Preface

Antibody–drug conjugates (ADCs) are on a roll. With eleven market approvals today – of which eight were garnered in the past 5 years alone – and a packed clinical pipeline nearing another 90, ADCs are increasingly homing in on the dream of more effective and selective cancer treatment using the concept of targeted drug delivery. It was early in the 20th century (1907) when Paul Ehrlich coined his dream of the selective killing of pathogens from a human host with a defined chemical compound. It was Ehrlich's imagination and perseverance that culminated in the first chemotherapy for a specific disease, i.e. treatment of syphilis with Salvarsan. Moreover, it served as an inspiration for many others to translate this “magic bullet” concept to other disease areas, including cancer. In fact, the targeted delivery of a (highly) cytotoxic payload to cancerous cells by means of attachment to an antibody, thereby increasing the therapeutic window, has been the cornerstone for the success of the field of ADCs today.

It has been a long and rocky road. Already in the early 1950s, Mathé and colleagues demonstrated that diazotization of aminopterin, followed by subjecting this reactive intermediate to a mix of immunoglobulins extracted from the blood of immunized hamsters, could prolong the lives of xenografted mice. This pivotal experiment was soon followed by other efforts involving the random conjugation of antibodies with a range of cytotoxic drugs (folate analogs, mustards, vinca alkaloids), leading to the first patient studies in the 1980s. Unfortunately, no clinical benefit was noted for this early generation of ADCs, for many reasons, including murine antibodies leading to immune responses, relatively non-potent drugs, lack of control of stoichiometry and attachment site, and notably, the lack of a suitable linker connecting the antibody and the payload. In this light, it is not surprising that the introduction of a suitable chemical linker by companies like Wyeth and Bristol Myers Squib (BMS) in the late 20th century turned out to be a major step-up in improving the properties of the ADC as a whole, eventually leading to early approval of ADCs like Mylotarg^® and Adcetris^®, landmarking the current success of the fields of ADCs. In fact, it may be calculated based on historical developments that the success rate of ADC is unprecedented in the field of oncology, averaging at around 14%, taking into consideration all ADCs entering clinical trials ADCs in the period of 1995–2014,^1,2  which may further rise in case an additional number of the 14 ADCs still under active clinical evaluation reach approval (Table 1).

Clearly, a good ADC linker is much more than only “the part in the middle” and fulfills many important properties. First and foremost, a linker provides a stable connection between an antibody and a small-molecule payload, i.e., persisting during circulation of the conjugate in the bloodstream. At the same time, a linker must ensure the efficient release of cytotoxin upon internalization into cancerous tissue. Thirdly, the chemical ligation of the linker to payload must be achieved without compromising binding efficiency of the antibody, must retain antibody stability, despite the attachment of multiple copies of a (typically highly hydrophobic) small-molecule drug, and finally must ensure that the pharmacokinetic properties of the ADC are not too negatively impacted.

This book provides a contemporary overview of ADC linkers and their properties. After a general introduction of ADCs (Chapter 1), a comprehensive review of all clinical-stage (and emerging preclinical) conjugation chemistries is provided (Chapter 2), followed by an in-depth discussion of linker-design elements, including drug-release mechanisms, i.e. hydrolytic release at acidic pH, enzymatic cleavage, and disulfide bond reduction (Chapter 3). The next three chapters discuss various specific linker subcategories, including non-cleavable linkers (Chapter 4), protease-sensitive linkers (Chapter 5), and acid-sensitive linkers (Chapter 6). While most linker technologies (and most ADCs in the clinic) pertain to amino-functionalized payloads, alcohol-releasing linkers form an important subset (Chapter 7). The emerging field of click-release linkers is then discussed (Chapter 8), followed by two chapters specifically devoted to polar linkers, such as PEG-derived linkers (Chapter 9) and other polar linkers and linker-drugs (Chapter 10). The concluding chapter provides a clear demonstration of how cunning linker design can lead to a highly successful ADC linker-drug technology (Chapter 11).

Finally, this book would not have been possible without the excellent insights and clear summaries provided by the various authors. We are greatly thankful for their respective contributions to this book.

The ADC field is in a good space, with the chemical linker as the “crucial part in the middle”. Enjoy reading.

John Lambert

Floris van Delft