Diazaborines Are a Versatile Platform to Develop ROS‐Responsive Antibody Drug Conjugates**

Abstract Antibody–drug conjugates (ADCs) are a new class of therapeutics that combine the lethality of potent cytotoxic drugs with the targeting ability of antibodies to selectively deliver drugs to cancer cells. In this study we show for the first time the synthesis of a reactive‐oxygen‐species (ROS)‐responsive ADC (VL‐DAB31‐SN‐38) that is highly selective and cytotoxic to B‐cell lymphoma (CLBL‐1 cell line, IC 50 value of 54.1 nM). The synthesis of this ADC was possible due to the discovery that diazaborines (DABs) are a very effective ROS‐responsive unit that are also very stable in buffer and in plasma. DFT calculations performed on this system revealed a favorable energetic profile (Δ G R=−74.3 kcal mol −1 ) similar to the oxidation mechanism of aromatic boronic acids. DABs’ very fast formation rate and modularity enabled the construction of different ROS‐responsive linkers featuring self‐immolative modules, bioorthogonal functions, and bioconjugation handles. These structures were used in the site‐selective functionalization of a VL antibody domain and in the construction of the homogeneous ADC.