From Anthramycin to Pyrrolobenzodiazepine (PBD)‐Containing Antibody–Drug Conjugates (ADCs)

Abstract

The pyrrolo[2,1‐c][1,4]benzodiazepines (PBDs) are a family of sequence‐selective DNA minor‐groove binding agents that form a covalent aminal bond between their C11‐position and the C2‐NH2 groups of guanine bases. The first example of a PBD monomer, the natural product anthramycin, was discovered in the 1960s, and the best known PBD dimer, SJG‐136 (also known as SG2000, NSC 694501 or BN2629), was synthesized in the 1990s and has recently completed Phase II clinical trials in patients with leukaemia and ovarian cancer. More recently, PBD dimer analogues are being attached to tumor‐targeting antibodies to create antibody–drug conjugates (ADCs), a number of which are now in clinical trials, with many others in pre‐clinical development. This Review maps the development from anthramycin to the first PBD dimers, and then to PBD‐containing ADCs, and explores both structure–activity relationships (SARs) and the biology of PBDs, and the strategies for their use as payloads for ADCs.

Identification of GPC2 as an Oncoprotein and Candidate Immunotherapeutic Target in High-Risk Neuroblastoma

“…Importantly, ADCs with the identical linker have recently been found to be stable in human and monkey serum, but exhibit some instability in mouse serum most likely due to selective cleavage by the carboxlesterase 1C enzyme in certain murine models (Seaman et al, 2017). However, the half-life of PBD dimers in vivo is very short and thus the likelihood of free toxin contributing to the in vivo tumor regression observed here is low (Mantaj et al, 2017; Seaman et al, 2017). Finally, by validating dense cell surface expression of GPC2 in medulloblastomas and retinoblastomas we have additionally nominated these lethal pediatric malignancies to also potentially benefit from GPC2-directed therapies.…”

“…We next developed a GPC2 directed ADC, D3-GPC2-PBD, by conjugating D3-GPC2-IgG1 with pyrrolobenzodiazepine (PBD) dimers, achieving a drug-antibody ratio (DAR) of 2.6 (Figure 7C). PBD dimers are a potent cytotoxic DNA minor groove interstrand crosslinking agent that are increasingly being used for anticancer therapy (Mantaj et al, 2017; Saunders et al, 2015; Seaman et al, 2017), and was selected here because of the relatively higher potency of DNA damaging agents compared to tubulin binding agents in this disease.…”

“…PBD dimers have several advantages over other ADC payloads, including utilizing a unique mechanism of action resulting in rapidly formed and more persistent PBD-DNA adducts with limited DNA helix disruption thus escaping DNA repair mechanisms (Mantaj et al, 2017). Consequently, it is not unexpected that PBD dimer containing ADCs have activity in multidrug resistant malignancies, a fact that is immediately relevant for children with neuroblastoma (Saunders et al, 2015; Seaman et al, 2017).…”

A DNA-Interacting Payload Designed to Eliminate Cross-Linking Improves the Therapeutic Index of Antibody–Drug Conjugates (ADCs)

“…Despite (8). Since DNA-interacting agents are widely used in cancer therapy, and two of the four approved ADCs use a DNA interacting compound (calicheamicin), there has been a recent shift in emphasis towards using such compounds as payloads in ADCs (9)(10)(11)(12)(13)(14)(15). Indeed, the first ADC of a highly potent DNA interacting agent to be evaluated in the clinic was gemtuzumab ozogamicin, which incorporated calicheamicin, a compound that causes DNA double strand breaks.…”

The role of pharmacology in anticancer drug development

“…It showed favourable pharmacokinetics (plasma peak levels of 171 nM, far above the GI50 value) and interesting in vivo activity against several HTX models (p<0.01). These data led to the development of SJG-136, a pyrrolobenzodiazepine dimer that went into a clinical Phase I study and Phase II studies in ovarian cancer and leukaemia [30]. Phortress ( Figure 3) is a water-soluble benzothiazole prodrug of 5F-203, that is active (low nanomolar GI 50 ), and selective against breast, ovarian and lung cancer [31].…”