Large‐scale production and properties of human plasma‐derived activated Factor VII concentrate

Tomokiyo, Kazuhiko; Yano, Hiroyuki; Imamura, M.; Nakano, Yoshiaki; Nakagaki, Tomohiro; Ogata, Youichi; Terano, Tsuyoshi; Miyamoto, Seiji; Funatsu, Asami

doi:10.1046/j.1423-0410.2003.00247.x

Cited by 23 publications

(9 citation statements)

References 27 publications

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“…Its activated form (hFVIIa) is used to control bleeding episodes in patients affected by haemophilia A or B with circulating inhibitory antibodies against FVIII or FIX (Brinkhous et al 1989; Lusher et al 1998). Currently, the available sources of hFVIIa either come from plasma concentrates (Tomokiyo et al 2003) or are derived from the recombinant technology (Hedner and Lee 2011). Today, the only recombinant human FVIIa (rhFVIIa) available is NovoSeven ® (rhFVIIa; Eptacog alfa; Novo Nordisk, Copenhagen, Denmark), which is produced in baby hamster kidney (BHK) cells that are cultured in the presence of newborn calf serum.…”

Section: Introductionmentioning

confidence: 99%

N-/O-glycosylation analysis of human FVIIa produced in the milk of transgenic rabbits

et al. 2013

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Human coagulation factor VIIa is a glycoprotein that promotes haemostasis through activation of the coagulation cascade extrinsic pathway. Most haemophilia A/B patients with inhibitors are treated by injection of plasma-derived or recombinant FVIIa. The use of recombinant products raises questions about the ability of the host cell to produce efficiently post-translationally modified proteins. Glycosylation is especially critical considering that it can modulate protein safety and efficacy. The present paper reports the N-/O-glycosylation pattern of a new recombinant human factor VIIa expressed in the mammary glands of transgenic rabbits. Glycosylation was investigated by chromatography and advanced mass spectrometry techniques for glycan identification and quantitation. Mass spectrometry (MS)/MS analyses were performed to confirm the glycan structures as well as the position and branching of specific monosaccharides or substituents. The two N-glycosylation sites were found to be fully occupied mostly by mono- and bi-sialylated biantennary complex-type structures, the major form being A2G2S1. Some oligomannose/hybrid structures were retrieved in lower abundance, the major ones being GlcNAcα1,O-phosphorylated at the C6-position of a Man residue (Man-6-(GlcNAcα1,O-)phosphate motif) as commonly observed on lysosomal proteins. No immunogenic glycotopes such as Galili (Galα1,3Gal) and HD antigens (N-glycolylneuraminic acid (NeuGc)) were detected. Concerning O-glycosylation, the product exhibited O-fucose and O-glucose-(xylose)0, 1, 2 motifs as expected. The N-glycosylation consistency was also investigated by varying production parameters such as the period of lactation, the number of consecutive lactations and rabbit generations. Results show that the transgenesis technology is suitable for the long-term production of rhFVIIa with a reproducible glycosylation pattern.

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Section: Introductionmentioning

confidence: 99%

N-/O-glycosylation analysis of human FVIIa produced in the milk of transgenic rabbits

et al. 2013

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“…In the production of plasma-derived FVIIa, FVII is converted to FVIIa with the following two steps to achieve high recovery and quality: (1) partial activation on anion exchange resin and, (2) further activation in the solution after eluting from the resin [46]. A flow diagram of the preparation of MC710 is shown in Fig.…”

Section: Fig 1 Advantage Of Co-administration Of Fviia and Fxmentioning

confidence: 99%

Prospective Efficacy and Safety of a Novel Bypassing Agent, FVIIa/FX Mixture (MC710) for Hemophilia Patients with Inhibitors

Tomokiyo¹,

Nakatomi²,

Hamamoto³

et al. 2012

Hemophilia

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“…87 Bivalirudin (Angiomax) started life as hirugen 88 with Biogen and is currently a product of The Medicines Company. [127][128][129][130][131][132][133][134][135][136][137] Another complication is provided by the intrinsic catalytic activity Downloaded by [New York University (NYU)] at 10:11 11 September 2016 of the zymogen (factor VII) form, *,138 resulting in the observation of relatively small increases in activity on activation. [89][90][91][92][93] Factor VII (proconvertin) was first described by Alexander and coworkers.…”

Section: Vitamin K-dependent Proteinsmentioning

confidence: 99%

- Plasma Immunoglobulins

2012

Biotechnology of Plasma Proteins

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Large‐scale production and properties of human plasma‐derived activated Factor VII concentrate

Abstract: We established a large-scale manufacturing process of human plasma-derived FVIIa concentrate with a high yield, making it possible to provide sufficient FVIIa concentrate for use in haemophiliacs with inhibitory antibodies.

Cited by 23 publications

References 27 publications

N-/O-glycosylation analysis of human FVIIa produced in the milk of transgenic rabbits

N-/O-glycosylation analysis of human FVIIa produced in the milk of transgenic rabbits

Prospective Efficacy and Safety of a Novel Bypassing Agent, FVIIa/FX Mixture (MC710) for Hemophilia Patients with Inhibitors

- Plasma Immunoglobulins

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