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

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, IC50 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 (Delta GR=-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.

Automated summary

ADCs are a new class of therapeutics combining cytotoxic drugs and antibodies to selectively deliver drugs to cancer cells. The synthesis of a ROS-responsive ADC in this study demonstrated the effectiveness of DABs and their potential for constructing different ROS-responsive linkers. DFT calculations showed a favorable energetic profile, enabling the site-selective functionalization of antibody domains and construction of homogeneous ADCs.