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Conjugated blood coagulation factor viii

A kind of FVIII, the technology of conjugation, is applied in the field of coagulation factor VIII of conjugated form

Inactive Publication Date: 2013-02-20
CANTAB BIOPHARMACEUTICALS PATENT LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] Thus, PEGylation of Factor FVIII presents some unique and different challenges than FIX

Method used

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  • Conjugated blood coagulation factor viii
  • Conjugated blood coagulation factor viii
  • Conjugated blood coagulation factor viii

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0131] Example 1: Disulfide PEGylation of FVIII

[0132] Disulfide pegylation of human FVIII was performed according to a modified version of the procedure described by Shaunak et al. in Nat Chem Biol. 2006;2(6):312-313.

Embodiment 2

[0133] Example 2: Reduction of disulfide bonds

[0134] TheraPEG TM The PEGylation process requires the reduction of disulfide bonds. Using a suitable reducing agent such as dithiothreitol (DTT), 2-mercaptoethanol or tris(2-carboxyethyl)phosphine (TCEP), in the presence or absence of selenocystamine (SeCys) For reduction, the concentration of reducing agent used is, for example, 0.5-5 mm DTT or TCEP in low molar excess.

Embodiment 3

[0135] Example 3: PEGylation of FVIII

[0136] TheraPEG for PEGylation of FVIII in small scale reactions (e.g. 5-20 μg of FVIII) TM use for a preliminary assessment. This can help identify conditions under which PEGylated FVIII can be reproducibly prepared using the PEG reactant. Benzamidine or other excipients may be added to prevent proteolysis or to promote protein stabilization.

[0137] Scale up the reaction (eg, 0.2-0.32 mg of FVIII) to produce PEGylated FVIII for initial in vitro testing. A series of PEG-FVIII samples with different PEG molecular weights (eg, 10, 20, and 30 kDa) and different numbers of conjugated PEG moieties (eg, 1-8) were prepared for in vitro analysis.

[0138] The effect of temperature on the PEGylation reaction can be assessed to determine whether temperature affects the conversion of FVIII to PEG-FVIII. However, if preliminary in vitro assessments indicate that higher temperatures (eg, 10-30°C) negatively affect the activity of the pegylate...

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Abstract

The present invention provides a biocompatible polymer conjugated to FVIII via one or more cysteine residues, suitably via a linker across a reduced disulphide bond in FVIII, and pharmaceutical compositions comprising such conjugated forms of FVIII.

Description

technical field [0001] The present invention relates to factor VIII in conjugated form. Background technique [0002] Factor VIII (FVIII) is an essential clotting factor also known as antihemophilic factor (AHF). In humans, Factor VIII is encoded by the F8 gene. Defects in this gene cause hemophilia A, a well-known recessive X-linked blood clotting disorder that affects about 1 in 5,000 males. [0003] The X-chromosome-linked F8 gene encodes a polypeptide of 2351 amino acids from 26 exons, which forms a mature FVIII molecule of 2332 amino acids after being cleaved from the signal peptide (Wang et al.Int.J.Pharmaceutics, 259:1-15 (2003)). It has been found that FVIII is synthesized and released into the blood by vascular cells, glomerular cells, tubular endothelium cells and sinusoidal cells of the liver, but the initial release of FVIII in the human body is Where the point is is still highly debated. The FVIII molecule consists of six protein domains; NH 2 -A1-A2-B-A3-...

Claims

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Application Information

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IPC IPC(8): A61K47/48A61P7/04A61K38/37
CPCA61K47/48215A61K38/37C07K14/755A61K45/06A61K47/60A61P7/00A61P7/04A61K9/0019A61K9/0021A61K2300/00
Inventor W·亨利
Owner CANTAB BIOPHARMACEUTICALS PATENT LTD
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