Recombinant human interleukin-2 and polyethylene coupling compound

A technology of polyethylene glycol and conjugates, which is applied in the field of conjugates of recombinant human interleukin-2 and polyethylene glycol, and can solve the problems of large loss of biological activity

Inactive Publication Date: 2008-01-16
北京紫辰医药生物技术研究所 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Moreover, due to direct modification of the active site or steric hi

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0020] Example 1CH 3 O-PEG 5000 -OCH 2 CONH-Gly-CONH-(rhIL-2)(I 1 ) Preparation 1.1 CH 3 O-PEG 5000 -OCH 2 Preparation of COOH

[0021] Add 20.0 g (4 mmol) of monomethoxypolyethanol (MW5000) into a round-bottomed flask equipped with a water separator, add toluene to dissolve, distill, and constantly replenish dry toluene, heat to reflux in an oil bath until no Moisture evaporates. The water separator was removed, and 8 mmol of potassium tert-butoxide was added, and the reaction was carried out under reflux for 1 hour. Then 8 mmol of ethyl bromoacetate was slowly added, and the reaction was refluxed for 6 hours. Filtration, the filtrate was evaporated to dryness under reduced pressure, with CH 2 Cl 2 Dissolve the residue, add anhydrous ether to precipitate a solid, filter the solid, dissolve it in water, slowly add 0.1N sodium hydroxide solution until the pH reaches 10, and stir at room temperature for 2 hours. Then adjust the pH to 3 with 0.1N hydrochloric acid solu...

Embodiment 2

[0027] Example 2CH 3 O-PEG 12000 -OCH 2 CONH-Gly-CONH-(rhIL-2)(I 2 ) preparation

[0028] With reference to the method of Example 1.1, CH 3 O-PEG 12000 -OCH 2 COOH.

[0029] With reference to the method of embodiment 1.2, use CH 3 O-PEG 12000 -OCH 2 COOH instead of CH 3 O-PEG 5000 -OCH 2 COOH to CH 3 O-PEG 12000 -OCH 2 CONH-Gly-COOSu.

[0030] With reference to the method of embodiment 1.3, use CH 3 O-PEG 12000 -OCH 2 CONH-Gly-COOSu instead of CH 3 O-PEG 5000 -OCH 2 CONH-Gly-COOSu, reacts with rhIL-2 to produce CH 3 O-PEG 12000 -CH 2 CONH-Gly-CONH-(rhIL-2).

Embodiment 3

[0031] Example 3CH 3 O-PEG 12000 -OCH 2 CONH-Ala-CONH-(rhIL-2)(I 3 ) preparation

[0032] With reference to the method of Example 2, replace glycine with L-alanine to prepare CH 3 O-PEG 12000 -OCH 2 CONH-Ala-COOSu.

[0033] With reference to the method of embodiment 1.3, use CH 3 O-PEG 12000 -OCH 2 CONH-Ala-COOSu instead of CH 3 O-PEG 5000 -OCH 2 CONH-Gly-COOSu, reacts with rhIL-2 to produce CH 3 O-PEG 12000 -CH 2 CONH-Ala-CONH-(rhIL-2).

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Abstract

The invention relates to a coupling compound formed by the recombinant human interleukin-2 connecting with the monomethyl polyethylene glycol through the amino acid or the oligopeptide; the coupling compound has rather good plasma stability, and can release and recompose the recombinant human interleukin slowly to actively play the pharmacological action.

Description

technical field [0001] The present invention relates to a conjugate formed by linking recombinant human interleukin-2 with monomethyl polyethylene glycol through amino acid or oligopeptide; this conjugate has good plasma stability and can slowly release recombinant human interleukin in vivo to exert its pharmacological activity effect. Background technique [0002] Recombinant human interleukin-2 has biological activities such as promoting the maturation and differentiation of T cells, activating lymphokine-activated killer cells, and promoting the production of interferon. It is one of the most important cytokines in immunotherapy and has good clinical antitumor effects. active. [0003] However, as a protein drug, recombinant human interleukin-2 is easily inactivated by enzymatic hydrolysis in the body, and its biological half-life is short, which affects its pharmacological effects. [0004] Polyethylene glycol (PEG) is a neutral polymer with good biocompatibility, high...

Claims

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Application Information

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IPC IPC(8): A61K47/48C07K17/08A61K38/20A61P35/00A61K47/60
Inventor 李广善靳雪峰傅李芳
Owner 北京紫辰医药生物技术研究所
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