Journal Article

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

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

2025

Overview

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 QMP ) 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 QMP engineering, respectively, was confirmed. In HB mice, Padua KA -HSA QMP exhibited negligible extravascular distribution and the highest plasma levels at early time points followed by the steepest decay. Conversely, Padua KR -HSA QMP showed increased extravascular distribution and a 3-fold longer functional half-life (80 hours). These findings support the use of Padua KA -HSA QMP and Padua KR -HSA QMP as hyperactive short- or long-term therapeutics, respectively, with opportunities for tailored HB replacement therapy. Coagulation factor IX (FIX) contributes to hemostasis through both plasma activity and binding to extravascular collagen IV. Here, the authors show that collagen binding of albumin-fused hyperactive FIX can be engineered to tailor the pharmacokinetics, distribution, and functional properties in mice for tailored short- or long-term hemophilia B therapy.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/1 / 13/109 / 13/51 / 14/34 / 631/45/612/1221 / 631/45/612/1222 / 631/61/338/469 / 631/61/51/2314 / 64/60 / 82/103 / 82/29 / 82/80 / 82/83 / 96 / Amino acids / Animals / Binding / Coagulation / Coagulation factor IX / Coagulation factors / Collagen / Collagen (type IV) / Collagen - metabolism / Collagen Type IV - metabolism / Engineering / Factor IX - genetics / Factor IX - metabolism / Factor IX - pharmacokinetics / Factor IX deficiency / Fc receptors / Half-Life / Hemophilia / Hemophilia B - blood / Hemophilia B - genetics / Hemophilia B - metabolism / Hemophilia B - therapy / Hemostasis / Hemostatics / Histocompatibility Antigens Class I - genetics / Histocompatibility Antigens Class I - metabolism / Human serum albumin / Humanities and Social Sciences / Humans / Male / Mice / Mice, Inbred C57BL / multidisciplinary / Neonates / Pharmacokinetics / Plasma / Plasma levels / Protein Binding / Protein Engineering / Proteins / Receptors, Fc - genetics / Receptors, Fc - metabolism / Recombinant Fusion Proteins - genetics / Recombinant Fusion Proteins - metabolism / Recombinant Fusion Proteins - pharmacokinetics / Science / Science (multidisciplinary) / Serum albumin / Serum Albumin, Human - genetics / Serum Albumin, Human - metabolism / Therapy