人睫状神经因子类似物rh-CNTF（A~（17）R~（63）15）的重组制备、PEG修饰和生物学特性研究
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摘要
蛋白质药物具有专一性强、时效高等优点,在临床治疗学中正得到越来越广泛的应用,但这类药物目前还存在着一些必须解决的问题,如给药系统不完善、定位给药困难,稳定性差、容易被酶类降解,因从循环系统中被快速清除导致体内半衰期短,生物利用率低等。针对这些问题,科学家基本遵循两种解决途径,第一是寻找一条蛋白质药物高生物利用度的给药途径;第二是通过化学修饰来优化蛋白质的代谢动力学特性,以延长其半衰期,达到长效稳定的目的。
化学修饰法是指在分子水平上对蛋白质进行改造,即在体外将蛋白质的侧链基团通过人工方法与一些化学基团,特别是具有生物相容性的大分子进行共价连接,从而改变蛋白质的性质。其主要优点是可以延长蛋白质在体内的半衰期,降低免疫原性和抗原性,另外还可以减弱蛋白酶的水解作用,增加蛋白分子的可溶性等。用于蛋白质修饰的大分子很多,常见的如聚乙二醇类,多糖类,同源蛋白质以及人工合成的多肽等。其中,聚乙二醇因其具有良好的生物相容性、反应简单、价格低廉等优点而受到较多的重视。
本研究希望通过对突变型人睫状神经因子rh-CNTF(A~(17)R~(63)15)的聚乙二醇修饰,获得低免疫原性、高稳定性的单聚PEG-rhCNTF(A~(17)R~(63)15),改善该蛋白药物的药代动力学以及给药便利程度。
本项目完成的工作和得到的结论包括以下方面:
1、完成了rh-CNTF(A~(17)R~(63)15)的重组纯化;
2、选择了合适的PEG修饰剂、优化PEG修饰条件并放大验证了PEG修饰工艺和纯化工艺;
3、建立了PEG修饰后纯化工艺、获得了单链PEG-rhCNTF目标产物;
4、探索了单聚PEG-rhCNTF(A~(17)R~(63)15)的初步特性;
5、分析比较了rh-CNTF(A~(17)R~(63)15)和PEG-rhCNTF(A~(17)R~(63)15)的免疫原性及药代动力学的差异,并对其药效作用进行对比研究。
以上工作为开发长效低免疫原性的PEG-rhCNTF药物奠定了基础
Protein drugs have a good advantages of the specificity and pharmacodynamics . It has been widely used in the clinical therapeutics, but these drugs are still that there are some issues that will be addressed, such as drug delivery systems are imperfect, difficult-specific drug delivery ,low stability , easy to be degradated by enzymes, due to the rapid removal from the circulatory system so that it has a short half-life, low bioavailability in vivo. To solve these problems, scientists practiced two ways, the first is to find delivery means of a high bioavailability of protein drug ; the second is to use chemical modification to optimize the dynamics of protein metabolism to extend its half-life, to get more efficiency and stability.
Chemical modification is means that protein will be modified at the molecular level, which will be attached some chemical groups to side-chain groups of proteins by artificial methods in the in vitro ,in particular, covalently connected with biocompatible macromolecule, to change the protein biological properties. Its main advantages are the extension half-life of target protein in the body to reduce the immunogenicity and antigenicity, can also weaken the role of protease hydrolysis, increase soluble molecules such as proteins. There are a lot of macromolecules used for modification protein such as polyethylene glycol, polysaccharides, protein homology, as well as synthetic peptides. Of these, polyethylene glycol has a better biocompatibility, a simple reaction , low price so that has been more attention.
This test goal is that study on PEGylation of rh-CNTF to obtain a low immunogenicity, high stability of the monomer PEG-rhCNTF (A~(17)R~(63)15), at the same time to improve the target protein pharmacokinetics and administration.
In this study, the detailed contents we have accomplished and the conclusions we have gotten are shown as follows:
1、The construction and purification of rh-CNTF (A~(17)R~(63)15) ;
2、The selection of eligible PEGylation reagents, the optimization and verification of technologies of PEGylation and purification by middle scale experiment;
3、The establishment of methods of protein purification process of post-PEGylation and gaining the target protein, mono-PEG-rhCNTF (A~(17)R~(63)15) ;
4、The investigation of basic characteristics of mono-PEG-rhCNTF (A~(17)R~(63)15) ;
5、The investigation on the difference of immunogenicity and pharmacokinetics between PEG-rhCNTF (A~(17)R~(63)15) and rh-CNTF (A~(17)R~(63)15) , and the comparison on the pharmacodynamics.
