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

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 () and Jan Terje Andersen ()
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Kristin Hovden Aaen: University of Oslo
Maria Francesca Testa: University of Ferrara
Jeannette Nilsen: University of Oslo
Rebecca Tarantino: University of Ferrara
Cesare Canepari: IRCCS San Raffaele Scientific Institute
Mascia Benedusi: University of Ferrara
Sopisa Benjakul: University of Oslo
Mari Nyquist-Andersen: University of Oslo
Marie Leangen Herigstad: University of Oslo
Alessio Cantore: IRCCS San Raffaele Scientific Institute
Giuseppe Valacchi: University of Ferrara
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

Nature Communications, 2025, vol. 16, issue 1, 1-15

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-62955-9

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