In vitro-engineered non-antibody protein therapeutics.
In vitro-engineered non-antibody protein therapeutics.
复制标题
体外设计的非抗体蛋白疗法。
DOI：
10.1007/s13238-017-0386-6
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发表时间：
2018-01
期刊：
影响因子：
21.1
通讯作者：
Chen Z
中科院分区：
文献类型：
--
作者：
Simeon R;Chen Z
抗体已被证明是治疗多种疾病的一种有价值的方式，这主要是由于其高靶标结合亲和力和特异性。不幸的是，抗体在几个方面也受到限制，其中最主要的是制造成本极高。因此，非抗体结合蛋白长期以来一直受到追捧作为替代疗法。新的结合蛋白支架不断被设计或发现，其中一些已被 FDA 批准用于人类。本综述重点关注已经在人类中使用或目前正在临床试验中评估的蛋白质支架。尽管并非所有分子都有望获得批准，但显着的好处确保这些分子将继续被研究和开发作为抗体的治疗替代品。根据介导配体结合的氨基酸的位置，我们将临床开发中的所有蛋白质支架分为两大类：配体结合残基位于暴露的柔性环中的支架，以及结合残基位于蛋白质二级结构（例如α螺旋）中的支架。属于第一类的支架包括adnectin、anticalins、avimer、Fynomers、Kunitz结构域和knottin，而属于第二类的支架包括affibody、β-发夹模拟物和设计的锚蛋白重复蛋白（DARPins）。大多数这些支架是热稳定的，可以很容易地在微生物中生产或完全化学合成。此外，许多这些支架源自人类蛋白质，因此具有非常低的免疫原性潜力。与抗体相比，这些蛋白质支架作为治疗剂的其他优点和局限性将被讨论。
Antibodies have proved to be a valuable mode of therapy for numerous diseases, mainly owing to their high target binding affinity and specificity. Unfortunately, antibodies are also limited in several respects, chief amongst those being the extremely high cost of manufacture. Therefore, non-antibody binding proteins have long been sought after as alternative therapies. New binding protein scaffolds are constantly being designed or discovered with some already approved for human use by the FDA. This review focuses on protein scaffolds that are either already being used in humans or are currently being evaluated in clinical trials. Although not all are expected to be approved, the significant benefits ensure that these molecules will continue to be investigated and developed as therapeutic alternatives to antibodies. Based on the location of the amino acids that mediate ligand binding, we place all the protein scaffolds under clinical development into two general categories: scaffolds with ligand-binding residues located in exposed flexible loops, and those with the binding residues located in protein secondary structures, such as α-helices. Scaffolds that fall under the first category include adnectins, anticalins, avimers, Fynomers, Kunitz domains, and knottins, while those belonging to the second category include affibodies, β-hairpin mimetics, and designed ankyrin repeat proteins (DARPins). Most of these scaffolds are thermostable and can be easily produced in microorganisms or completely synthesized chemically. In addition, many of these scaffolds derive from human proteins and thus possess very low immunogenic potential. Additional advantages and limitations of these protein scaffolds as therapeutics compared to antibodies will be discussed.