Preclinical Evaluation of ADCs Delivering Highly Potent Pyrrolobenzodiazepine (PBD) Dimers

The pyrrolobenzodiazepines (PBDs) are tricyclic natural products that exert their biological activity by binding and covalently bonding in the minor groove of DNA. An important development in the history of the PBDs was the synthesis of nonnatural PBD dimers that have the ability to form highly cytotoxic DNA cross-links. Rational structural modification can produce PBD dimers with exquisite potency making them ideal candidates for the 'warhead' component of antibody drug conjugates. Two different sites on PBD dimers have been utilised to attach linkers, N10 and C2, and antibody PBD conjugates (APCs) of both types have shown impressive in vitro and in vivo activity against both haematological malignancies and solid tumours. Several APCs including vadastuximab talirine and rovalpituzumab tesirine have progressed into early phase clinical trials. ADCs delivering PBD dimer payloads represent a novel mode of action in the ADC area. An important feature of the highly cytotoxic DNA interstrand cross-links produced by the PBD dimers is their persistence in cells. This contributes to their potency and also to their ability to affect slowly proliferating target cells, including cancer stem cells. The PBD dimers are a highly flexible platform with many advantages over existing payloads. These include the ability to target low copy number antigens and to exploit low drug-antibody ratios due to the high warhead potency. APCs are active in tumour types inherently resistant to other warhead classes and against multidrug-resistant tumours.