Kozlowski A, Charles S A, Harris J M
Shearwater Corporation, Huntsville, Alabama 35801, USA.
BioDrugs. 2001;15(7):419-29. doi: 10.2165/00063030-200115070-00001.
The chemical attachment of poly(ethylene glycol) [PEG] to therapeutic proteins produces several benefits, including enhanced plasma half-life, lower toxicity, and increased drug stability and solubility. In certain instances, pegylation of a protein can increase its therapeutic efficacy by reducing the ability of the immune system to detect and mount an attack on the compound. A PEG-protein conjugate is formed by first activating the PEG moiety so that it will react with, and couple to, the protein. PEG moieties vary considerably in molecular weight and conformation, with the early moieties (monofunctional PEGs; mPEGs) being linear with molecular weights of 12kD or less, and later moieties being of increased molecular weights. PEG2, a recent innovation in PEG technology, involves the coupling of a 30kD (or less) mPEG to lysine that is further reacted to form a branched structure that behaves like a linear mPEG of much larger molecular weight. These compounds are pH and temperature stable, and this factor along with the large molecular weight may account for the restricted volume of distribution seen with drugs utilising these reagents. Three PEG-protein conjugates are currently approved for clinical use in the US, with more under clinical development. Pegademase is used in the treatment of severe combined immunodeficiency disease, pegaspargase for the treatment of various leukaemias, and pegylated interferon-alpha for chronic hepatitis C virus infections. As illustrated in the case of the 2 pegylated interferon-alphas, all pegylated proteins are not equal. The choice of PEG reagent and coupling chemistry is critical to the properties of the PEG-protein conjugate, with the molecular weight of the moiety affecting its rate and route of clearance from the body, and coupling chemistry affecting the strength of the covalent attachment of PEG to therapeutic protein.
聚乙二醇（PEG）与治疗性蛋白质的化学连接带来了诸多益处，包括延长血浆半衰期、降低毒性以及提高药物稳定性和溶解性。在某些情况下，蛋白质的聚乙二醇化可通过降低免疫系统检测和攻击该化合物的能力来提高其治疗效果。PEG - 蛋白质偶联物是通过首先激活PEG部分使其与蛋白质反应并偶联而形成的。PEG部分在分子量和构象上有很大差异，早期的部分（单功能PEG；mPEG）是线性的，分子量为12kD或更小，而后来的部分分子量增加。PEG2是PEG技术的一项最新创新，涉及将30kD（或更小）的mPEG与赖氨酸偶联，进一步反应形成一种分支结构，其行为类似于分子量更大的线性mPEG。这些化合物在pH和温度方面稳定，这一因素以及大分子重量可能解释了使用这些试剂的药物所观察到的分布容积受限的现象。目前有三种PEG - 蛋白质偶联物在美国被批准用于临床，还有更多处于临床开发阶段。培加酶用于治疗严重联合免疫缺陷病，聚乙二醇天冬酰胺酶用于治疗各种白血病，聚乙二醇化干扰素 - α用于治疗慢性丙型肝炎病毒感染。如两种聚乙二醇化干扰素 - α的情况所示，并非所有聚乙二醇化蛋白质都是相同的。PEG试剂和偶联化学的选择对于PEG - 蛋白质偶联物的性质至关重要，部分的分子量影响其从体内清除的速率和途径，而偶联化学影响PEG与治疗性蛋白质共价连接的强度。
