Characterization of a recombinant factor IX molecule fused to coagulation factor XIII-B subunit.
Mice
Rats
Animals
Factor IX
/ genetics
Factor XIII
/ pharmacology
Recombinant Fusion Proteins
/ therapeutic use
Hemophilia B
/ drug therapy
Hemorrhage
/ prevention & control
Hemostatics
/ therapeutic use
Albumins
Fibrinogen
/ therapeutic use
Vascular Diseases
Half-Life
Joint Diseases
/ drug therapy
Recombinant Proteins
/ pharmacology
albumin
extended half-life Factor IX
factor XIII-B sub-unit
fibrinogen
fusion protein
Journal
Haemophilia : the official journal of the World Federation of Hemophilia
ISSN: 1365-2516
Titre abrégé: Haemophilia
Pays: England
ID NLM: 9442916
Informations de publication
Date de publication:
Nov 2023
Nov 2023
Historique:
revised:
19
08
2023
received:
12
06
2023
accepted:
29
08
2023
medline:
14
11
2023
pubmed:
14
9
2023
entrez:
14
9
2023
Statut:
ppublish
Résumé
Severe haemophilia B (HB) is characterized by spontaneous bleeding episodes, mostly into joints. Recurrent bleeds lead to progressive joint destruction called haemophilic arthropathy. The current concept of prophylaxis aims at maintaining the FIX level >3-5 IU/dL, which is effective at reducing the incidence of haemophilic arthropathy. Extended half-life FIX molecules make it easier to achieve these target trough levels compared to standard FIX concentrates. We previously reported that the fusion of a recombinant FIX (rFIX) to factor XIII-B (FXIIIB) subunit prolonged the half-life of the rFIX-LXa-FXIIIB fusion molecule in mice and rats 3.9- and 2.2-fold, respectively, compared with rFIX-WT. However, the mechanism behind the extended half-life was not known. Mass spectrometry and ITC were used to study interactions of rFIX-LXa-FXIIIB with albumin. Pharmacokinetic analyses in fibrinogen-KO and FcRn-KO mice were performed to evaluate the effect of albumin and fibrinogen on in-vivo half-life of rFIX-LXa-FXIIIB. Finally saphenous vein bleeding model was used to assess in-vivo haemostatic activity of rFIX-LXa-FXIIIB. We report here the key interactions that rFIX-LXa-FXIIIB may have in plasma are with fibrinogen and albumin which may mediate its prolonged half-life. In addition, using the saphenous vein bleeding model, we demonstrate that rFIX-FXIIIB elicits functional clot formation that is indistinguishable from that of rFIX-WT.
Substances chimiques
Factor IX
9001-28-9
Factor XIII
9013-56-3
Recombinant Fusion Proteins
0
Hemostatics
0
Albumins
0
Fibrinogen
9001-32-5
Recombinant Proteins
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
1483-1489Subventions
Organisme : NIH HHS
ID : R01HL126974
Pays : United States
Organisme : NIH HHS
ID : R01HL126974
Pays : United States
Informations de copyright
© 2023 John Wiley & Sons Ltd.
Références
Yin R, Liu C. Human coagulation factor IX: a systematic review of its characteristics. Blood Coagul Fibrinolysis. 2022;33:1-7.
Muszbek L, Bereczky Z, Bagoly Z, Komáromi I, Katona É. Factor XIII: a coagulation factor with multiple plasmatic and cellular functions. Physiol Rev. 2011;91(03):931-972.
Milowszewski K, Losowski MS. The half life of Factor XIII in vivo. Br H Haematol. 1970;19:685-690.
LeQuellec S, Enjolras N, Perot E, Girard J, Negrier C, Dargaud Y. Fusion of factor IX to factor XIII-B sub-unit improves the pharmacokinetic profile of factor IX. Thromb Haemost. 2018;118:2053-2063.
Wolberg AS. Plasma factor XIII: understanding the 99%. Blood. 2014;123:1623-1624.
Hurják B, Kovács Z, Döncző B, et al. N-glycosylation of blood coagulation factor XIII subunit B and its functional consequence. J Thromb Haemost. 2020;18:1302-1309.
Jamil MA, Singh S, El-Maarri O, Oldenburg J, Biswas A. Exploring diverse coagulation factor XIII subunit expression datasets: a bioinformatic analysis. Int J Mol Sci. 2022;23:4725.
Ząbczyk M, Natorska J, Undas A. Factor XIII and fibrin clot properties in acute venous thromboembolism. Int J Mol Sci. 2021;22:1607-1618.
Singh S, Akhter MS, Dodt J, et al. Identification of potential novel interacting partners for coagulation factor XIII B (FXIIIB) subunit, a protein associated with a rare bleeding disorder. Int J Mol Sci. 2019;20:2682.
Byrnes JR, Wilson C, Boutelle AM, et al. The interaction between fibrinogen and zymogen FXIII-A2B2 is mediated by fibrinogen residues γ390-396 and the FXIIIB subunits. Blood. 2016;128(15):1969-1978.
Singh S, Nazabal A, Kaniyappan S, et al. The plasma factor XIII heterotetrameric complex structure: unexpected unequal pairing within a symmetric complex. Biomolecules. 2019;9:765.
Rosenfeld J, Capdevielle J, Guillemot JC, Ferrara P. In-gel digestion of proteins for internal sequence analysis after one- or two-dimensional gel electrophoresis. Anal Biochem. 1992;203:173-179.
Jeno P, Mini T, Moes S, Hintermann E, Horst M. Internal sequences from proteins digested in polyacrylamide gels. Anal Biochem. 1995;224:75-82.
Kall L, Storey JD, MacCoss MJ, Noble WS. Assigning significance to peptides identified by tandem mass spectrometry using decoy databases. J Proteome Res. 2008;7:29-34.
Suh TT, Holmback K, Jensen NJ, et al. Resolution of spontaneous bleeding events but failure f pregnancy in fibrinogen deficient mice. Genes Des. 2015;9:2020-2033.
Mahmood I. Naive pooled-data approach for pharmacokinetic studies in pediatrics with a very small sample size. Am J Ther. 2014;21:269-274.
Mahmood I, Duan J. Population pharmacokinetics with a very small sample size. Drug Metabol Drug Interact. 2009;24:259-274.
Souri M, Osaki T, Ichinose A. The non-catalytic B subunit of coagulation factor XIII accelerates fibrin cross-linking. J Biol Chem. 2015;290:12027-12039.
Klykov O, van der Zwaan C, Heck AJR, Meijer AB, Scheltema RA. Missing regions within the molecular architecture of human fibrin clots structurally resolved by XL-MS and integrative structural modeling. Proc Natl Acad Sci USA. 2020;117:1976-1987.
van der Flier A, Liu Z, Tan S, et al. FcRn rescues recombinant factor VIII Fc fusion protein from a VWF independent FVIII clearance pathway in mouse hepatocytes. PLoS ONE. 2015;10:e0124930.
Sand KM, Dalhus B, Christianson GJ, et al. Dissection of the neonatal Fc receptor (FcRn)-albumin interface using mutagenesis and anti-FcRn albumin-blocking antibodies. J Biol Chem. 2014;289:17228-17239.
Mohammed BM, Monroe DM, Gailani D. Mouse models of hemostasis. Platelets. 2020;31:417-422.
Mohammed BM, Cheng Q, Matafonov A, Monroe DM, Meijers JCM, Gailani D. Factor XI promotes hemostasis in factor IX-deficient mice. J Thromb Haemost. 2018;16:2044-2049.