Antibody–drug conjugates (ADCs) are an anticancer therapy utilizing an antibody to carry a cytotoxic molecule directly to a tumour, thus avoiding the systemic side effects that can occur when non-targeted anticancer agents are administered systemically. Today, we recognize ADCs as being comprised of three distinct components, the antibody itself, the cytotoxic payload, and the chemical linker that joins the two together.
The origin of the ADC concept can be traced back over a century to the German scientist and physician Paul Ehrlich (Figure 1) who first proposed the concept of selectively delivering a cytotoxic drug (which he termed a “toxophore”) to a tumour via a targeting agent (which he termed a “haptophore”).1,2 Ehrlich also coined the phrase ‘magic bullet’ to describe his vision, and this term is still used by some today to describe the concept of ADCs.
Paul Ehrlich (1854–1915).
Ehrlich's concept of a targeted therapy was first exemplified when methotrexate (MTX) was linked to an antibody targeting leukemia cells. However, early studies relied on the first-generation targeting agents available at the time, such as mouse polyclonal antibodies, and non-covalent association of the payloads to the antibody. Not surprisingly, these early ADCs based on immunogenic antibodies and sub-optimal linkage of the payload led to rapid excretion and significant systemic toxicities. In 1975, the landmark development of mouse monoclonal antibodies (mAbs) based on hybridoma technology developed by Kohler and Milstein greatly advanced the development of ADCs. The first human clinical trial followed less than a decade later, with the antimitotic vinca alkaloid vindesine as the cytotoxic payload. Further advances in antibody engineering enabled the production of humanized mAbs with significantly reduced immunogenicity in humans compared with the murine mAbs used for early ADCs. Also, advances in construction of the chemical linker between the payload and antibody provided greater product stability while ensuring that the payload would cleave at the appropriate time at the tumour site. This accumulated experience led to the four ADCs and two immunotoxins presently approved, and to the approximately 70 others presently at various stages of clinical development.
Since the first evaluation of methotrexate as a payload, many other chemical entities and protein toxins with various mechanisms of action have been investigated. The enediyne calicheamicin, a DNA-cleaving agent, was the first payload to be approved in ADC format (in the form of gemtuzumab ozogamicin, Mylotarg®) in 2000. It was subsequently withdrawn from the market in 2010 due to efficacy/toxicity issues, but was reapproved in 2017 due to the efficacy demonstrated in a sub-set of acute myeloid leukaemia (AML) patients. The maytansines and auristatins (both tubulin inhibitors) are presently the predominant payload classes incorporated into ADCs but, more recently, DNA-interactive agents such as topoisomerase inhibitors, DNA cross-linkers [i.e., the pyrrolobenzodiazepine (PBD) dimers], DNA mono-alkylators [e.g., the indolobenzodiazepines (IGNs), pyridinobenzodiazepines (PDDs) and duocarmycins] along with protein toxins have all been incorporated into ADCs with varying degrees of success.
The genesis of this book was an attempt to document the different types of payloads developed and evaluated, and to chart the progress of each of these payload classes in an effort to encapsulate the latest industry thinking on ADC payload development. It includes chapters on payloads that are components of ADCs which have reached the approval stage, and some that are still at the research and development stage.
Inevitably, a book of this size and complexity has involved a significant effort from all the authors associated with the 22 chapters, and the editors would like to acknowledge their hard work, dedication and patience in bringing this book to completion.
David E. Thurston and Paul J. M. Jackson
