Sleep Darrell, Cameron Jason, Evans Leslie R
Novozymes Biopharma UK Ltd, Nottingham, UK.
Biochim Biophys Acta. 2013 Dec;1830(12):5526-34. doi: 10.1016/j.bbagen.2013.04.023. Epub 2013 Apr 29.
Albumin is the most abundant plasma protein, is highly soluble, very stable and has an extraordinarily long circulatory half-life as a direct result of its size and interaction with the FcRn mediated recycling pathway. In contrast, many therapeutic molecules are smaller than the renal filtration threshold and are rapidly lost from the circulation thereby limiting their therapeutic potential. Albumin can be used in a variety of ways to increase the circulatory half-life of such molecules.
This article will review the mechanisms which underpin albumin's extraordinarily long circulatory half-life and how the understanding of these processes are currently being employed to extend the circulatory half-life of drugs which can be engineered to bind to albumin, or are conjugated to, or genetically fused to, albumin.
The recent and growing understanding of the pivotal role of FcRn in maintaining the extended circulatory half-life of albumin will necessitate a greater and more thorough investigation of suitable pre-clinical model systems for assessing the pharmacokinetic profiles of drugs associated, conjugated or fused to albumin.
Association, conjugation or fusion of therapeutic drugs to albumin is a well-accepted and established half-life extension technology. The manipulation of the albumin-FcRn interaction will facilitate the modulation of the circulatory half-life of albumin-enabled drugs, leading to superior pharmacokinetics tailored to the disease state and increased patient compliance. This article is part of a Special Issue entitled Serum Albumin.
白蛋白是血浆中含量最丰富的蛋白质，具有高度溶解性、非常稳定，并且由于其大小以及与FcRn介导的再循环途径的相互作用，其循环半衰期极长。相比之下，许多治疗性分子小于肾脏滤过阈值，会迅速从循环中流失，从而限制了它们的治疗潜力。白蛋白可通过多种方式用于延长此类分子的循环半衰期。
本文将综述白蛋白循环半衰期极长的相关机制，以及目前如何利用对这些过程的理解来延长可设计为与白蛋白结合、与白蛋白缀合或与白蛋白基因融合的药物的循环半衰期。
最近对FcRn在维持白蛋白延长的循环半衰期方面的关键作用的认识不断增加，这将需要对合适的临床前模型系统进行更深入、更全面的研究，以评估与白蛋白相关、缀合或融合的药物的药代动力学特征。
治疗药物与白蛋白的结合、缀合或融合是一种公认的、成熟的半衰期延长技术。对白蛋白-FcRn相互作用的调控将有助于调节基于白蛋白的药物的循环半衰期，从而实现针对疾病状态的更优药代动力学，并提高患者的依从性。本文是名为《血清白蛋白》的特刊的一部分。
