Safety, Stability and Pharmacokinetic Properties of (super)Factor Va, a Novel Engineered Coagulation Factor V for Treatment of Severe Bleeding.

Abstract : Activated (super)Factor V ((super)FVa) is a novel engineered FV with excellent prohemostatic efficacy. (Super)FVa has three APC cleavage site mutations and an interdomain disulfide bond. Stability, pharmacokinetics, and immunogenic and thrombogenic potential are reported here. Stability and circulating half-life were determined after incubation in buffer and human plasma, and after injection into FVIII-deficient mice. Immunogenicity potential was assessed by B- and T-cell specific epitope prediction and structural analysis using surface area and atomic depth computation. Thrombogenic potential was determined by quantification of lung fibrin deposition in wild-type mice after intravenous injection of (super)FVa (200 U/kg), recombinant human (rh) Tissue Factor (0.4-16 pmol/kg), rhFVIIa (3 mg/kg) or saline. FVa retained full activity over 30 h in buffer, the functional half-life in human plasma was 4.9 h, and circulating half-life in FVIII-deficient mice was ~30 min. Predicted immunogenicity was not increased compared to human FV. While rh Tissue Factor, the positive control, resulted in pronounced lung fibrin depositions (mean 121 μg/mL), (super)FVa did not (6.7 μg/mL), and results were comparable to fibrin depositions with rhFVIIa (7.6 μg/mL) or saline (5.6 μg/mL). FVa has an appropriate safety and stability profile for further preclinical development as a prohemostatic against severe bleeding.
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Article dans une revue
Pharmaceutical Research, American Association of Pharmaceutical Scientists, 2016, 33 (6), pp.1517-26. 〈10.1007/s11095-016-1895-3〉
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Soumis le : lundi 4 juillet 2016 - 11:43:53
Dernière modification le : jeudi 11 janvier 2018 - 06:15:24

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Andrew J Gale, Vikas Bhat, Jean-Luc Pellequer, John H Griffin, Laurent O Mosnier, et al.. Safety, Stability and Pharmacokinetic Properties of (super)Factor Va, a Novel Engineered Coagulation Factor V for Treatment of Severe Bleeding.. Pharmaceutical Research, American Association of Pharmaceutical Scientists, 2016, 33 (6), pp.1517-26. 〈10.1007/s11095-016-1895-3〉. 〈hal-01341163〉

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