Linker and conjugation chemistry as determinants of ADC toxicity profiles
Bioconjugate Insights 2026; 1(4), 203–214
DOI: 10.18609/bci.2026.024
ADC toxicity reflects the interplay of target biology, payload potency, linker chemistry, conjugation method, drug-to-antibody ratio (DAR), physicochemical properties, and dosing schedule. Linkers and conjugation chemistry are active determinants of toxicity because they control when, where, and in what form the payload is released. Cleavable peptide linkers, including valine-citrulline and tetrapeptide motifs, can drive efficient intracellular payload release and bystander killing, but may also increase exposure of non-tumor cells after antigen-independent uptake. By contrast, non-cleavable linkers and selected enzyme-cleavable systems, such as b-glucuronide linkers, can improve systemic stability and limit premature release, though sometimes at the cost of reduced bystander activity. The key translational point is that plasma stability alone does not predict safety; ADC toxicity depends on the entire disposition pathway, including circulation stability, target and off-target uptake, lysosomal processing, catabolite permeability, payload exposure, and cumulative tissue injury.