Strategies and challenges for the next generation of antibody–drug conjugates

Key Points The development of antibody–drug conjugates (ADCs) has benefited from general improvements in the design of therapeutic monoclonal antibodies (mAbs) and from specific improvements in regard to methods for conjugate synthesis through which both homogeneity and stability is enhanced. Diversification of linking strategies and payloads has opened new perspectives to improve drug delivery to tumours while reducing drug exposure to normal tissues. To enhance the therapeutic index of ADCs, either the potency of the cytotoxic agent has to be improved to lower the minimum effective dose or the tumour selectivity has to be improved to increase the maximum tolerated dose. Protein structural characterization tools such as mass spectrometry and the development of quantitative bioanalytical assays will contribute to the identification of early-developability criteria for all of the ADC components (antibody, drug and linker). Recent ADC development has created a renewed interest in natural cytotoxic products, which are typically highly potent cytotoxic agents but often have unacceptable toxicities. In the future, breakthroughs in the efficacy of ADCs are likely to involve conjugates with previously unknown mechanisms of action. Alternative formats to mAbs, such as protein scaffolds (designed ankyrin-repeat proteins (DARPins), nanobodies, single-chain variable fragments (scFvs) and peptide–drug conjugates), dual-labelled ADCs and biparatopic drug conjugates, present new research avenues. There are several possible indications for ADCs: as single agents in patients with refractory or relapsing disease; in palliative settings, for consolidation or maintenance; and in combination with other agents as first-line therapy or in relapsed patients. Antibody–drug conjugate (ADCs), which aim to target highly cytotoxic drugs specifically to cancer cells, are one of the fastest growing classes of anticancer therapeutics, with more than 50 such agents currently in clinical trials. This Review discusses lessons learned and emerging strategies in the development of ADCs, including aspects such as target selection, the development of warheads, the optimization of linkers and new conjugation chemistries, and provides an overview of agents that are currently in clinical trials. Antibody–drug conjugates (ADCs) are one of the fastest growing classes of oncology therapeutics. After half a century of research, the approvals of brentuximab vedotin (in 2011) and trastuzumab emtansine