Antibody-drug conjugates (ADCs) delivering pyrrolobenzodiazepine (PBD) dimers for cancer therapy
JA Hartley - Expert Opinion on Biological Therapy, 2021 - Taylor & Francis
Expert Opinion on Biological Therapy, 2021•Taylor & Francis
Introduction The rationally designed pyrrolobenzodiazepine (PBD) dimers emerged around
ten years ago as a new class of drug component for antibody-drug conjugates (ADC). They
produce highly cytotoxic DNA cross-links, exploiting a completely different cellular target to
the auristatin and maytansinoid tubulin inhibitor classes and a different mode of DNA
damage to other DNA interacting warheads such as calicheamicin. Areas covered The
properties which make the PBD dimers suitable warheads for ADCs, and the development of …
ten years ago as a new class of drug component for antibody-drug conjugates (ADC). They
produce highly cytotoxic DNA cross-links, exploiting a completely different cellular target to
the auristatin and maytansinoid tubulin inhibitor classes and a different mode of DNA
damage to other DNA interacting warheads such as calicheamicin. Areas covered The
properties which make the PBD dimers suitable warheads for ADCs, and the development of …
Introduction
The rationally designed pyrrolobenzodiazepine (PBD) dimers emerged around ten years ago as a new class of drug component for antibody-drug conjugates (ADC). They produce highly cytotoxic DNA cross-links, exploiting a completely different cellular target to the auristatin and maytansinoid tubulin inhibitor classes and a different mode of DNA damage to other DNA interacting warheads such as calicheamicin.
Areas covered
The properties which make the PBD dimers suitable warheads for ADCs, and the development of the two main payload structures talirine and tesirine, are discussed. The clinical experience with the twenty PBD dimer-containing ADCs to enter the clinic is reviewed, with a focus on vadastuximab talirine and rovalpituzumab tesirine, both of which were discontinued following pivotal studies, and loncastuximab tesirine and camidanlumab tesirine which are progressing towards approval.
Expert opinion
Reviewing the clinical efficacy and safety data from almost forty clinical trials of PBD dimer-containing ADCs highlights the complexities and challenges of ADC early clinical development. It enables some conclusions to be made about reasons for failure and suggests strategies to optimise the future clinical development of this promising class of ADCs in a rapidly expanding field.
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