Development of Diazaborines as ROS Sensitive Linkers for the Construction of Stimuli-Responsive Antibody Drug Conjugates

06 July 2021, Version 1
This content is a preprint and has not undergone peer review at the time of posting.


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. The synthesis of ADCs is challenging, and studies in this area show that their therapeutic effect is highly dependent on the chemistries used to connect both functions. Therefore, the linker evolved in recent years from being a simple chemical spacer to a functional structure that controls the potency and selectivity of ADCs. The linker provides a platform to integrate mechanisms to access synthetic homogeneity, stability in circulation and more importantly the installation of chemical units that release the drug as a response to the disease chemical environment. 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 (0.422 and 0.103M-1S-1 with 100 and 10 equiv. of H2O2 respectively), that is also very stable in buffer (over 14 days at different pHs) and in plasma (over 5 days). DFT calculation performed on this system revealed a favourable energetic profile (ΔGR = –74.3 kcal/mol) 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 and in the construction of the homogeneous ADC. The enclosed ROS-responsive linker technology based on DABs, is expected to become a valuable tool to prepare stimuli responsive therapeutic materials, as ROS is a very important hallmark in several important diseases


Antibody-drug conjugate
Boronic acids
Oxidative stress
Cleavable linkers

Supplementary materials

Supplementary Information
Supplementary Information for: Development of Diazaborines as ROS Sensitive Linkers for the Construction of Stimuli-Responsive Antibody Drug Conjugates


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