Characterization of recombinant factor IX fusion proteins enabling subcutaneous administration.
J Thromb Haemost
; 22(10): 2713-2723, 2024 Oct.
Article
en En
| MEDLINE
| ID: mdl-39019440
ABSTRACT
BACKGROUND:
The X-linked bleeding disorder hemophilia B, caused by mutation(s) in the coagulation factor (F)IX gene, leads to partial or total loss of its function, requiring lifelong FIX replacement therapy. Although new recombinant FIX (rIX) therapeutics like albumin fusion proteins (rIX-FP) enable longer plasma half-life and thus less frequent administration, the complexity of intravenous (i.v.) injection remains.OBJECTIVES:
The study aimed to characterize rIX-FP variants with anticipated enhanced specific activity, which would leverage rIX-FP's superior pharmacokinetic profile with beneficial characteristics for subcutaneous (s.c.) administration.METHODS:
Two rIX-FP variants, R338L ("Padua variant") and R338L/E410K, were characterized in vitro. Pharmacokinetic profiles of FIX antigen and activity levels were evaluated in FIX-deficient mice after i.v. and s.c. administration of these variants (dosing based on antigen levels). The efficacy of the most promising variant was tested after i.v. and s.c. administration (dosing based on activity) in a tail clip bleeding model. A marketed wild-type (WT) rIX-FP product served as the comparator.RESULTS:
Both rIX-FP variants showed a 4- to 5-fold increase in specific activity in vitro compared with rIX(WT)-FP, while FXIa-mediated activation was the fastest for rIX(WT)-FP and rIX(R338L)-FP. Compared with rIX(WT)-FP and rIX(R338L/E410K)-FP, rIX(R338L)-FP exhibited higher FIX activity exposure after i.v. and s.c. administration and demonstrated comparable efficacy with rIX(WT)-FP in reducing bleeding time and blood loss in FIX-deficient mice requiring â¼4 times lower protein amount.CONCLUSION:
rIX(R338L)-FP was shown to be a promising candidate for s.c. administration, exhibiting increased specific activity combined with higher activity-based exposure and indicating efficacy at a lower protein dose.Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Proteínas Recombinantes de Fusión
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Factor IX
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Hemofilia B
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Hemorragia
Límite:
Animals
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Humans
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Male
Idioma:
En
Revista:
J Thromb Haemost
Asunto de la revista:
HEMATOLOGIA
Año:
2024
Tipo del documento:
Article
País de afiliación:
Alemania
Pais de publicación:
Reino Unido