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Maleamic acid polymer derivatives and their bioconjugates

A technology of maleimide, polymer, applied in the field of polymer chemistry

Active Publication Date: 2006-02-08
NEKTAR THERAPEUTICS INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Applicants have therefore found that PEG maleimides may not be desirable reagents for conjugation to thiol groups or other active agents on the drug of interest

Method used

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  • Maleamic acid polymer derivatives and their bioconjugates
  • Maleamic acid polymer derivatives and their bioconjugates
  • Maleamic acid polymer derivatives and their bioconjugates

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0262] Hydrolysis rate of linked PEG maleimide examples

[0263] A series of representative methoxy-PEG maleimides with an average molecular weight of 5000 Daltons were synthesized and studied. Determine the maleimide for each of the following structures by measuring the UV absorption at 297 nm of a solution of mPEG maleimide at a concentration of 5 mg / mL in 50 mM phosphate buffer at a pH of approximately 7.5 Ring hydrolysis reaction kinetics. The general structure of polymer maleimide is shown below. The exact structure corresponding to each linker is provided in Table 1 above (L 1 , L 2 and L 3 ).

[0264]

[0265] Table 2, Hydrolysis rate of mPEG (5k-Da) maleimide (5 mg / mL) dissolved in 50 mM phosphate buffer (pH ~ 7.5) as determined by UV absorption at 297 nm

[0266] Structure Half-life Relative rate

[0267] (Hour)

[0268] L 1 -AMTR 8.8 3.66

[0269] L 1 -AMPE 19.4 1.66

[0270] L 1 -MCH 16.3 1.98

[0271] L 2 -BU 19.6 1.65

[0272] L...

Embodiment 2

[0278] Hydrolysis of a branched linked polymer maleimide, mPEG2-MAL-40K

[0279]

[0280] The polymer maleimide drawn on hair, mPEG2-MAL-40K, was obtained from Nektar (Huntsville, AL). The maleimide ring of the polymer derivative undergoes limited hydrolysis under certain conditions to form the corresponding maleamic acid derivative described below.

[0281] The hydrolysis reaction was monitored analytically by HPLC to observe the decrease in the percentage of parent maleimide over time. The kinetics of the hydrolysis reaction were determined under the following conditions: a pH value of about 5.5, using a HEPES buffer solution at about 25°C.

[0282] By plotting the logarithm of maleamic acid or maleimide concentration versus time (the latter shown in image 3 ), a linear relationship can be obtained.

[0283] This data was then used to determine the half-life of the hydrolysis reaction, which was calculated to be approximately 34 days under the test conditions. Thus...

Embodiment 3

[0285] Study on the Hydrolysis Rate of Polymer Succinimide Conjugate

[0286] Hydrolysis rates of representative proteins and small molecule model conjugates were studied to examine the relationship between the polymer-terminated maleimide itself and the ring-opening tendency of its conjugates.

[0287] Since large biomolecular components such as proteins have a significant impact on the retention of linked molecules in typical LC columns, it is often more difficult to determine the kinetics of maleimide conjugates than the polymers themselves. In this analysis, the ring-opened acid form of maleamic acid could not be cleanly separated from the ring-opened or ring-closed form. However, combined analytical methods based on size exclusion chromatography (HPLC-SE) and protein analysis electrophoresis (SDS-PAGE) have been successfully used to evaluate polymeric maleimide protein conjugates and those made with nonproteinaceous model compounds. The ring-opening properties of the c...

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Abstract

The present invention is directed to maleamic acid derivatives of water soluble polymers, to chemically stable water-soluble polymer succinamic acid -active agent conjugates, and to methods for reproducibly preparing, characterizing and using such polymer reagents and their conjugates.

Description

field of invention [0001] The present invention relates generally to the field of polymer chemistry and more specifically to chemically stable active agent conjugates made from maleimide or maleamic acid functionalized water soluble polymers such as polyethylene glycol , and methods of synthesizing, characterizing, and using the polymeric reagents and conjugates. Background of the invention [0002] Thanks to recent advances in biotechnology, therapeutic proteins and other biomolecules such as antibodies and antibody chain fragments can now be produced on a large scale, making these biomolecules more widely available. Unfortunately, the clinical application of potential therapeutic biomolecules is often hampered by their rapid proteolytic degradation, low bioavailability, instability upon manufacture, storage or administration, or their immunogenicity. As a result of continued interest in the therapeutic use of administered proteins and other biomolec...

Claims

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Application Information

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IPC IPC(8): C08G65/333A61K47/48A61K47/60
Inventor A・柯兹罗斯克R・F・戈罗斯三世S・P・麦克玛奴斯
Owner NEKTAR THERAPEUTICS INC
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