CHAPTER 14: Pyrrolobenzodiazepine Dimers as Antibody–Drug Conjugate (ADC) Payloads

The pyrrolobenzodiazepine (PBD) ring system was first discovered in the 1960s and is found in several naturally occurring potent anti-tumour antibiotics. The mode of action of PBDs involves sequence-selective [purine–guanine–purine (PuGPu)] alkylation in the minor groove of DNA through covalent binding from guanine N2 to the PBD C11-position. Dimerization of the PBD ring system gives molecules that can cross-link DNA, which leads to a substantial increase in potency and DNA binding affinity and an extension of sequence-selectivity compared with monomers. PBD dimers feature as the cytotoxic component of numerous ADCs being evaluated in clinical trials. PBD-ADC clinical candidates loncastuximab tesirine, camidanlumab tesirine and rovalpituzumab tesirine employ a PBD N10 linkage while vadastuximab talirine uses a C2-linkage. The PBD dimer scaffold is versatile and offers many opportunities to diversify the ADC platform, with extensive research being performed worldwide to develop the next generation of PBD payload–linker molecules. The search for new PBD payload–linker molecules has mainly focused on changes in payload structure (e.g. PBD C2 modification and macrocyclisation), alternative conjugation strategies (e.g. haloacetamides, ‘click’ approaches and pyridyl disulphides), non-peptide triggers in the linker (e.g. disulphides) and non-cleavable derivatives (i.e. payload release through antibody degradation).