Abstract 2856: Pyrrolobenzodiazepine (PBD) dimers - potent next generation warheads in antibody drug conjugates (ADCs) targeted at both solid and haematological tumors.

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 a range of 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 the limitation that some tumour types lack sensitivity. Four PBD dimer drug linkers representing different PBD dimer warheads and two different attachment sites (N10 and C2) for the linker on the drug were synthesised. Trastuzumab-ADCs were prepared using these drug linkers with a drug-antibody ratio (DAR) below 3 and with attachment of the cleavable valine-alanine dipeptide linker to cysteine residues. Efficacy was evaluated in vitro against Her2 +ve and -ve cell lines and in vivo against human breast cancer Her2-expressing BT474 xenografts. All four ADCs showed durable complete regressions at 1mg/kg (i.v., qwk x 3) and significant growth delays at 0.3 mg/kg. A PBD-containing ADC was further evaluated against a haematological target. In vitro, the ADC gave a greater than 6-log differential cell killing between an expressing and a non-expressing cell line. In vivo, using the qwk x 3 treatment schedule, durable complete regressions were achieved at a dose of 0.1 mg/kg, whereas the naked antibody had no activity at a dose of 2.5 mg/kg. These data clearly demonstrate that antibody delivery of PBD dimers can result in curative antitumor activity against both solid and haematological tumor targets at low doses and DARs and represent the most promising next-generation ADCs for clinical development. Citation Format: John A. Hartley, Luke Masterson, Stephen Gregson, Thais Cailleau, Ebole Ezeadi, Jean-Noel Levy, Gary Kemp, Arnaud Tiberghien, Elizabeth Dunny, Francois D9Hooge, Lauren Adams, David Williams, Patrick van Berkel, Philip W. Howard. Pyrrolobenzodiazepine (PBD) dimers - potent next generation warheads in antibody drug conjugates (ADCs) targeted at both solid and haematological tumors. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2856. doi:10.1158/1538-7445.AM2013-2856