Discussion

The pyrrolobenzodiazepine (PBD) dimers are a class of rationally designed DNA minor groove, sequence selective, cross-linking agents. The non-distortive nature of PBD interstrand cross-links results in their persistence compared to those produced by conventional agents such as the nitrogen mustards and platinum drugs. Members of this class can exhibit picomolar or sub-picomolar activity against human tumour cell lines and demonstrate curative activity in human tumour xenograft models. The fully synthetic PBD dimers are ideally suited for a role in strategies aimed at targeting and releasing highly cytotoxic agents directly at a tumour site such as antibody drug conjugates (ADCs). They combine exquisite potency with a demonstrated therapeutic index (unlike other warheads such as calicheamycin), are not cross-resistant with widely used chemotherapy agents, and their unique mode of action sets them apart from the tubulin binders (maytansinoids and auristatins) that currently dominate the ADC arena but which have limitations.

This presentation will review the pre-clinical development of this novel class of ADCs and the emerging clinical data.