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

Abstract

Antibody-drug conjugates (ADCs) are an ew class of therapeutics that combine the lethality of potent cytotoxic drugs with the targeting ability of antibodies to selectively deliver drugs to cancer cells.Inthis study we showfor the first time the synthesis of ar eactive-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 avery effective ROSresponsive unit that are also very stable in buffer and in plasma. DFT calculations performed on this system revealed af avorable energetic profile (DGR = À74.3 kcal mol À1 )similar to the oxidation mechanism of aromatic boronic acids.D ABs very fast formation rate and modularity enabled the construction of different ROS-responsive linkers featuring self-immolative modules,b ioorthogonal functions,a nd bioconjugation handles.T hese structures were used in the site-selective functionalization of aV Lantibody domain and in the construction of the homogeneous ADC.