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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.

Abstract

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 (in 2013) have paved the way for ongoing clinical trials that are evaluating more than 60 further ADC candidates. The limited success of first-generation ADCs (developed in the early 2000s) informed strategies to bring second-generation ADCs to the market, which have higher levels of cytotoxic drug conjugation, lower levels of naked antibodies and more-stable linkers between the drug and the antibody. Furthermore, lessons learned during the past decade are now being used in the development of third-generation ADCs. In this Review, we discuss strategies to select the best target antigens as well as suitable cytotoxic drugs; the design of optimized linkers; the discovery of bioorthogonal conjugation chemistries; and toxicity issues. The selection and engineering of antibodies for site-specific drug conjugation, which will result in higher homogeneity and increased stability, as well as the quest for new conjugation chemistries and mechanisms of action, are priorities in ADC research.

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Figure 1: Structures of selected first-, second- and third-generation ADCs.
Figure 2: Example of first-, second- and third-generation ADC research and development.
Figure 3: Third-generation ADCs are designed to expand the therapeutic window.

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Correspondence to Alain Beck.

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Competing interests

A.B., L.G. and N.C. are employees of the Pierre Fabre Research Institute, Toulouse, France, which develops mAbs and ADCs, and has a collaboration agreement with AbbVie for the development of hepatocyte growth factor receptor (HGFR)-specific antibodies and ADCs (ABT-700 and ABBV-399). C.D. has received research funding from Pierre Fabre and Sanofi, and has worked as a consultant for Sanofi and Bristol-Myers Squibb.

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Glossary

Permeability glycoprotein 1

(PGP; also known as multidrug resistance protein 1 (MDR1), ATP-binding cassette subfamily B member 1 (ABCB1) or CD243). It is an important protein of the cell membrane that pumps many foreign substances out of cells.

Strain-promoted azide–alkyne cycloaddition

(SPAAC). A bioorthogonal non-toxic ligation reaction that allows site-specific conjugation.

Glycan remodelling

Enzymatic tailoring of the oligosaccharides of an antibody to enable the introduction of reactive groups that are exploited for the site-specific attachment of cytotoxic drugs.

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Beck, A., Goetsch, L., Dumontet, C. et al. Strategies and challenges for the next generation of antibody–drug conjugates. Nat Rev Drug Discov 16, 315–337 (2017). https://doi.org/10.1038/nrd.2016.268

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