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Glycopegylated factor IX

A polyethylene glycol, factor technology, applied in the production of these factor IX peptides, the field of manufacturing PEGylated factor IX comprising the above-mentioned parts, can solve the problems of lack of final product homogeneity, reduction of peptide biology or enzymatic activity, etc.

Inactive Publication Date: 2011-02-09
NOVO NORDISK AS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Of course, the random addition of PEG has its drawbacks, including lack of final product homogeneity, and possible reduction in biological or enzymatic activity of the peptide

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0449] Preparation of UDP-GalNAc-6'-CHO

[0450] Dissolve UDP-GalNAc (200 mg, 0.30 mmole) in 1 mM CuSO 4 solution (20mL) and 25mM NaH 2 PO 4 solution (pH 6.0, 20 mL). Then galactose oxidase (240 U, ​​240 μL) and catalase (13000 U, 130 μL) were added, and the reaction system was assembled with an oxygen-filled balloon and stirred at room temperature for seven days. The reaction mixture was then filtered (centrifuge tube, MWCO 5K) and the filtrate (-40 mL) was stored at 4°C until use. TLC (silica; ethanol / water (7 / 2); R f =0.77; visualization of anisaldehyde staining).

Embodiment 2

[0452] Preparation of UDP-GaINAc-6'-NH 2

[0453] To the above UDP-GalNAc-6'-CHO solution (2 mL or ~20 mg) was added ammonium acetate (15 mg, 0.194 mmole) and NaBH at 0 °C 3 CN (1M in THF; 0.17 mL, 0.17 mmole) and incubated overnight at room temperature. The reaction was filtered through an aqueous G-10 cartridge and the product was collected. Appropriate fractions were lyophilized and stored frozen. TLC (silica; ethanol / water (7 / 2); R f =0.72; developed by ninhydrin staining).

Embodiment 3

[0455] Preparation of UDP-Ga I NAc-6-NHCO(CH 2 ) 2 -O-PEG-OMe(1KDa)

[0456] Galactosylamino-1-phosphate-2-NHCO (CH 2 ) 2 -O-PEG-OMe (1 KDa) (58 mg, 0.045 mmole) was dissolved in DMF (6 mL) and pyridine (1.2 mL). Then UMP-morpholidate (60 mg, 0.15 mmole) was added and the resulting mixture was stirred at 70°C for 48 hours. The solvent was removed by bubbling nitrogen through the reaction mixture and the residue was purified by reverse phase chromatography (C-18 silica, step gradient between 10 and 80%, methanol / water). The desired fractions were collected and dried under reduced pressure to obtain 50 mg (70%) of a white solid. TLC (silica, propanol / H 2 O / NH 4 OH, (30 / 20 / 2), Rf = 0.54). MS (MALDI): 1485, 1529, 1618, 1706 observed.

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Abstract

The present invention provides conjugates between Factor IX and PEG moieties. The conjugates are linked via an intact glycosyl linking group interposed between and covalently attached to the peptide and the modifying group. The conjugates are formed from glycosylated peptides by the action of a glycosyltransferase. The glycosyltransferase ligates a modified sugar moiety onto a glycosyl residue onthe peptide. Also provided are methods for preparing the conjugates, methods for treating various disease conditions with the conjugates, and pharmaceutical formulations including the conjugates.

Description

[0001] Cross-reference with related applications [0002] This application claims priority to the following applications: U.S. Provisional Patent Application No. 60 / 527,089 (filed December 3, 2003, which is hereby incorporated by reference in its entirety for all purposes); U.S. Provisional Patent Application No. 60 / 539,387 (filed January 26, 2004); U.S. Provisional Patent Application No. 60 / 592,744 (filed July 29, 2004); U.S. Provisional Patent Application No. 60 / 614,518 (filed September 29, 2004); and U.S. Provisional Patent Application No. 60 / 623,387 (filed October 29, 2004), each of which is incorporated herein by reference in its entirety for all purposes. Background of the invention [0003] Vitamin K-dependent proteins such as Factor IX contain 9 to 13 gamma-carboxyglutamic acid residues (Gla) in their amino-terminal 45 residues. Gla residues are generated by enzymes in the liver that utilize vitamin K to carboxylate the side chains of glutamic acid residues in protein...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K38/00A61K31/00C07K1/00A61P7/02
Inventor S·德弗利斯R·J·拜尔C·鲍K·潘尼尔瑟瓦姆
Owner NOVO NORDISK AS
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