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  • Review Article
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Unlocking the potential of antibody–drug conjugates for cancer therapy

Nature Reviews Clinical Oncology volume 18, pages 327–344 (2021)Cite this article

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Abstract

Nine different antibody–drug conjugates (ADCs) are currently approved as cancer treatments, with dozens more in preclinical and clinical development. The primary goal of ADCs is to improve the therapeutic index of antineoplastic agents by restricting their systemic delivery to cells that express the target antigen of interest. Advances in synthetic biochemistry have ushered in a new generation of ADCs, which promise to improve upon the tissue specificity and cytotoxicity of their predecessors. Many of these drugs have impressive activity against treatment-refractory cancers, although hurdles impeding their broader use remain, including systemic toxicity, inadequate biomarkers for patient selection, acquired resistance and unknown benefit in combination with other cancer therapies. Emerging evidence indicates that the efficacy of a given ADC depends on the intricacies of how the antibody, linker and payload components interact with the tumour and its microenvironment, all of which have important clinical implications. In this Review, we discuss the current state of knowledge regarding the design, mechanism of action and clinical efficacy of ADCs as well as the apparent limitations of this treatment class. We then propose a path forward by highlighting several hypotheses and novel strategies to maximize the potential benefit that ADCs can provide to patients with cancer.

Key points

  • Antibody–drug conjugates (ADCs) comprise three main components: an antibody, a linker and a payload. The clinical properties of ADCs depend on the characteristics of all three of these components.

  • The mechanism of action of ADCs is complex, often requiring drug internalization followed by intracellular processing and payload release. Unlike many standard therapies used in oncology, ADCs must be acted upon by cancer cells for optimal effectiveness.

  • The pharmacodynamic properties of ADCs make them uniquely suited for activity in treatment-refractory cancers, which is reflected in the current clinical indications for ADCs in oncology.

  • ADCs exhibit both on-target and off-target toxicities; while most toxicities seem to be related to the nature of the payload, notable examples of target-dependent toxicities exist.

  • Important and potentially practice-changing innovations in ADC design, biomarker development and combination therapies are ongoing in preclinical and clinical studies.

  • An improved understanding of the interactions between ADCs and tumours is essential for clinicians and scientists to realize the true potential of this drug class for the treatment of cancer.

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Fig. 1: Modular components of ADCs.
Fig. 2: Mechanisms of action of ADCs.
Fig. 3: Proposed mechanisms of resistance to ADCs.
Fig. 4: Rational combination therapy strategies to augment ADC activity.

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Acknowledgements

All authors acknowledge support from the NCI Cancer Center Support Grant P30-CA008748. J.Z.D. acknowledges support from the Paul Calabresi Career Development Award for Clinical Oncology K12 CA184746 and a 2020 Conquer Cancer–Breast Cancer Research Foundation Young Investigator Award. S.C. acknowledges support from the Breast Cancer Research Foundation. The authors thank Linda Vahdat and Pedram Razavi of Memorial Sloan Kettering Cancer Center for editorial assistance and appreciate the helpful comments and suggestions provided by the journal editors and reviewers.

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  1. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Joshua Z. Drago, Shanu Modi & Sarat Chandarlapaty

  2. Weil Cornell Medicine, New York, NY, USA

    Joshua Z. Drago, Shanu Modi & Sarat Chandarlapaty

  3. Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Sarat Chandarlapaty

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J.Z.D. has received Honoraria from OncLive. S.M. has received institutional research support from AstraZeneca, Daiichi Sankyo, Genentech, Novartis and Seattle Genetics; has participated in consulting/advisory boards for AstraZeneca, Daiichi Sankyo, Genentech, Macrogenics and Seattle Genetics; and has received speakers’ bureau from AstraZeneca, Daiichi Sankyo, Genentech and Seattle Genetics. S.C. has received consulting fees from Eli Lilly, Novartis and Paige.ai, and has received research support (via his institution) from Daiichi-Sankyo, Eli Lilly, Novartis and Sanofi.

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Nature Reviews Clinical Oncology thanks Howard Burris III, Yasuhiro Matsumura, Dhaval K. Shah and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Drago, J.Z., Modi, S. & Chandarlapaty, S. Unlocking the potential of antibody–drug conjugates for cancer therapy. Nat Rev Clin Oncol 18, 327–344 (2021). https://doi.org/10.1038/s41571-021-00470-8

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