Antibody-drug conjugates (ADCs) are a growing class of cancer therapeutics that links a highly cytotoxic cancer drug (“payload”) to an antibody for highly specific cancer cell-targeting. The linker that connects the antibody and payload is key to ADC efficacy and is often designed to allow traceless release of the payload upon contact with cancer-specific biomarkers. However, commonly employed cleavable linkers suffer from poor solubility, instability in rodent plasma, and instability in circulation. Thus, there is continued need to develop improved cleavable linkers with different modes of action for the generation of superior ADCs. Cancer cells are known to exhibit increased intrinsic oxidative stress. Therefore, compared to healthy cells, cancer cells have elevated levels of Reactive-Oxygen Species (ROS), such as hydrogen peroxide (the most long-lived ROS). Thus, ROS has recently become an attractive target for the development of prodrugs which are only activated in the high-ROS environment of cancer. Several small molecule prodrugs have been developed which are activated by hydrogen peroxide allowing selective drug release and reduced off-target effects. In this work, we utilised this approach to develop ROS-responsive linkers for incorporation into ADCs. These linkers can self-immolate upon activation by hydrogen peroxide, releasing the cytotoxic payload only in contact with the high-ROS environment of cancer. These linkers are responsive yet stable in human and mouse plasma. ADCs containing such peroxide-cleavable linkers were synthesised and evaluated for their <i>in vitro</i> efficacy and mechanism of action in high-ROS breast cancer cell lines.

Peroxide-cleavable linkers for antibody-drug conjugates

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ACS Fall 2022

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