Deamidated interferon-beta

一种脱酰胺基、干扰素的技术，应用在生物学活性蛋白质化学领域

Inactive Publication Date: 2007-10-17
CHIRON CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] The present invention addresses these needs by deamidating interferon-beta

Method used

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  • Deamidated interferon-beta
  • Deamidated interferon-beta
  • Deamidated interferon-beta

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0050] Example 1: Elevated potency of IFN-β1b stability samples without HA

[0051] overview

[0052] Increased potency was observed in IFN-β1b stability samples without HA. The cytopathic effect (CPE) bioassay showed an increase in potency over time (T=0-6 months) in HA-free IFN-[beta] 25[deg.]C stability samples. An increase in the final deamidated product and its intermediate, the cyclic imide, was also observed in the 25 °C stability sample.

[0053] Glu-C peptide mapping identified the deamidation site at Asn25, which revealed that the major forms of deamidation in HA-free IFN-β1b stability samples were iso-Asp and cyclic imide analogues , while the Asp form slightly increased.

[0054] The results obtained from the RP-HPLC method indicated that the deamidated forms (cyclic imide, Asp and isoAsp) were significantly increased in the HA-free IFN-β stability samples.

[0055]CPE and antiproliferative assays showed that the deamidated form was more biologically active tha...

Embodiment 2

[0092] Example 2: Manufacturability Data

[0093] As noted above, experiments were performed to demonstrate various deamidation techniques. Data obtained from CPE bioassays demonstrate that deamidated IFN-β is readily prepared using methods suitable for large-scale pharmaceutical production. Specifically, a significant increase in biological activity was observed in various samples produced according to Good Manufacturing Practice (GMP) incubated at moderate (eg, room temperature) to high (eg, 37-40°C) temperatures for 14-40 days; Incubation of the GMP samples at room temperature and pH 8.8 for about 1 hour, and incubation at 2-8°C at pH 8.4 for about 14 days almost tripled the biological activity.

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Abstract

Interferon-ss protein analogs in which the asparagine at position 25, numbered in accordance with native interferon-ss, is deamidated exhibit a biological activity of native human interferon-ss at an increased level and do not require HA for protein stabilization. The deamidated product is suitable for large scale manufacturing for incorporation in HA-containing or HA-free therapeutics for treatment of diseases including multiple sclerosis. An endoproteinase-C peptide map technique that produces a fingerprint profile for proteins using an enzymatic digest followed by RP-HPLC is also useful in quality control as an ID and / or quantitative test for the deamidated products.

Description

[0001] background 1. Technical field [0002] The present invention is generally in the field of biologically active protein chemistry. More specifically, the present invention relates to mutated and chemically altered interferon beta analogs that differ from the native protein by substitution, deletion or modification of cysteine, asparagine and other residues. 2. Background technology [0003] Interferon beta was found to be useful in the treatment of human diseases, including multiple sclerosis. Multiple sclerosis (MS) is a chronic disease of the central nervous system that occurs when the protective sheath surrounding nerve fibers is destroyed, often disabling. About 30% of MS patients have a relapsing-remitting form of the disease in which symptoms disappear completely or partially after an attack, followed by a stable period lasting months or years. Administration of beta interferon (interferon-beta or IFN-beta) has been shown to reduce th...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K14/565A61P25/28A61K38/19
CPCC07K14/565A61K38/00A61P25/00A61P25/28A61P31/12
Inventor 古谷健二D·约翰逊-杰克逊D·T·鲁斯西奥
Owner CHIRON CORP
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