L-天冬酰胺酶(ASNase)是急性淋巴细胞白血病(ALL)一线治疗的重要组成部分,到2020年,一种侵袭性的血癌预计将困扰全球超过53,000人。最近,ASNase也被证明具有预防实体瘤转移的潜力。ASNase治疗是,然而,具有大量潜在的副作用,从免疫反应到严重毒性。因此,根据设计质量(QbD)原则,已设计出精巧的新产品,以最大程度地减少不良反应,同时增加患者的生存率。在以下页面中,请读者简要讨论这一领域的最新发展。首先,审查概述了制造和配方过程的最新改进,这会严重影响产品质量的重要方面,比如污染,聚集和酶活性。Follows,蛋白质工程的最新进展应用于生物更好的ASNases的开发(即,谷氨酰胺酶活性降低,蛋白水解抗性和较低的免疫原性)使用诸如定点诱变的技术,分子动力学,聚乙二醇化,讨论了PAS化和生物缀合。之后,注意力转向纳米医学,包括封装和固定等技术,旨在改善ASNase药代动力学。除了讨论最具创新性和代表性的学术研究成果外,审查概述了市场上已有的产品或处于最新开发阶段的产品。有了这个,该审查旨在为当前的产品开发提供坚实的背景,并支持对未来基于ASNase的药物的目标质量概况的讨论。
L-Asparaginase (ASNase) is a vital component of the first line treatment of acute lymphoblastic leukemia (ALL), an aggressive type of blood cancer expected to afflict over 53,000 people worldwide by 2020. More recently, ASNase has also been shown to have potential for preventing metastasis from solid tumors. The ASNase treatment is, however, characterized by a plethora of potential side effects, ranging from immune reactions to severe toxicity. Consequently, in accordance with Quality-by-Design (QbD) principles, ingenious new products tailored to minimize adverse reactions while increasing patient survival have been devised. In the following pages, the reader is invited for a brief discussion on the most recent developments in this field. Firstly, the
review presents an outline of the recent improvements on the manufacturing and formulation processes, which can severely influence important aspects of the product quality profile, such as contamination, aggregation and enzymatic activity. Following, the most recent advances in protein engineering applied to the development of biobetter ASNases (i.e., with reduced glutaminase activity, proteolysis resistant and less immunogenic) using techniques such as site-directed mutagenesis, molecular dynamics,
PEGylation, PASylation and bioconjugation are discussed. Afterwards, the attention is shifted toward nanomedicine including technologies such as encapsulation and immobilization, which aim at improving ASNase pharmacokinetics. Besides discussing the results of the most innovative and representative academic research, the
review provides an overview of the products already available on the market or in the latest stages of development. With this, the
review is intended to provide a solid background for the current product development and underpin the discussions on the target quality profile of future ASNase-based pharmaceuticals.