Walles M, Connor A, Hainzl D
Novartis Institute for Biomedical Research, 250 Massachusetts Ave, 1B-123, Cambridge, MA, United States.
Curr Top Med Chem. 2017;17(32):3463-3475. doi: 10.2174/1568026618666180118153502.
Non-cleavable linkers are used in a number of different modalities for various reasons, such as linking an active drug moiety to half-life extending molecules, to groups that enable a specific tissue or cell targeting or to facilitate active uptake into target cells. Non-cleavable linkers do not have a designated weak point in their structure that can lead to cleavage by proteases, hydrolases or chemically by pH changes. Consequently, when designing a conjugate, the choice of a non-cleavable over a cleavable linker is usually a consequence of pursuing a certain mode of action where the stability of the complex is more important than a fast liberation of the active moiety. Linkers of various length, polarity, stability and flexibility are used for different types of conjugates and the linker design is mostly driven by the particular purpose and desired mode of action. This article reviews non-cleavable linkers applied predominantly in Antibody Drug Conjugates (ADCs), and how they influence these conjugates in terms of ADME properties (absorption, distribution, metabolism and elimination) and safety.
出于多种原因，不可裂解连接子被用于许多不同的模式中，例如将活性药物部分与延长半衰期的分子连接、与能够实现特定组织或细胞靶向的基团连接，或促进向靶细胞的主动摄取。不可裂解连接子在其结构中没有特定的弱点，不会因蛋白酶、水解酶或因pH变化而发生化学裂解。因此，在设计缀合物时，选择不可裂解连接子而非可裂解连接子通常是追求某种作用方式的结果，在这种作用方式中，复合物的稳定性比活性部分的快速释放更为重要。各种长度、极性、稳定性和灵活性的连接子用于不同类型的缀合物，连接子的设计主要由特定目的和期望的作用方式驱动。本文综述了主要应用于抗体药物缀合物（ADC）中的不可裂解连接子，以及它们在药代动力学性质（吸收、分布、代谢和消除）和安全性方面如何影响这些缀合物。
