Self‑immolative and traceless linkers are rapidly becoming one of the most powerful “hidden” levers in ADC design, quietly transforming a single antibody scaffold into multiple distinct medicines and unlocking payloads once considered too toxic to use. In this Medness Spotlight, Suhail Ahmed Kabeer walks through how these vanishing linkers work, why the trastuzumab platform (Kadcyla, Enhertu, SYD985) is the ideal case study, and how clean‑release chemistry enables potent warheads like duocarmycins and next‑generation TOP1 inhibitors to be deployed safely and selectively in tumors.
The article also explores how self‑immolative systems are extending ADCs beyond traditional internalizing targets, enabling extracellular payload release and potent bystander effects in challenging settings such as heterogeneous HER2 expression and non‑internalizing antigens.
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