Thromb Haemost 2018; 118(12): 2053-2063
DOI: 10.1055/s-0038-1675787
Coagulation and Fibrinolysis
Georg Thieme Verlag KG Stuttgart · New York

Fusion of Factor IX to Factor XIII-B Sub-Unit Improves the Pharmacokinetic Profile of Factor IX

Sandra Le Quellec
1  EA4609–Hemostase et Cancer, Universite Claude Bernard Lyon I, Lyon, France
2  Unite d'Hemostase Clinique, Hospices Civils de Lyon, Lyon, France
3  Laboratoire d'hematologie, Hospices Civils de Lyon, Lyon, France
,
Nathalie Enjolras
1  EA4609–Hemostase et Cancer, Universite Claude Bernard Lyon I, Lyon, France
,
Eloïse Perot
1  EA4609–Hemostase et Cancer, Universite Claude Bernard Lyon I, Lyon, France
,
Jonathan Girard
1  EA4609–Hemostase et Cancer, Universite Claude Bernard Lyon I, Lyon, France
,
Claude Negrier
1  EA4609–Hemostase et Cancer, Universite Claude Bernard Lyon I, Lyon, France
2  Unite d'Hemostase Clinique, Hospices Civils de Lyon, Lyon, France
3  Laboratoire d'hematologie, Hospices Civils de Lyon, Lyon, France
,
Yesim Dargaud
1  EA4609–Hemostase et Cancer, Universite Claude Bernard Lyon I, Lyon, France
2  Unite d'Hemostase Clinique, Hospices Civils de Lyon, Lyon, France
3  Laboratoire d'hematologie, Hospices Civils de Lyon, Lyon, France
› Author Affiliations
Funding This work was partly supported by a grant from Fondation Groupama pour la Santé “Vaincre les maladies rares” and ADRHEC.
Further Information

Publication History

09 June 2018

06 October 2018

Publication Date:
19 November 2018 (eFirst)

Abstract

Prophylaxis is currently considered the optimal care for severe haemophilia. For patients and their families one of the major difficulties with prophylaxis is the need for frequent venipunctures. The half-life of standard factor IX (FIX) concentrates is approximately 18 hours, which requires 2 or 3 intravenous infusions per week to achieve bleeding prevention in patients with severe haemophilia B. Prolonging the half-life of FIX can therefore reduce the frequency of infusions. Recently, extended half-life recombinant FIX (rFIX) concentrates have been developed. We designed a new rFIX molecule fused to coagulation FXIII-B sub-unit. This sub-unit is responsible for the long half-life of the FXIII molecule (10–12 days). The rFIX-LXa-FXIIIB fusion protein contains a short linker sequence cleavable by activated FX (FXa), to separate rFIX from the carrier protein as soon as traces of FXa are generated, leaving rFIX free to perform its enzymatic role in the tenase complex. The rFIX-LXa-FXIIIB fusion protein was expressed in human hepatic Huh-7 cells and Chinese hamster ovary cells, and both wild-type rFIX (rFIX-WT) and rFIX-LXa-FXIIIB showed similar clotting activity and thrombin generation capacity in vivo after injection in haemophilia B mice compared with rFIX-WT. The half-life of the rFIX-LXa-FXIIIB molecule in WT mice and rats was 3.9- and 2.2-fold longer, respectively, compared with rFIX-WT. A potential advantage of this new molecule is its capacity to bind to fibrinogen via FXIII-B, which might accelerate fibrin clot formation and thus improve haemostatic capacity of the molecule.

Authors' Contributions

Yesim Dargaud designed the molecule. Yesim Dargaud, Nathalie Enjolras and Sandra Le Quellec designed the study. Sandra Le Quellec, Nathalie Enjolras, Eloïse Pérot, Jonathan Girard and Yesim Dargaud performed experiments. Sandra Le Quellec, Nathalie Enjolras and Yesim Dargaud analysed the data and wrote the manuscript. Claude Negrier critically read and edited the manuscript.