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<p>The efficacy of hemophilia B (HB) replacement therapy is evaluated by coagulation factor IX (FIX) activity in plasma, although FIX bound to extravascular type IV collagen (Col4) also contributes to efficient hemostasis. Here, we investigated the impact of engineering FIX for improved (K5R) or reduced (K5A) Col4 binding on the pharmacokinetic properties of FIX Padua, fused to human serum albumin (HSA<sub>QMP</sub>) engineered for favorable neonatal Fc receptor (FcRn) engagement. Hyperactive features and extended plasma half-life in human FcRn expressing mice, attributed to FIX Padua and HSA<sub>QMP</sub> engineering, respectively, was confirmed. In HB mice, Padua<sub>KA</sub>-HSA<sub>QMP</sub> exhibited negligible extravascular distribution and the highest plasma levels at early time points followed by the steepest decay. Conversely, Padua<sub>KR</sub>-HSA<sub>QMP</sub> showed increased extravascular distribution and a 3-fold longer functional half-life (80 hours). These findings support the use of Padua<sub>KA</sub>-HSA<sub>QMP</sub> and Padua<sub>KR</sub>-HSA<sub>QMP</sub> as hyperactive short- or long-term therapeutics, respectively, with opportunities for tailored HB replacement therapy.</p>

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Tailored collagen binding of albumin-fused hyperactive coagulation factor IX dictates in vivo distribution and functional properties

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年9月29日

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  • Kristin Hovden Aaen,
  • Maria Francesca Testa,
  • Jeannette Nilsen,
  • Rebecca Tarantino,
  • Cesare Canepari,
  • Mascia Benedusi,
  • Sopisa Benjakul,
  • Mari Nyquist-Andersen,
  • Marie Leangen Herigstad,
  • Alessio Cantore,
  • Giuseppe Valacchi,
  • Inger Sandlie,
  • Francesco Bernardi,
  • Mirko Pinotti,
  • Alessio Branchini,
  • Jan Terje Andersen

摘要

The efficacy of hemophilia B (HB) replacement therapy is evaluated by coagulation factor IX (FIX) activity in plasma, although FIX bound to extravascular type IV collagen (Col4) also contributes to efficient hemostasis. Here, we investigated the impact of engineering FIX for improved (K5R) or reduced (K5A) Col4 binding on the pharmacokinetic properties of FIX Padua, fused to human serum albumin (HSAQMP) engineered for favorable neonatal Fc receptor (FcRn) engagement. Hyperactive features and extended plasma half-life in human FcRn expressing mice, attributed to FIX Padua and HSAQMP engineering, respectively, was confirmed. In HB mice, PaduaKA-HSAQMP exhibited negligible extravascular distribution and the highest plasma levels at early time points followed by the steepest decay. Conversely, PaduaKR-HSAQMP showed increased extravascular distribution and a 3-fold longer functional half-life (80 hours). These findings support the use of PaduaKA-HSAQMP and PaduaKR-HSAQMP as hyperactive short- or long-term therapeutics, respectively, with opportunities for tailored HB replacement therapy.