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

Author

Listed:
  • Kristin Hovden Aaen

    (University of Oslo
    Oslo University Hospital Rikshospitalet
    University of Oslo)

  • Maria Francesca Testa

    (University of Ferrara)

  • Jeannette Nilsen

    (University of Oslo
    Oslo University Hospital Rikshospitalet
    University of Oslo)

  • Rebecca Tarantino

    (University of Ferrara)

  • Cesare Canepari

    (IRCCS San Raffaele Scientific Institute
    Vita-Salute San Raffaele University)

  • Mascia Benedusi

    (University of Ferrara)

  • Sopisa Benjakul

    (University of Oslo
    Oslo University Hospital Rikshospitalet
    University of Oslo)

  • Mari Nyquist-Andersen

    (University of Oslo
    Oslo University Hospital Rikshospitalet
    University of Oslo)

  • Marie Leangen Herigstad

    (University of Oslo
    Oslo University Hospital Rikshospitalet
    University of Oslo)

  • Alessio Cantore

    (IRCCS San Raffaele Scientific Institute
    Vita-Salute San Raffaele University)

  • Giuseppe Valacchi

    (University of Ferrara
    NC State University
    Kyung Hee University)

  • Inger Sandlie

    (University of Oslo)

  • Francesco Bernardi

    (University of Ferrara)

  • Mirko Pinotti

    (University of Ferrara)

  • Alessio Branchini

    (University of Ferrara)

  • Jan Terje Andersen

    (University of Oslo
    Oslo University Hospital Rikshospitalet
    University of Oslo)

Abstract

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.

Suggested Citation

  • Kristin Hovden Aaen & Maria Francesca Testa & Jeannette Nilsen & Rebecca Tarantino & Cesare Canepari & Mascia Benedusi & Sopisa Benjakul & Mari Nyquist-Andersen & Marie Leangen Herigstad & Alessio Can, 2025. "Tailored collagen binding of albumin-fused hyperactive coagulation factor IX dictates in vivo distribution and functional properties," Nature Communications, Nature, vol. 16(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-62955-9
    DOI: 10.1038/s41467-025-62955-9
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