Pharmacological characteristics of a novel, recombinant fusion protein linking coagulation factor VIIa with albumin (rVIIa‐FP)

Abstract

BackgroundRecombinant factor VIIa (rFVIIa) is approved for use in controlling bleeding episodes in people with hemophilia who have developed inhibitors to replacement therapy. Due to its short half-life (t½), frequent injections are required, limiting its use as a prophylactic treatment. A novel, recombinant fusion protein linking coagulation factor VIIa with albumin (rVIIa-FP) has been developed to extend the t½ of rFVIIa.ObjectivesThe aim of our studies was to investigate the pharmacokinetic/pharmacodynamic characteristics of rVIIa-FP in preclinical animal species.MethodsPharmacokinetic (PK) parameters were derived after single intravenous dosing in hemophilia A mice, rats, rabbits and monkeys. PK analysis was based on human FVII plasma levels determined by measuring FVII antigen levels by ELISA in mice and rats, and FVIIa activity using STACLOT® VIIa-rTF in rabbits and monkeys. Induction of thrombin generation was investigated in mice, while hemostatic activity was assessed by thrombus formation in rabbits.ResultsCompared with rFVIIa, rVIIa-FP displayed a prolonged t½, enhanced in vivo recovery and reduced clearance in all species investigated. In mice, 16 h after treatment with rVIIa-FP, thrombin levels were quantifiable, indicating prolonged efficacy, whereas values had approached baseline at this time after treatment with rFVIIa. After 12 h, hemostatic efficacy was negligible in rFVIIa-treated rabbits, but sustained in animals receiving rVIIa-FP.ConclusionsThese studies indicate that the longer t½ of rVIIa-FP compared with rFVIIa translates into extended activity. These findings suggest that rVIIa-FP has the potential to be administered less frequently than rFVIIa-containing concentrates in clinical use.

Fc-based half-life extension of human FVIIa – a new player for hemophilia treatment?

“…However, similar data in mice also exist with CSL-Behring's FVIIa-FP [5]. Moreover, using a venous stasis model in rabbits, FVIIa-FP administration resulted in a greater thrombus size 12 hours after protein administration vs. that of rFVIIa [6]. Moreover, using a venous stasis model in rabbits, FVIIa-FP administration resulted in a greater thrombus size 12 hours after protein administration vs. that of rFVIIa [6].…”

“…However, similar data in mice also exist with CSL-Behring's FVIIa-FP [5]. However, similar data in mice also exist with CSL-Behring's FVIIa-FP [5].…”

T Cells Expressing CD19/CD20 Bispecific Chimeric Antigen Receptors Prevent Antigen Escape by Malignant B Cells

“…However, almost all of the components utilized in the OR-gate CARs presented in this study have been tested in the clinic, including the two scFv domains, the long and short extracellular spacers, as well as the transmembrane and cytoplasmic signaling domains (3–5, 7, 8, 39). Long, flexible linker peptides consisting of glycine and serine residues have been utilized in fusion peptides such as rVIIa-FP, which is in clinical trial (40, 41). It remains possible that rigid peptide linkers or new combinations of previously tested peptide components could result in immunogenicity.…”

The role of albumin receptors in regulation of albumin homeostasis: Implications for drug delivery

“…Another example is recombinant FVIIa (NovoSeven ® ) with a half-life of only 2.4 hours in humans [253]. After fusion to the Nterminal end of human albumin, separated with a flexible glycine serine linker, the half-life increases up to 4-fold , and the fusion is now in clinical trials for treatment of haemophilia [251][252][253][254][255]. This strategy has also been chosen for coagulation factor IX [248][249][250].…”

“…Examples include hirudin [256], CD4 [258], insulin [260], growth hormone [259], granulocyte colony stimulating factor [244],  and  interferons [245][246][247], thioredoxin [266,267], coagulation factors [248][249][250][251][252][253][254][255] and antibody fragments [204,[261][262][263]268]. An illustrating example is recombinant interferon 2b used for treatment of chronic hepatitis C with only a half-life of 4 hours in humans, however, upon genetic fusion to human albumin the half-life increases by 35-fold to 141 hours [246].…”