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Beyond antibodies: ankyrins and DARPins. From basic research to drug approval.
Current Opinion in Pharmacology ( IF 4 ) Pub Date : 2020-07-13 , DOI: 10.1016/j.coph.2020.05.004
Achille Patrizio Caputi 1 , Pierluigi Navarra 2
Affiliation  

This Pharmacological Perspective describes the pathway that, starting from the deep understanding of ankyrins — a family of proteins with high variability-binding and high specificity-binding characteristics — led to the development of a new class of recombinant-binding proteins, the DARPins (designed ankyrin repeat proteins). These are envisaged as alternatives to mAbs and related biologics, with the potential to overcome certain shortcomings of mAbs. DARPins have relatively low molecular weights (14–21 kDas) and more favorable PK profiles than mAbs, are stable proteins that can be easily produced in Escherichia coli and can be used in their monovalent form or conjugated to other moieties, for example, polyethylene glycol (PEG) to enhance their half-life. DARPins can also be engineered to produce bi-specific or tri-specific compounds that bind different epitopes of the same target or two different targets. Abicipar, a first-in-class anti-VEGF-A DARPin had similar efficacy compared to anti-VEGF biologics (bevacizumab, ranibizumab) in preclinical studies and was not inferior to ranibizumab in the treatment of age-related macular degeneration (AMD) with a reduced number of intravitreal injections. Abicipar has recently been submitted for regulatory approval for use in AMD.



中文翻译:

超越抗体:锚蛋白和 DARPins。从基础研究到药物批准。

药理学角度介绍了,从锚蛋白的深刻理解开始的途径-一个家庭的高可变性结合和高特异性结合特性的蛋白质-导致了一类新的重组结合蛋白的发展,的DARPin(设计锚蛋白重复蛋白)。这些被设想为 mAb 和相关生物制剂的替代品,有可能克服 mAb 的某些缺点。DARPins 具有相对较低的分子量 (14–21 kDas) 和比 mAb 更有利的 PK 谱,是可以在大肠杆菌中轻松生产的稳定蛋白质并且可以以其单价形式使用或与其他部分(例如聚乙二醇 (PEG))缀合以延长其半衰期。DARPins 也可以被设计成产生双特异性或三特异性化合物,这些化合物结合同一靶标或两个不同靶标的不同表位。Abicipar 是一种一流的抗 VEGF-A DARPin,在临床前研究中与抗 VEGF 生物制剂(贝伐单抗、雷珠单抗)相比具有相似的疗效,并且在治疗年龄相关性黄斑变性 (AMD) 方面并不逊色于雷珠单抗。玻璃体内注射次数减少。Abicipar 最近已提交监管部门批准用于 AMD。

更新日期:2020-07-14
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