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Factor VII glycoforms

A factor and serum technology, applied in coagulation/fibrinolytic factors, blood diseases, genetic engineering, etc., can solve problems such as differences

Inactive Publication Date: 2012-11-07
NOVO NORDISK AS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

These modifications may differ qualitatively or quantitatively when heterologous cells are used as hosts to produce large quantities of the protein

Method used

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  • Factor VII glycoforms
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Examples

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preparation example Construction

[0119] Method: The present invention relates to a method for preparing a preparation comprising any one of the above-mentioned (i)-(vi) glycosyl patterns, and in a further embodiment, the present invention relates to making coagulation factor VII and coagulation factor VII-related polypeptides A method for optimizing the glycotype distribution of . These methods include the following steps:

[0120] (a) cultivating cells capable of expressing coagulation factor VII or coagulation factor VII-related polypeptides under a first set of predetermined culture conditions;

[0121] (b) recovering coagulation factor VII or coagulation factor VII-related polypeptides from the above culture to obtain preparations comprising these polypeptides; and

[0122] (c) analyzing the structure of the oligosaccharides linked to these polypeptides to determine the glycosylation pattern.

[0123] The method also includes:

[0124] (d1) changing the culture conditions of step (a) to obtain a second...

Embodiment 1

[0161] Example 1: Preparation and Analysis of Factor VII Preparations with Altered Glycotype Patterns

[0162] Factor VII preparations with altered glycoform patterns were prepared using the following experiment.

[0163] I. Preparation: A BHK cell line transformed with a plasmid encoding Factor VII was adapted to grow in suspension culture in the absence of serum. The cells were continuously passaged in a spinner culture, and the volume gradually increased due to the addition of new medium as the number of cells increased.

[0164] Finally, 6L of the seed culture was inoculated into a 100-liter preparative reactor containing a large-pore Cytopore 1 carrier (Pharmacia), on which the suspension cells were thus immobilized. Cultures were maintained at 36°C, pH 6.7-6.9 and 50% DO. As the number of cells increases, the volume in the preparative reactor gradually increases due to the addition of new medium. When the cell density reaches about 2×10 6 Cells / ml, start to enter t...

Embodiment 2

[0179] Example 2: Analysis of Factor VII Preparations with Altered Glycotype Patterns

[0180] Factor VII was prepared as described in Example 1 except that Factor VII was harvested from the 500-l culture. Glycotype analysis was performed as described in Example 1. Three different formulations (A, B, and C) were analyzed and compared to a reference formulation (D).

[0181]Bioavailability was determined in a canine model as follows: 12 Beagle dogs were divided into 4 groups for a four-limb crossover study. Each animal was dosed with test formulation A, B, or C, or reference formulation D, at a dose of approximately 90 μg / kg in N-glycylglycine buffer (pH 5.5) containing Sodium (2.92mg / ml), Calcium Chloride Dihydrate (1.47mg / ml), Mannitol (30mg / ml) and Polysorbate 80. Blood samples were taken at 10, 30, and 60 minutes and at 2, 3, 4, 6, and 8 hours post-dose. Plasma was obtained from these blood samples and factor VII was quantified by ELISA.

[0182] The bioavailability ...

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Abstract

The present invention provides preparations of Factor VIIa polypeptides or Factor VIIa-related polypeptides that exhibit predetermined glycoform patterns. The preparations of the invention exhibit improved functional properties and are useful for treating Factor VII-mediated conditions.

Description

[0001] This application is a divisional application of an invention application with a filing date of October 2, 2001, a Chinese application number of 01816746.2, and an invention title of "glycosylated coagulation factor VII". technical field [0002] The present invention relates to compositions comprising Factor VII as well as other coagulation factors having altered asparagine-linked glycosylation patterns. Background technique [0003] Proteins involved in the coagulation cascade include, for example, factor VII, factor VIII, factor IX, factor X, and protein C, all of which have been shown to be effective therapeutic agents for the treatment of various conditions. Therefore, there is a growing need for a single form of pharmaceutically acceptable formulation comprising these proteins with predetermined clinical efficacy. [0004] Due to the disadvantages of using human plasma as a source of pharmaceutical products, it is preferred to produce these proteins in recombinan...

Claims

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Application Information

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IPC IPC(8): C12P21/00C07K19/00A61K38/36A61P7/04C12R1/91C12N15/09A61K38/00A61K38/48C07K14/47C07K14/745C12N1/15C12N1/19C12N5/10C12N9/64C12N15/12C12P21/02C12Q1/02
CPCY10S514/802C12N9/6437G01N2400/02A61K38/4846C12Y304/21021C12P21/02Y10S514/834A61K38/00A61P7/04A61K38/16
Inventor 汉斯.K.平格尔尼尔斯.K.克劳森
Owner NOVO NORDISK AS
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