Department of Genetics and Advanced Medical Technology, Medical Biotechnology Research Center, Faculty of Medicine, AJA University of Medical Sciences, Tehran, Iran.
Department of Medical Laboratory, Kashan University of Medical Sciences, Kashan, Iran.
Prep Biochem Biotechnol. 2021;51(6):519-529. doi: 10.1080/10826068.2020.1839907. Epub 2021 Jan 18.
Nowadays, proteins are frequently administered as therapeutic agents in human diseases. However, the main challenge regarding the clinical application of therapeutic proteins is short circulating plasma half-life that leads to more frequent injections for maintaining therapeutic plasma levels, increased therapy costs, immunogenic reactions, and low patient compliance. So, the development of novel strategies to enhance the pharmacokinetic profile of therapeutic proteins has attracted great attention in pharmaceuticals. So far, several techniques, each with their pros and cons, have been developed including chemical bonding to polymers, hyper glycosylation, Fc fusion, human serum albumin fusion, and recombinant PEG mimetics. These techniques mainly classify into three strategies; (i) the endosomal recycling of neonatal Fc receptor which is observed for immunoglobulins and albumin, (ii) decrease in receptor-mediated clearance, and (iii) increase in hydrodynamic radius through chemical and genetic modifications. Recently, novel PEG mimetic peptides like proline/alanine/serine repeat sequences are designed to overcome pitfalls associated with the previous technologies. Biodegradability, lack of or low immunogenicity, product homogeneity, and a simple production process, currently make these polypeptides as the preferred technology for plasma half-life extension of therapeutic proteins. In this review, challenges and pitfalls in the pharmacokinetic enhancement of therapeutic proteins using PEG-mimetic peptides will be discussed in detail.
如今，蛋白质经常被用作人类疾病的治疗剂。然而，治疗性蛋白质临床应用的主要挑战是其较短的血浆半衰期，这导致需要更频繁地注射以维持治疗性血浆水平，增加治疗成本、免疫原性反应和低患者依从性。因此，开发新型策略来增强治疗性蛋白质的药代动力学特征引起了制药界的极大关注。到目前为止，已经开发了几种技术，每种技术都有其优缺点，包括与聚合物的化学结合、过度糖基化、Fc 融合、人血清白蛋白融合和重组聚乙二醇类似物。这些技术主要分为三种策略：（i）内体再循环新生儿 Fc 受体，这种现象在免疫球蛋白和白蛋白中观察到；（ii）减少受体介导的清除；（iii）通过化学和遗传修饰增加流体动力学半径。最近，设计了新型聚乙二醇类似肽，如脯氨酸/丙氨酸/丝氨酸重复序列，以克服先前技术相关的缺陷。生物降解性、低免疫原性或无免疫原性、产品均一性和简单的生产工艺，使这些多肽成为延长治疗性蛋白质血浆半衰期的首选技术。在本文中，将详细讨论使用聚乙二醇类似肽增强治疗性蛋白质药代动力学的挑战和缺陷。
