Abstract Number: PB1160
Meeting: ISTH 2020 Congress
Background: The half-life of FVIII products determines not only injection frequency, but also FVIII trough level and is, therefore, a critical parameter for the treatment burden of hemophilia A patients.
Aims: The development of a novel recombinant FVIII with von-Willebrand-Factor-independent half-life prolongation while maintaining the characteristics of FVIII wild-type after its activation.
Methods: Albumin-binding domains (ABD) were incorporated into a single chain FVIII molecule construct. Human cells were transfected with several FVIII-ABD variants and supernatants were screened for FVIII expression and activity. The most promising FVIII-ABD variants were produced, purified, and investigated for von-Willebrand-Factor binding potency as well as for thrombin-mediated activation. Half-life was assessed by pharmacokinetic studies in hemophilia A mice and in albumin-deficient mice which express the human instead of the murine neonatal Fc receptor. The in vivo functionality was investigated in hemophilia A mice using a tail transection assay determining bleeding time and blood loss after a standardized cut.
Results: The screening of various FVIII-ABD fusion molecules demonstrated good expression and in vitro functionality of several candidates. However, only a few variants extended the in vivo half-life of FVIII significantly. An inverse correlation between half-life extension and binding of FVIII-ABD to von-Willebrand factor was found, indicating the half-life limiting effect of the latter. Finally, a FVIII-ABD variant was selected that exhibited an up to 4-fold longer half-life compared to Moroctocog alfa while retaining full in vivo functionality in terms of efficient stop of bleeding.
Conclusions: A next generation recombinant FVIII molecule with four albumin-binding domains was generated resulting in a half-life extension of up to 4-fold while preserving the wild type characteristics of activated FVIII with full in vivo functionality.
To cite this abstract in AMA style:Kistner S, Daufenbach J, Herbener P, Schüttrumpf J. Raising Factor VIII’s Half-life to the Next Level [abstract]. Res Pract Thromb Haemost. 2020; 4 (Suppl 1). https://abstracts.isth.org/abstract/raising-factor-viiis-half-life-to-the-next-level/. Accessed September 21, 2023.
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