Linker Chemistry in Antibody-Drug Conjugates: Current Strategies, Clinical Pharmacokinetic Analyses, and Linker-Free Outlooks.
TL;DR
This Viewpoint collects and discusses a plethora of linkers employed in ADC development, specifically focusing on advancements in antibody modification and linker cleavage chemistries.
Abstract
With the increasing cancer incidence and death tolls worldwide, antibody-drug conjugates (ADCs) have emerged as a promising platform to selectively deliver cytotoxic payloads to cancerous tissues. This platform has the potential to spare patients from off-target effects compared to traditional chemotherapy. Despite the clinical success of some ADCs, many in the pipeline did not even reach the clinical stage. We turn our attention to their linker chemistry that connects the antibody and the drug molecules together. Despite their small size, linkers play a key role in governing the payload release kinetics and location. In this Viewpoint, we collect and discuss a plethora of linkers employed in ADC development, specifically focusing on advancements in antibody modification and linker cleavage chemistries. The choice of linker chemistry has evolved over time, going from stochastically attached non-stimuli-responsive to site-specifically modified cleavable linkers. Then we correlate the linker technologies to their pharmacokinetic outcomes in clinics, followed by a discussion of the upcoming "linker-free" technology for more facile and efficient antibody-conjugated targeted delivery.