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Synergistic biomolecule-polymer conjugates

a biomolecule and polymer technology, applied in the field of synergistic biomolecule polymer conjugates, can solve the problems of reducing the bioactivity of the parent protein and organic therapeutic molecules, reducing the biological activity of the proteins that are pegylated by conventional permanent branched or linear peg compounds, etc., to achieve the effect of exacerbate systemic toxicity

Inactive Publication Date: 2013-08-01
PEG BIOSCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention provides bioconjugates that are degraded into multiple bioactive fragments that can be readily excreted or cleared from the body, unlike conventional protein conjugates which are stable in blood plasma and can accumulate in tissue leading to systemic toxicity. The invention also provides synergistic biomolecule-branched polymer conjugates that have permanent and cleavable linkages, as well as linear polymers with permanent and cleavable linkages. These structures ensure that the polymers are degraded into bioactive fragments and are cleared from the body, thereby reducing the risk of systemic toxicity and tissue accumulation. The technical effects of the invention include improved biocompatibility and reduced risk of toxicity and tissue accumulation.

Problems solved by technology

In general, Pegylation may alter the physicochemical properties of the proteins and therapeutic molecules resulting in decreased bioactivity of the parent proteins and organic therapeutic molecules.
This condition, however, is rarely achieved after a single administration of low molecular weight peptides and protein drugs.
However, the drawback in prior art Pegylation methodologies is the loss of biological activity of the proteins that are pegylated by conventional permanent branched or linear PEG compounds.
Such loss of biological activity is due to the steric hindrance created by the large PEG polymers that are being attached to the biologically active protein of interest.
For many therapeutic proteins, a significant loss in biological activity can result in a poor PK-PD profile which often limits the therapeutic application of Pegylation.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

example 1

Fmoc-Lys(Boc)-20K mPEG Ester 1

[0108]To a solution of 20 kDa mPEG (1 g, 0.05 mmol) and Fmoc-Lys(Boc)-OH (117mg, 0.25 mmol) in anhydrous dichloromethane cooled in an ice-water bath was added dicyclohexylcarbodiimide (166 mg, 0.8 mmol), and the mixture was stirred under nitrogen and allowed to warm to room temperature overnight. The N,N′-dicyclohexylurea was removed from the reaction mixture by filtration. The filtrate was dried in vacuo. The residue was dissolved in anhydrous dichloromethane, and the white solid was precipitated by addition of tert-butyl methyl ether. The white solid product 1 was collected and washed with tert-butyl methyl ether.

example 2

Fmoc-Lys(α-10K mPEG, carbamate)-20K mPEG Ester 3

[0109]To a solution of Fmoc-Lys(Boc)-20K mPEG Ester 1 (0.8 g, 0.04 mmol) in anhydrous dichloromethane (4 mL) was added 4 mL of Trifluoroacetic acid. The reaction was stirred for one hour at room temperature, and the white solid was precipitated by tert-butyl methyl ether (70 mL). The solid product Fmoc-Lys-20K mPEG Ester 2 was collected and washed by tert-butyl methyl ether.

[0110]A solution Fmoc-Lys-20K mPEG Ester 2 (0.35 g, 0.018 mmol), 10K mPEG succinimidyl carbonate (SC-mPEG) (225 mg, 0.022 mmol), and triethylamine (110 mg, 1.08 mmol) in anhydrous methylene chloride (9 mL) was stirred at room temperature under nitrogen overnight. The reaction mixture was concentrated by partial removal of solvent under vacuum. The product Fmoc-Lys(α-10K mPEG, carbamate)-20K mPEG Ester 3 was precipitated by addition of tert-butyl methyl ether, filtered and collected. Product 3 can be further purified by chromatography.

example 3

30k Da Lys (α-10kPEG carbamate, 20kPEG ester) succinimidyl suberate ester 5

[0111]Fmoc-Lys(α-10K mPEG, carbamate)-20K mPEG Ester 3 (0.5 g, 0.016 mmol) was dissolved in 11 mL of a mixture of dichloromethane / diethylamine (5:6), and the reaction mixture was stirred at room temperature for 3.5 hours. The solid product 4 was precipitated by addition of tert-butyl methyl ether (70 mL), filtered, and collected.

[0112]A solution of Lys(α-10K mPEG, carbamate)-20K mPEG Ester 4 (0.4 g, 0.013 mmol), Suberic acid bis(N-hydroxysuccinimide ester) (26 mg, 0.07 mmol) and triethylamine (3 mg, 0.03 mmol) in a mixture of anhydrous methylene chloride (7 mL) and dimethylformamide (3 mL) was stirred at room temperature under nitrogen for 9 hours. The reaction mixture was concentrated by partial removal of solvent under vacuum, and the white solid was precipitated by addition of tert-butyl methyl ether. The solid product 5 was collected and washed by tert-butyl methyl ether.

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Abstract

The synergistic biomolecule-polymer conjugates are the long-acting, in vivo controlled continuous-release and hybrid synergy systems of biomolecules that provide increased biological activities and enhanced pharmacological properties for achieving greater therapeutic efficacies.

Description

FIELD OF THE INVENTION[0001]The present invention relates to the novel synergistic biomolecule-polymer conjugates produced from the attachment of the permanent-cleavable-linkages or all-cleavable-linkages polymers to biologically active molecules to provide synergistically enhanced biological activities in vivo and improved pharmacokinetic (PK) and pharmacodynamic (PD) properties of delivered biomolecules for achieving optimum therapeutic efficacies. The synergistic biomolecule-polymer conjugates integrate the advantages of PK and PD properties of large and small biomolecule-polymer conjugates in vivo. The present invention further relates to the novel synergistic Interferon-α-polymer (Synergy-IFN-α-polymer) conjugates, which are the in vivo enzyme-controlled, continuous-release and hybrid synergy systems of interferon that provide the increased biological activity and enhanced pharmacological properties for achieving greater interferon-α related therapies.BACKGROUND OF THE INVENTIO...

Claims

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Application Information

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IPC IPC(8): C08G65/333
CPCC07K1/1077C07K17/06C08G65/33344C08L2203/02C08G65/332C08G65/33396A61K47/48215A61K47/60A61K47/50A61K47/56A61P31/12A61P43/00
Inventor LEE, CHYI
Owner PEG BIOSCI
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