Lillicrap D . Life in the shadow of a dominant partner: the FVIII-VWF association and its clinical implications for hemophilia A. Blood. 2016; 128(16):2007-2016. PMC: 5073181. DOI: 10.1182/blood-2016-04-713289. View

Przeradzka M, Meems H, van der Zwaan C, Ebberink E, van den Biggelaar M, Mertens K . The D' domain of von Willebrand factor requires the presence of the D3 domain for optimal factor VIII binding. Biochem J. 2018; 475(17):2819-2830. DOI: 10.1042/BCJ20180431. View

Powell J, Pasi K, Ragni M, Ozelo M, Valentino L, Mahlangu J . Phase 3 study of recombinant factor IX Fc fusion protein in hemophilia B. N Engl J Med. 2013; 369(24):2313-23. DOI: 10.1056/NEJMoa1305074. View

Roopenian D, Akilesh S . FcRn: the neonatal Fc receptor comes of age. Nat Rev Immunol. 2007; 7(9):715-25. DOI: 10.1038/nri2155. View

Weinstein M, Chute L . Two distinct forms of Factor VIII coagulant protein in human plasma. Cleavage by thrombin, and differences in coagulant activity and association with von Willebrand factor. J Clin Invest. 1984; 73(2):307-16. PMC: 425020. DOI: 10.1172/JCI111215. View

Valentino L, Cong L, Enockson C, Song X, Scheiflinger F, Muchitsch E . The biological efficacy profile of BAX 855, a PEGylated recombinant factor VIII molecule. Haemophilia. 2014; 21(1):58-63. DOI: 10.1111/hae.12532. View

Franchini M, Lippi G . Von Willebrand factor and thrombosis. Ann Hematol. 2006; 85(7):415-23. DOI: 10.1007/s00277-006-0085-5. View

Sanders S, Purcell S, Silva M, Palerme S, James P . Relationship between diagnosis and intervention in women with inherited bleeding disorders and menorrhagia. Haemophilia. 2012; 18(3):e273-6. DOI: 10.1111/j.1365-2516.2011.02740.x. View

Santagostino E, Martinowitz U, Lissitchkov T, Pan-Petesch B, Hanabusa H, Oldenburg J . Long-acting recombinant coagulation factor IX albumin fusion protein (rIX-FP) in hemophilia B: results of a phase 3 trial. Blood. 2016; 127(14):1761-9. PMC: 4825413. DOI: 10.1182/blood-2015-09-669234. View

10.

Dumont J, Liu T, Low S, Zhang X, Kamphaus G, Sakorafas P . Prolonged activity of a recombinant factor VIII-Fc fusion protein in hemophilia A mice and dogs. Blood. 2012; 119(13):3024-30. PMC: 3953019. DOI: 10.1182/blood-2011-08-367813. View

11.

Lenting P, de Groot P, De Meyer S, Vanhoorelbeke K, Pruss C, Lillicrap D . Correction of the bleeding time in von Willebrand factor (VWF)-deficient mice using murine VWF. Blood. 2007; 109(5):2267-8. DOI: 10.1182/blood-2006-10-054718. View

12.

Foster P, Fulcher C, Marti T, Titani K, ZIMMERMAN T . A major factor VIII binding domain resides within the amino-terminal 272 amino acid residues of von Willebrand factor. J Biol Chem. 1987; 262(18):8443-6. View

13.

Bendetowicz A, Morris J, Wise R, Gilbert G, Kaufman R . Binding of factor VIII to von willebrand factor is enabled by cleavage of the von Willebrand factor propeptide and enhanced by formation of disulfide-linked multimers. Blood. 1998; 92(2):529-38. View

14.

Lenting P, VAN Schooten C, Denis C . Clearance mechanisms of von Willebrand factor and factor VIII. J Thromb Haemost. 2007; 5(7):1353-60. DOI: 10.1111/j.1538-7836.2007.02572.x. View

15.

Mei B, Pan C, Jiang H, Tjandra H, Strauss J, Chen Y . Rational design of a fully active, long-acting PEGylated factor VIII for hemophilia A treatment. Blood. 2010; 116(2):270-9. DOI: 10.1182/blood-2009-11-254755. View

16.

Wise R, Barr P, Wong P, Kiefer M, Brake A, Kaufman R . Expression of a human proprotein processing enzyme: correct cleavage of the von Willebrand factor precursor at a paired basic amino acid site. Proc Natl Acad Sci U S A. 1990; 87(23):9378-82. PMC: 55168. DOI: 10.1073/pnas.87.23.9378. View

17.

Madabhushi S, Shang C, Dayananda K, Rittenhouse-Olson K, Murphy M, Ryan T . von Willebrand factor (VWF) propeptide binding to VWF D'D3 domain attenuates platelet activation and adhesion. Blood. 2012; 119(20):4769-78. PMC: 3367877. DOI: 10.1182/blood-2011-10-387548. View

18.

Manco-Johnson M, Abshire T, Shapiro A, Riske B, Hacker M, Kilcoyne R . Prophylaxis versus episodic treatment to prevent joint disease in boys with severe hemophilia. N Engl J Med. 2007; 357(6):535-44. DOI: 10.1056/NEJMoa067659. View

19.

van den Biggelaar M, Meijer A, Voorberg J, Mertens K . Intracellular cotrafficking of factor VIII and von Willebrand factor type 2N variants to storage organelles. Blood. 2008; 113(13):3102-9. DOI: 10.1182/blood-2008-05-159699. View

20.

Stennicke H, Kjalke M, Karpf D, Balling K, Johansen P, Elm T . A novel B-domain O-glycoPEGylated FVIII (N8-GP) demonstrates full efficacy and prolonged effect in hemophilic mice models. Blood. 2013; 121(11):2108-16. PMC: 3596971. DOI: 10.1182/blood-2012-01-407494. View