![]() A striking example is the human epidermal growth factor receptor 2 (HER2) space, 4 where Kadcyla (ado‑trastuzumab emtansine), an ADC with first generation conjugation chemistry and a tubulin inhibitor as payload (DM1), achieved approval, but it was only after a change in linker-payload chemistry that the true therapeutic possibilities were revealed with Enhertu (trastuzumab deruxtecan), an ADC carrying a high load of moderately potent Topoisomerase-I inhibitor, recently leading to a significant increase in efficacy up to a redefinition of treatable patient population. This development was enabled by a constantly evolving understanding of the interplay between the different ADC components and their relationship with disease biology. Since then, the pace of approvals has increased in line with maturing technologies, resulting in 11 additional ADC approvals between 20. Consequently the market dynamics were slow, with just three approved ADC drugs until 2017. While this led to successful ADC product approvals, it became clear that the resulting narrow therapeutic windows hampered the use of the modality for broader targets and indications. ![]() Early ADC developments centred on using cytotoxins with the highest potency together with limited linker designs. Since then, the field has continued to evaluate and improve the individual ADC components: antibody, linker and payload. ![]() More than 20 years ago, the first ADC, Mylotarg, was approved for use in patients with relapsed or refractory acute myeloid leukaemia (AML). There are 14 approved ADCs on the global market, all for oncology indications, and over 140 ADCs currently in clinical development” The culmination of two decades of learning The ultimate goal of the ADC concept is to maximise the potency of treatment and reduce unwanted side effects on healthy tissues. Functionality of ADCs is dependent on being internalised together with the target into the endosomal/lysosomal compartment, where the cytotoxin is released by controllable chemistry leading to the death of the cancer cell. ![]() 3 The linker is designed to have properties that physically connect the antibody and cytotoxic drug, and facilitate favourable pharmacokinetic behaviour in circulation, as well as controlled release of the cytotoxin once delivered. The payload is selected with a mode of action tailored to the clinical indication and based on available chemistry that enables the stable attachment of the payload to the antibody at well-defined sites of conjugation in suitable stoichiometry (drug-to-antibody ratio DAR). The antibody is chosen based on its high selectivity and affinity for the tumour-associated antigen and its ability to facilitate internalisation or endocytosis, wherein molecules such as proteins are engulfed by the cell membrane and drawn into the cell. 2 The role of the antibody is to deliver the payload to a specific site such as a cancer cell. To engineer an ideal ADC, the drug must achieve a cohesive, molecular partnership between the cellular target, antibody, cytotoxic payload and chemical linker. The fundamental basis of engineering ADCs is to conjugate specific antibodies, using a chemical linker, to a potent anti-cancer drug – often referred to as a cytotoxic payload in the context of ADCs. Early dose-limiting toxicities have prohibited the expansion of ADCs into larger and more complex tumour indications, dampening the initial hopes of a new “magic bullet” in the fight against cancer. 1 While the first successes underscored the potential of this class of targeted therapies, they also revealed bottle‑necks inhibiting these first‑generation products from fully delivering on their initial promise. In total, there are 14 approved ADCs on the global market, all for oncology indications, and over 140 ADCs currently in clinical development. An ADC combines the specificity of an antibody and the potent power of an anti‑cancer agent or disease-relevant toxin. ANTIBODY-DRUG conjugates (ADCs) are therapeutic molecules designed as highly targeted medicines with the promise of changing the way we treat cancer and other diseases.
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