Tissue distribution of rIX-FP after intravenous application to rodents.
factor IX
hemophilia B
rIX-FP
recombinant fusion proteins
tissue distribution
Journal
Journal of thrombosis and haemostasis : JTH
ISSN: 1538-7836
Titre abrégé: J Thromb Haemost
Pays: England
ID NLM: 101170508
Informations de publication
Date de publication:
12 2020
12 2020
Historique:
received:
27
01
2020
revised:
30
06
2020
accepted:
11
08
2020
pubmed:
19
8
2020
medline:
15
5
2021
entrez:
19
8
2020
Statut:
ppublish
Résumé
Hemophilia B is caused by coagulation factor IX (FIX) deficiency. Recombinant fusion protein linking coagulation FIX with recombinant albumin (rIX-FP; Idelvion To complete and confirm the QWBA study data by directly measuring rIX-FP protein and activity levels in tissues following intravenous (i.v.) administration to normal rats and FIX-deficient (hemophilia B) mice. After i.v. administration of rIX-FP at a dose of 2000 IU/kg, animals were euthanized at specific time points up to 72 hours postdosing. Subsequently, plasma and various tissues, which were selected based on the previous QWBA results, were harvested and analyzed for FIX antigen levels using an ELISA (both species) or an immunohistochemistry method (mice only), as well as for FIX activity levels (mice only) using a chromogenic assay. In rats, rIX-FP distributed extravascularly into all tissues analyzed (ie, liver, kidney, skin and knee) with peak antigen levels reached between 1 and 7 hours postdosing. In hemophilia B mice, rIX-FP tissue distribution was comparable to rats. FIX antigen levels correlated well with FIX activity readouts. Our results confirm QWBA data showing that rIX-FP distributes into relevant target tissues. Importantly, it was demonstrated that rIX-FP available in tissues retains its functional activity and can thus facilitate its therapeutic activity at sites of potential injury.
Sections du résumé
BACKGROUND
Hemophilia B is caused by coagulation factor IX (FIX) deficiency. Recombinant fusion protein linking coagulation FIX with recombinant albumin (rIX-FP; Idelvion
OBJECTIVES
To complete and confirm the QWBA study data by directly measuring rIX-FP protein and activity levels in tissues following intravenous (i.v.) administration to normal rats and FIX-deficient (hemophilia B) mice.
METHODS
After i.v. administration of rIX-FP at a dose of 2000 IU/kg, animals were euthanized at specific time points up to 72 hours postdosing. Subsequently, plasma and various tissues, which were selected based on the previous QWBA results, were harvested and analyzed for FIX antigen levels using an ELISA (both species) or an immunohistochemistry method (mice only), as well as for FIX activity levels (mice only) using a chromogenic assay.
RESULTS
In rats, rIX-FP distributed extravascularly into all tissues analyzed (ie, liver, kidney, skin and knee) with peak antigen levels reached between 1 and 7 hours postdosing. In hemophilia B mice, rIX-FP tissue distribution was comparable to rats. FIX antigen levels correlated well with FIX activity readouts.
CONCLUSIONS
Our results confirm QWBA data showing that rIX-FP distributes into relevant target tissues. Importantly, it was demonstrated that rIX-FP available in tissues retains its functional activity and can thus facilitate its therapeutic activity at sites of potential injury.
Identifiants
pubmed: 32810892
doi: 10.1111/jth.15069
pii: S1538-7836(22)03762-X
doi:
Substances chimiques
Recombinant Fusion Proteins
0
Factor IX
9001-28-9
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3194-3202Informations de copyright
© 2020 International Society on Thrombosis and Haemostasis.
Références
Srivastava A, Brewer AK, Mauser-Bunschoten EP, et al. Guidelines for the management of hemophilia. Haemophilia. 2013;19:e1-e47.
Ferreira CN, de Oliveira SM, Sant'Ana Dusse LM, das Gracas Carvalho M. A cell-based model of coagulation and its implications. Rev Bras Hematol Hemoter. 2010;32:416-421.
Hoffman M, Monroe DM. Coagulation 2006: a modern view of hemostasis. Hematol Oncol Clin North Am. 2007;21:1-11.
Konkle BA, Huston H, Nakaya Fletcher S, Hemophilia B. In: Adam MP, Ardinger HH, Pagon RA, et al., eds. GeneReviews®. Seattle, WA: University of Washington, Seattle; 1993-2019, 2000.
Giangrande P. Haemophilia B: Christmas disease. Expert Opin Pharmacother. 2005;6:1517-1524.
