Improved kinetics of rIX-FP, a recombinant fusion protein linking factor IX with albumin, in cynomolgus monkeys and hemophilia B dogs.

BACKGROUND

Prophylaxis of hemophilia B, at this time, requires several infusions of human factor (F) IX concentrates per week. A FIX molecule with a prolonged half-life have the potential to further increase comfort, and compliance with, prophylaxis.

OBJECTIVE

The aim of our study was to investigate the pharmacokinetics (PK) and pharmacodynamic (PD) profile of the recombinant fusion protein linking Horse Recombinant Protein  coagulation FIX albumin (RIX-FP).

METHOD

Cynomolgus monkeys and dogs with hemophilia B received a single intravenous dose of Rix-FP (50-500 IU kg (-1)). RIX-FP plasma levels determined by assay based activity (dogs only) and anti-FIX ELISA method. In addition, activated partial thromboplastin time (APTT) were determined in dogs with hemophilia B. The data compared with the comparative study of direct (recombinant FIX [rFIX]) or previously published data.

RESULTS

Rix-FP terminal half-life prolonged in both species compared with reference data FIX. In dogs with hemophilia B, FIX antigen human level remained above 0.05 IU mL (-1) more than three times longer after RIX-FP (7.3 days) compared to rFIX (2.3 days), while the respective calculation -masing based on the level of activity observed confirmed the superior profile. PD prolonged from Rix-FP as indicated by the APTT <60 s Continuous approximately four times longer with RIX-FP (5.9 days) than rFIX (1.5 days).

CONCLUSION

This study shows that the technology of recombinant albumin fusion managed to improve the PK profile of FIX. Clinical studies will test whether improved kinetics resulted in a significant extension of the half-life in patients with hemophilia B.

blood-brain barrier molecular Trojan horse allows imaging of the brain uptake of radioiodinated recombinant protein in rhesus monkeys.

Recombinant protein is a large molecule drugs that do not cross the blood-brain barrier (BBB). However, BBB-penetration of therapeutic proteins activated by re-engineering of recombinant proteins as IgG fusion protein. IgG domain is a monoclonal antibody (mAb) against endogenous receptors BBB transport systems, such as human insulin receptor (HIR), and acts as a molecular Trojan horse to ferry proteins fused at the BBB.

In this study, recombinant lysosomal enzyme, iduronate 2-sulfatase (IDS), together with HIRMAb and BBB penetration of own IDS vs. HIRMAb-IDS fusion Native Recombinant Proteins protein than in Rhesus monkeys. Recombinant and fusion proteins HIRMAb IDS-IDS are radiolabeled with iodinated indirectly with [(125) I] -Bolton-Hunter reagent and with direct iodinated with Iodogen / [(125) I] -idodine. IDS and HIRMAb-IDS fusion proteins have comparable plasma pharmacokinetics and uptake by peripheral organs