佩乐能PEG_IFN的分子设计及按体重给药讲述.pptVIP

* 聚乙二醇的主要作用是加大分子量降低肾脏清除率和减少免疫原性，避免蛋白酶及免疫细胞的识别和清除 * 这张幻灯片形象的表示，随着PEG 分子量的增大，PEG IFN的分子量越大（对干扰素与受体结合的干扰越大）。 * 经过大量反复试验，先灵葆雅得出结论：随着PEG 分子量的增加，半衰期越来越长。 This cartoon depicts the effect of increased peg-size on half-life. PEG molecules range in molecular weight from 300 to 4000 Daltons can be arranged in linear or branched chains. The extent to which pegylation modifies the pharmacokinetic and pharmacodynamic profile of a native protein depends on the structure and size of the PEG molecule (x-axis) and the site of attachment of the PEG chain. In general, the larger the PEG chain, the greater the extension of the protein’s half-life (y-axis). The 12 kDa molecule promotes high biological activity along with enhanced pharmacokinetic behavior. Choosing a single 12 kilodalton polyethylene glycol (PEG) molecule was key to designing the pegylation strategy for interferon ?-2b. A smaller polymer 5 kilodalton would have had an inadequate effect on the clearance of the molecule, whereas larger PEGs 20 kilodalton (PEG) decrease the activity of the molecule and are more difficult to clear from the body.PEG conjugation increases the serum half-life and thereby prolong patient exposure to interferon ?-2b without altering the biologic potency to the protein. The underlying interferon is still the active antiviral agent. Since size and attachment position of the PEG molecule can affect biologic activity of the protein. PEG-INTRON? was designed to deliver the most “active” pegylated interferon alfa-2b to suppress the virus over a full one-week period. * 随着PEG分子量的增大，半衰期越长，但另一方面，其生物学活性（信号传导活性，包括抗病毒活性及抗增生活性）越来越低，这是由于对干扰素与受体结合的干扰越来越大。 This cartoon depicts the effect of increased peg-size on activity. As the peg size attached to alfa-2b increases (molecular weight) less activity is observed. This is most likely due to stearic hindrance (ie the molecules ability to bind to the receptor). The 12 kDa molecule promotes high biological activity along with enhanced pharmacokinetic b