Linker Chemistry for Tumor Microenvironment-Responsive Payload Release in ADCs
DOI:
https://doi.org/10.54097/qq36d868Keywords:
Antibody-drug conjugates; tumor microenvironment; ADCs linkers.Abstract
Antibody drug conjugates (ADCs) represent a class of transformative anti-cancer therapeutic drugs, and linker components play an important role in balancing the stability of plasma and tumor specific payload release. This article analyzes the chemical design of ADC linkers and their responsive release strategies to the unique tumor microenvironment (TME). Firstly, the linkers are systematically classified into cleavable and non-cleavable types, with a focus on their different mechanisms. Further analysis is conducted on the subtypes of cleavable linkers, including pH sensitive, reduction sensitive, and enzyme cleavable variants. Detailed instructions are provided on how to cleave each linker under specific TME conditions, such as acidic or high glutathione environments. This article reveals the key trade-off between the powerful bystander effect provided by the cuttable joint and the superior system stability of the uncut joint through comparative analysis. In addition to the established design, the article also explores prospective linker technologies that respond to undeveloped TME cues such as hypoxia, elevated reactive oxygen species (ROS), and metal ions, and proposes new concepts such as dual reaction and gate linkers. This comprehensive analysis not only provides a framework for understanding current connector technology, but also offers valuable insights for guiding the rational design of next-generation ADCs with enhanced therapeutic indices. The continuous innovation of joint chemistry is crucial for realizing the full potential of precision oncology.
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