Bjorkman S, Shapiro AD, Berntorp E. Pharmacokinetics of recombinant factor IX in relation to age of the patient: implications for dosing in prophylaxis. Haemophilia. 2001;7:133-139.
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.
De Moerloose P, Urbancik W, Van Den Berg HM, Richards M. A survey of adherence to haemophilia therapy in six European countries: results and recommendations. Haemophilia. 2008;14:931-938.
Cavazza M, Kodra Y, Armeni P, et al. Social/economic costs and quality of life in patients with haemophilia in Europe. Eur J Health Econ. 2016;17(Suppl 1):53-65.
Schulte S. Half-life extension through albumin fusion technologies. Thromb Res. 2009;124(Suppl 2):S6-S8.
Metzner HJ, Weimer T, Kronthaler U, Lang W, Schulte S. Genetic fusion to albumin improves the pharmacokinetic properties of factor IX. Thromb Haemost. 2009;102:634-644.
Nolte MW, Nichols TC, 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.
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.
Martinowitz U, Lissitchkov T, Lubetsky A, et al. Results of a phase I/II open-label, safety and efficacy trial of coagulation factor IX (recombinant), albumin fusion protein in haemophilia B patients. Haemophilia. 2015;21:784-790.
Negrier C, Abdul Karim F, Lepatan LM, et al. Efficacy and safety of long-acting recombinant fusion protein linking factor IX with albumin in haemophilia B patients undergoing surgery. Haemophilia. 2016;22:e259-e266.
Kenet G, Chambost H, Male C, et al. Long-acting recombinant fusion protein linking coagulation factor IX with albumin (rIX-FP) in children. Results of a phase 3 trial. Thromb Haemost. 2016;116:659-668.
Santagostino E, Martinowitz U, Lissitchkov T, et al. Long-acting recombinant coagulation factor IX albumin fusion protein (rIX-FP) in hemophilia B: results of a phase 3 trial. Blood. 2016;127:1761-1769.
Gui T, Lin HF, Jin DY, et al. Circulating and binding characteristics of wild-type factor IX and certain Gla domain mutants in vivo. Blood. 2002;100:153-158.
Gailani D. Factor IX binding to collagen. J Thromb Haemost. 2009;7:1840-1842.
Nazeef M, Sheehan JP. New developments in the management of moderate-to-severe hemophilia B. J Blood Med. 2016;7:27-38.
Stafford DW. Extravascular FIX and coagulation. Thromb J. 2016;14:35.
Herzog E, Harris S, Henson C, et al. Biodistribution of the recombinant fusion protein linking coagulation factor IX with albumin (rIX-FP) in rats. Thromb Res. 2014;133:900-907.
Chang CH, Chou TK, Yang CY, Chang TJ, Wu YH, Lee TW. Biodistribution and pharmacokinetics of transgenic pig-produced recombinant human factor IX (rhFIX) in rats. Vivo. 2008;22:693-697.
Sternebring O, Christensen JK, Bjornsdottir I. Pharmacokinetics, tissue distribution, excretion, and metabolite profiling of PEGylated rFIX (nonacog beta pegol, N9-GP) in rats. Eur J Pharm Sci. 2016;92:163-172.
Sun J, Hua B, Livingston EW, et al. Abnormal joint and bone wound healing in hemophilia mice is improved by extending factor IX activity after hemarthrosis. Blood. 2017;129:2161-2171.
Gopalakrishnan R, Hedner U, Ghosh S, et al. Bio-distribution of pharmacologically administered recombinant factor VIIa (rFVIIa). J Thromb Haemost. 2010;8:301-310.
Sun J, Hakobyan N, Valentino LA, Feldman BL, Samulski RJ, Monahan PE. Intraarticular factor IX protein or gene replacement protects against development of hemophilic synovitis in the absence of circulating factor IX. Blood. 2008;112:4532-4541.
Gui T, Reheman A, Ni H, et al. Abnormal hemostasis in a knock-in mouse carrying a variant of factor IX with impaired binding to collagen type IV. J Thromb Haemost. 2009;7:1843-1851.
Cooley B, Funkhouser W, Monroe D, et al. Prophylactic efficacy of BeneFIX vs Alprolix in hemophilia B mice. Blood. 2016;128:286-292.
Morfini M. Pharmacokinetic drug evaluation of albutrepenonacog alfa (CSL654) for the treatment of hemophilia. Expert Opin Drug Metab Toxicol. 2016;12:1359-1365.
Gill JC, Roberts J, Li Y, Castaman G. Sustained high trough factor IX activity levels with continued use of rIX-FP in adult and paediatric patients with haemophilia B. Haemophilia. 2019;25:e219-e222.