Re-evaluating antibody-drug conjugate linker stability: assessment, interpretation, and clinical translation

Antibody-drug conjugates (ADCs) have emerged as an important class of anticancer therapeutics. Their highly modular design offers multiple opportunities to refine their properties and improve clinical performance by tuning individual components, including the antibody, linker, and payload. Recent ADC optimization efforts have focused on more stable linker designs, apparently based on the assumption that premature payload release, rather than ADC uptake and intracellular catabolism, is the primary driver of off-target toxicity and limited antitumor activity. However, clinical data highlight a more complex picture. Several clinically successful ADCs employ relatively unstable linkers, including some with short systemic half-lives. In contrast, ADCs with increased linker stability have not consistently demonstrated improved clinical outcomes and, in many cases, have been associated with unexpected toxicities. In this article, we examine common assumptions regarding ADC linker stability, highlight limitations of preclinical models in predicting human payload exposure, address appropriate methods to assess ADC stability, and discuss the clinical implications of altering ADC linker stability. By re-evaluating the role of linker stability in ADC design, this review aims to inform more rational strategies for the development of next-generation ADCs.