Abstract
Paul Ehrlich pioneered the use of cytotoxic chemotherapy and pointed to the future of antibodies as 'magic bullets'. These two classes of therapeutic agent are both widely used in oncology, but they have largely developed independently. Naked antibodies have specificity but, as single agents, often have limited antitumour activity, particularly against solid tumours. Because of their favourable safety profile, antibodies can be combined successfully with chemotherapy, which alone suffers from lack of tumour specificity and significant systemic toxicity.
Development of antibody-drug conjugates (ADCs) has the aim of achieving potent and selective target cell killing by taking advantage of the selectivity of a monoclonal antibody combined with the potent cell-killing activity of a small molecule cytotoxic. Although simple in concept, developing clinically effective ADCs has proven to be highly challenging and it is only recently that they are emerging as an important and rapidly growing class of therapeutic agents against both haematological malignancies and solid tumours with potential in other therapeutic areas.
The three components of an ADC - antibody, linker and drug - all need careful optimization. In addition, the choice of target antigen is critical to the activity and tolerability of an ADC. The current status of approved ADCs, and the considerable pipeline of ADCs in clinical and pre-clinical development will be reviewed. The rational design of improved linker and conjugation technologies and novel classes of drug warhead will be discussed. This will include the highly potent DNA minor groove interstrand cross-linking pyrrolobenzodiazepine (PBD) dimer class of warhead which is currently being evaluated in multiple clinical trials. The considerable manufacturing, pharmacological and clinical challenges posed by ADCs will also be discussed.
