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治疗酶的生产和纯化。

Production and Purification of Therapeutic Enzymes.

机构信息

iBB-Institute for Biosciences and Bioengineering, Department of Bioengineering, Instituto Superior Técnico, Universidade de Lisboa, Lisbon, Portugal.

Faculty of Engineering, Universidade Lusófona de Humanidades e Tecnologias, Lisbon, Portugal.

出版信息

Adv Exp Med Biol. 2019;1148:1-24. doi: 10.1007/978-981-13-7709-9_1.

DOI:10.1007/978-981-13-7709-9_1
PMID:31482492
Abstract

The use of therapeutic enzymes embraces currently a vast array of applications, abridging from diggestive disorders to cancer therapy, cardiovascular and lysosomal storage diseases. Enzyme drugs bind and act on their targets with great affinity and specificity, converting substrates to desired products in a reduced time frame with minimal side reactions. These characteristics have resulted in the development of a multitude of enzyme biopharmaceuticals for a wide range of human disorders.The advances in genetic engineering and DNA recombination techniques facilitated the production of therapeutical human-like enzymes, using different cells as host organisms. The selection of hosts generally privileges those that secrete the enzyme into the culture medium, as this eases the purification process, and those that are able to express complex glycoproteins, with glycosylation patterns and other post-translational modifications close to human proteins. Moreover, engineering approaches such as pegylation, encapsulation in micro- and nanocarriers, and mutation of amino acid residues of the native enzyme molecule to yield variants with improved therapeutic activity, half-life and/or stability, have been also addressed. Engineered enzyme products have been designed to display enhanced delivery to target sites and reduced adverse side-effects (e.g., immunogenicity) upon continuous drug administration.Irrespectively of the production method, the final formulation of therapeutic enzymes must display high purity and specificity, and they are often marketed as lyophilized pure preparations with biocompatible buffering salts and diluents to prepare the reconstituted aqueous solution before treatment.

摘要

治疗性酶的应用涵盖了从消化紊乱到癌症治疗、心血管和溶酶体贮积病等广泛的领域。酶药物与它们的靶标具有很高的亲和力和特异性结合,将底物在更短的时间内转化为所需的产物,同时产生最小的副反应。这些特性导致了多种酶类生物制药的发展,用于治疗广泛的人类疾病。

遗传工程和 DNA 重组技术的进步促进了治疗性人类样酶的生产,使用不同的细胞作为宿主生物体。宿主的选择通常偏向于将酶分泌到培养基中的那些,因为这简化了纯化过程,并且那些能够表达复杂糖蛋白的宿主,其糖基化模式和其他翻译后修饰与人类蛋白质接近。此外,还采用了工程方法,如聚乙二醇化、微纳米载体包封以及改变天然酶分子的氨基酸残基,以产生具有改善的治疗活性、半衰期和/或稳定性的变体。工程酶产品被设计为显示出增强的向靶部位的传递,并且在持续药物给药时减少不良的副作用(例如免疫原性)。

无论采用何种生产方法,治疗性酶的最终制剂都必须具有高纯度和特异性,并且通常作为冻干的纯制剂销售,其中含有生物相容性缓冲盐和稀释剂,以便在治疗前制备复溶的水溶液。

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Thiol-maleimide poly(ethylene glycol) crosslinking of L-asparaginase subunits at recombinant cysteine residues introduced by mutagenesis.通过突变引入重组半胱氨酸残基,巯基-马来酰亚胺聚乙二醇交联天冬酰胺酶亚基。
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Antibody Directed Enzyme Prodrug Therapy (ADEPT): Trials and tribulations.抗体导向酶药物疗法(ADEPT):试验与磨难。
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Therapeutic Enzymes: Applications and Approaches to Pharmacological Improvement.治疗性酶:药理学改善的应用与方法
Curr Pharm Biotechnol. 2017;18(7):531-540. doi: 10.2174/1389201018666170808150742.
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Sophisticated Cloning, Fermentation, and Purification Technologies for an Enhanced Therapeutic Protein Production: A Review.用于增强治疗性蛋白质生产的先进克隆、发酵和纯化技术:综述
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