Holz Emily, Darwish Martine, Tesar Devin B, Shatz-Binder Whitney
Department of Pharmaceutical Development, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
Department of Protein Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
Pharmaceutics. 2023 Feb 10;15(2):600. doi: 10.3390/pharmaceutics15020600.
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.
在过去几十年中，用于治疗目的的分子实体的复杂性持续演变。推动创新的一个主要动力是制药行业内满足新疾病领域需求和/或给药挑战的长期任务。随着新的作用机制被发现，以及我们对现有机制的理解不断加深，支持治疗性开发所需和/或利用的特性持续扩展。一个快速发展的关注领域是化学增强型肽和蛋白质疗法。虽然多种偶联分子，如抗体-药物偶联物、肽/蛋白质-聚乙二醇偶联物和蛋白质结合疫苗已经成熟，但其他一些，如抗体-寡核苷酸偶联物和使用非聚乙二醇聚合物的肽/蛋白质偶联物，在临床开发中则更新颖。本综述将评估基于蛋白质的化学偶联物的当前发展态势，特别关注药代动力学调节、安全性/耐受性、进入难以到达的靶点以及生物利用度等方面的考虑因素。此外，出于本综述的目的，所讨论的分子类型分为两类：（1）通过蛋白质或肽生物偶联增强的疗法，以及（2）需要化学修饰的蛋白质和肽疗法。总体而言，每年进入研发流程的新型基于肽或蛋白质的疗法的广度为追求更复杂的治疗策略指明了前进的道路。
