Consolidating the information comprised of the observed biotransformation species proposed structures, their concentration-time profiles and common chemical reactions that can be expected under such circumstances, we propose the biotransformation pathways for ADC1-4 depicted in Figure . After dosing, the ADC can undergo two competing reactions: 1) hydrolysis on the thio-succinimide linker, further stabilizing the conjugated payload and 2) deconjugation of the linker-payload, exposing the free thiol. For AZD8205, the vast majority of ADC went through reaction 1 as the main biotransformation pathway ensuring its in vivo stability. Upon deconjugation, further minor biotransformation products were identified. This represents a very small, albeit analytically interesting fraction of the circulating ADC pool. Understanding the underlying mechanisms behind the ADC biotransformation is critical to advance the drug candidate through discovery and development . While for small molecule drug candidates, the ADME studies and metabolite ID analysis is routinely performed, the biotransformation of therapeutic proteins is technically highly challenging. Nonetheless, there is an urgent need for understanding the comprehensive biotransformation profile of therapeutic proteins, because of the rapidly increasing diversity of complex therapeutic protein formats, and the resulting knowledge gap in connecting SAR to drug efficacy and safety.