Hamostaseologie 2021; 41(S 01): S46-S47
DOI: 10.1055/s-0041-1728190
Poster
Hereditary bleeding disorders

Characterization of rFIX fusion proteins enabling subcutaneous administration

K Schön
1   R&D, CSL Behring GmbH, Marburg
,
J Riedesel
1   R&D, CSL Behring GmbH, Marburg
,
W Seyfert-Brandt
1   R&D, CSL Behring GmbH, Marburg
,
M Mischnik
1   R&D, CSL Behring GmbH, Marburg
,
S Pestel
1   R&D, CSL Behring GmbH, Marburg
,
W Azar
2   R&D, CSL Behring GmbH, Victoria
,
C Hardy
2   R&D, CSL Behring GmbH, Victoria
,
MW Nolte
1   R&D, CSL Behring GmbH, Marburg
,
P Claar
1   R&D, CSL Behring GmbH, Marburg
› Institutsangaben
 
 

    Objective The recessive X-linked bleeding disorder Hemophilia B is caused by a mutation in the coagulation factor (F) IX gene leading to partial or total loss of its function. Although new recombinant FIX therapeutics like the albumin-fusion protein rIX-FP (IDELVION®) enable longer half-life in circulation and thus less frequent administration, the complexity of intravenous (IV) injection affects patients’ quality of life. Therefore, this project focused on the characterization of rIX-FP-variants with anticipated enhanced specific activity, that would combine rIX-FP’s superior pharmacokinetic (PK) profile with that of subcutaneous (SC) administration.

    Material and Methods Three different rIX-FP-variants were generated via mutation on the respective amino acid positions: R338L (“Padua mutant”), R338L + E410K or R318Y + T343R + R338E. The resulting rIX-FP-variants were subsequently recombinantly produced, purified and further characterized in vitro. PK profiles of selected variants were evaluated in FIX-deficient mice after SC administration based on antigen levels. Efficacy of the most promising variant was finally tested after activity-based IV dosing in a tail-clip bleeding assay. Data were compared to the marketed wildtype (WT) rIX-FP product.

    Results All three rIX-FP-variants showed increased specific activity in vitro compared to WT rIX-FP (4 to 5-fold), whilst FXIa-mediated activation was the fastest for rIX-FP(R338L) and WT rIX-FP. rIX-FP(R338L) furthermore exhibited a favorable PK profile compared to WT rIX-FP (i.e. comparable area under the curve (AUC0-inf) based on antigen values but 7.2-fold higher AUC0-inf based on activity values). Compared to untreated FIX-deficient mice, it moreover demonstrated significantly reduced bleeding time and total blood loss, whilst efficacy was comparable to the marketed WT rIX-FP. The double and triple rIX-FP-variants were excluded from complete in vivo testing due to an inferior PK profile and internal depriorization, respectively.

    Conclusion rIX-FP(R338L) demonstrated an increased specific activity combined with a favorable activity-based PK profile. Subsequently, comparable efficacy to the marketed rIX-FP product could be achieved at one sixth of the antigen dose. Hence, rIX-FP(R338L) could be a promising option for SC administration in hemophilia B patients, reducing the burden of IV dosing.


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    Publikationsverlauf

    Artikel online veröffentlicht:
    18. Juni 2021

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