The studies above have laid the good foundation for developing the second generation long acting PEGylated drugs of rh-CNTF (A~(17)R~(63)15) .
化学修饰法是指在分子水平上对蛋白质进行改造,即在体外将蛋白质的侧链基团通过人工方法与一些化学基团,特别是具有生物相容性的大分子进行共价连接,从而改变蛋白质的性质。其主要优点是可以延长蛋白质在体内的半衰期,降低免疫原性和抗原性,另外还可以减弱蛋白酶的水解作用,增加蛋白分子的可溶性等。用于蛋白质修饰的大分子很多,常见的如聚乙二醇类,多糖类,同源蛋白质以及人工合成的多肽等。其中,聚乙二醇因其具有良好的生物相容性、反应简单、价格低廉等优点而受到较多的重视。
本研究希望通过对突变型人睫状神经因子rh-CNTF(A~(17)R~(63)15)的聚乙二醇修饰,获得低免疫原性、高稳定性的单聚PEG-rhCNTF(A~(17)R~(63)15),改善该蛋白药物的药代动力学以及给药便利程度。
本项目完成的工作和得到的结论包括以下方面:
1、完成了rh-CNTF(A~(17)R~(63)15)的重组纯化;
2、选择了合适的PEG修饰剂、优化PEG修饰条件并放大验证了PEG修饰工艺和纯化工艺;
3、建立了PEG修饰后纯化工艺、获得了单链PEG-rhCNTF目标产物;
4、探索了单聚PEG-rhCNTF(A~(17)R~(63)15)的初步特性;
5、分析比较了rh-CNTF(A~(17)R~(63)15)和PEG-rhCNTF(A~(17)R~(63)15)的免疫原性及药代动力学的差异,并对其药效作用进行对比研究。
以上工作为开发长效低免疫原性的PEG-rhCNTF药物奠定了基础
Protein drugs have a good advantages of the specificity and pharmacodynamics . It has been widely used in the clinical therapeutics, but these drugs are still that there are some issues that will be addressed, such as drug delivery systems are imperfect, difficult-specific drug delivery ,low stability , easy to be degradated by enzymes, due to the rapid removal from the circulatory system so that it has a short half-life, low bioavailability in vivo. To solve these problems, scientists practiced two ways, the first is to find delivery means of a high bioavailability of protein drug ; the second is to use chemical modification to optimize the dynamics of protein metabolism to extend its half-life, to get more efficiency and stability.
Chemical modification is means that protein will be modified at the molecular level, which will be attached some chemical groups to side-chain groups of proteins by artificial methods in the in vitro ,in particular, covalently connected with biocompatible macromolecule, to change the protein biological properties. Its main advantages are the extension half-life of target protein in the body to reduce the immunogenicity and antigenicity, can also weaken the role of protease hydrolysis, increase soluble molecules such as proteins. There are a lot of macromolecules used for modification protein such as polyethylene glycol, polysaccharides, protein homology, as well as synthetic peptides. Of these, polyethylene glycol has a better biocompatibility, a simple reaction , low price so that has been more attention.
This test goal is that study on PEGylation of rh-CNTF to obtain a low immunogenicity, high stability of the monomer PEG-rhCNTF (A~(17)R~(63)15), at the same time to improve the target protein pharmacokinetics and administration.
In this study, the detailed contents we have accomplished and the conclusions we have gotten are shown as follows:
1、The construction and purification of rh-CNTF (A~(17)R~(63)15) ;
2、The selection of eligible PEGylation reagents, the optimization and verification of technologies of PEGylation and purification by middle scale experiment;
3、The establishment of methods of protein purification process of post-PEGylation and gaining the target protein, mono-PEG-rhCNTF (A~(17)R~(63)15) ;
4、The investigation of basic characteristics of mono-PEG-rhCNTF (A~(17)R~(63)15) ;
5、The investigation on the difference of immunogenicity and pharmacokinetics between PEG-rhCNTF (A~(17)R~(63)15) and rh-CNTF (A~(17)R~(63)15) , and the comparison on the pharmacodynamics.
The studies above have laid the good foundation for developing the second generation long acting PEGylated drugs of rh-CNTF (A~(17)R~(63)15) .
引文
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