Pyrrolobenzodiazepine

Anthramycin contains pyrrolobenzodiazepine core

Pyrrolobenzodiazepines or PBDs, a class of natural products with antibiotic or anti-tumor properties, are produced by various actinomycetes (a broad group of bacteria that form thread-like filaments in the soil and are responsible for the distinctive scent of freshly exposed, moist soil), are sequence selective DNA alkylating compounds with significant antitumor properties. As a class of DNA-crosslinking agents they are significantly more potent than systemic chemotherapeutic drugs. Some PBDs have the ability to recognize and bond to specific sequences of DNA.^[1][2]

As DNA minor groove binding agents, pyrrolobenzodiazepines bind and cross-link specific sites of DNA of the cancer cell. This blocks the cancer cells’ division without distorting its DNA helix, thus potentially avoiding the common phenomenon of emergent drug resistance.

Use in ADCs

Some dimeric pyrrolobenzodiazepines are used as the cytotoxic drug payloads in antibody-drug conjugates, including vadastuximab talirine, also known as SGN-CD33A, which is being developed by Seattle Genetics for the treatment of patients acute myeloid leukemia, also called acute myelocytic leukemia or AML.^[3] Other companies, including Kolltan Pharmaceuticals (New Haven, Connecticut) and Genentech/Roche are developing novel antibody-drug conjugates with pyrrolobenzodiazepine as the cytotoxic drug payload. In May 2015 Kolltan Pharmaceuticals presented preclinical data from its anti-KIT antibody drug conjugate development program at the 11th Annual PEGS - The Essential Protein Engineering Summit (Boston). The preclinical agent, KTN0182A, is an anti-KIT, Pyrrolobenzodiazepine (PBD)-containing antibody-drug conjugate which demonstrated potent anti-tumor activity in vitro and in vivo against a broad range of tumor types.^[4]

Alternative mechanisms of action

In vitro, pyrrolobenzodiazepines typically demonstrate IC50 values in the low to mid picomolar range in a variety of cell types, and unlike the anti-tubulin agents, they can induce cell death in both dividing and non-dividing cells. Fully synthetic PBD dimers are ideally suited for the role of payload in an antibody-drug conjugate because, unlike other cytotoxic payloads such as calicheamycin, they combine potency with a demonstrated therapeutic index, 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 antibody-drug conjugate arena.^[5]

Development

Spirogen, a wholly owned subsidiary of AstraZeneca’s MedImmune founded in 2001 as a spin-out from several institutions, including University College London, and with partial funding by Cancer Research UK, has developed a novel class of highly potent cytotoxic warheads based on its proprietary pyrrolobenzodiazepines (PBDs). The company has been developing its PBD technology for more than ten years, including a standalone PBD agent in a Phase II study in acute myeloid leukemia.^[6]

References