Tailored collagen binding of albumin-fused hyperactive coagulation factor IX dictates in vivo distribution and functional properties.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 41022699.
- Also identified by DOI 10.1038/s41467-025-62955-9 and PMC identifier 12480940.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
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 (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.
Medical subject headings
- Factor IX
- Hemophilia B
- Serum Albumin, Human
- Recombinant Fusion Proteins
- Collagen Type IV
- Collagen