Abstract:
Over the past few decades, the complexity of molecular entities being advanced for therapeutic purposes has continued to evolve. A main propellent fueling innovation is the perpetual mandate within the pharmaceutical industry to meet the needs of novel disease areas and/or delivery challenges. As new mechanisms of action are uncovered, and as our understanding of existing mechanisms grows, the properties that are required and/or leveraged to enable therapeutic development continue to expand. One rapidly evolving area of interest is that of chemically enhanced peptide and protein therapeutics. While a variety of conjugate molecules such as antibody-drug conjugates, peptide/protein-PEG conjugates, and protein conjugate vaccines are already well established, others, such as antibody-oligonucleotide conjugates and peptide/protein conjugates using non-PEG polymers, are newer to clinical development. This review will evaluate the current development landscape of protein-based chemical conjugates with special attention to considerations such as modulation of pharmacokinetics, safety/tolerability, and entry into difficult to access targets, as well as bioavailability. Furthermore, for the purpose of this review, the types of molecules discussed are divided into two categories: (1) therapeutics that are enhanced by protein or peptide bioconjugation, and (2) protein and peptide therapeutics that require chemical modifications. Overall, the breadth of novel peptide- or protein-based therapeutics moving through the pipeline each year supports a path forward for the pursuit of even more complex therapeutic strategies.
摘要:
在过去的几十年里,用于治疗目的的分子实体的复杂性继续发展。主要的推进剂加油创新是制药行业的永久任务,以满足新疾病领域和/或交付挑战的需求。随着新的作用机制被发现,随着我们对现有机制的理解的增长,需要和/或利用以使治疗发展的性质继续扩大。一个快速发展的关注领域是化学增强的肽和蛋白质治疗剂。虽然各种缀合分子如抗体-药物缀合物,肽/蛋白质-PEG缀合物,和蛋白质结合疫苗已经很成熟,其他人,例如使用非PEG聚合物的抗体-寡核苷酸缀合物和肽/蛋白质缀合物,对临床发展来说是更新的。这篇综述将评估基于蛋白质的化学缀合物的当前发展格局,特别注意诸如药代动力学的调节等考虑因素,安全性/耐受性,进入难以进入的目标,以及生物利用度。此外,为了这次审查的目的,所讨论的分子类型分为两类:(1)通过蛋白质或肽生物缀合增强的治疗剂,和(2)需要化学修饰的蛋白质和肽治疗剂。总的来说,每年新的基于肽或蛋白质的疗法在管道中流动的广度为追求更复杂的治疗策略提供了前进的道路。