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Challenges and advancements in the pharmacokinetic enhancement of therapeutic proteins
Preparative Biochemistry & Biotechnology ( IF 2.0 ) Pub Date : 2021-01-18 , DOI: 10.1080/10826068.2020.1839907
Farnaz Khodabakhsh 1 , Morteza Salimian 2 , Mohammad Hossein Hedayati 3 , Reza Ahangari Cohan 4 , Dariush Norouzian 4
Affiliation  

Abstract

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.



中文翻译:

治疗性蛋白质药代动力学增强的挑战和进展

摘要

如今,蛋白质经常被用作人类疾病的治疗剂。然而,关于治疗性蛋白质临床应用的主要挑战是循环血浆半衰期短,这导致更频繁的注射以维持治疗血浆水平、增加治疗成本、免疫原性反应和低患者依从性。因此,开发用于增强治疗性蛋白质药代动力学特征的新策略已引起药物学界的极大关注。到目前为止,已经开发了多种技术,每种技术都有其优点和缺点,包括与聚合物的化学键合、超糖基化、Fc 融合、人血清白蛋白融合和重组 PEG 模拟物。这些技术主要分为三种策略;(i) 在免疫球蛋白和白蛋白中观察到的新生儿 Fc 受体的内体循环,(ii) 受体介导的清除减少,以及 (iii) 通过化学和遗传修饰增加流体动力学半径。最近,新的 PEG 模拟肽(如脯氨酸/丙氨酸/丝氨酸重复序列)旨在克服与先前技术相关的缺陷。生物可降解性、缺乏或低免疫原性、产品同质性和简单的生产过程,目前使这些多肽成为治疗性蛋白质血浆半衰期延长的首选技术。在这篇综述中,将详细讨论使用 PEG 模拟肽增强治疗性蛋白质的药代动力学的挑战和陷阱。(iii) 通过化学和遗传修饰增加流体动力学半径。最近,新的 PEG 模拟肽(如脯氨酸/丙氨酸/丝氨酸重复序列)旨在克服与先前技术相关的缺陷。生物可降解性、缺乏或低免疫原性、产品同质性和简单的生产过程,目前使这些多肽成为治疗性蛋白质血浆半衰期延长的首选技术。在这篇综述中,将详细讨论使用 PEG 模拟肽增强治疗性蛋白质的药代动力学的挑战和陷阱。(iii) 通过化学和遗传修饰增加流体动力学半径。最近,新的 PEG 模拟肽(如脯氨酸/丙氨酸/丝氨酸重复序列)旨在克服与先前技术相关的缺陷。生物可降解性、缺乏或低免疫原性、产品同质性和简单的生产过程,目前使这些多肽成为治疗性蛋白质血浆半衰期延长的首选技术。在这篇综述中,将详细讨论使用 PEG 模拟肽增强治疗性蛋白质的药代动力学的挑战和陷阱。生物可降解性、缺乏或低免疫原性、产品同质性和简单的生产过程,目前使这些多肽成为治疗性蛋白质血浆半衰期延长的首选技术。在这篇综述中,将详细讨论使用 PEG 模拟肽增强治疗性蛋白质的药代动力学的挑战和陷阱。生物可降解性、缺乏或低免疫原性、产品同质性和简单的生产过程,目前使这些多肽成为治疗性蛋白质血浆半衰期延长的首选技术。在这篇综述中,将详细讨论使用 PEG 模拟肽增强治疗性蛋白质的药代动力学的挑战和陷阱。

更新日期:2021-01-18
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