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Antibody–drug conjugates come of age in oncology

Nature Reviews Drug Discovery volume 22, pages 641–661 (2023)Cite this article

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Abstract

Antibody–drug conjugates (ADCs) combine the specificity of monoclonal antibodies with the potency of highly cytotoxic agents, potentially reducing the severity of side effects by preferentially targeting their payload to the tumour site. ADCs are being increasingly used in combination with other agents, including as first-line cancer therapies. As the technology to produce these complex therapeutics has matured, many more ADCs have been approved or are in late-phase clinical trials. The diversification of antigenic targets as well as bioactive payloads is rapidly broadening the scope of tumour indications for ADCs. Moreover, novel vector protein formats as well as warheads targeting the tumour microenvironment are expected to improve the intratumour distribution or activation of ADCs, and consequently their anticancer activity for difficult-to-treat tumour types. However, toxicity remains a key issue in the development of these agents, and better understanding and management of ADC-related toxicities will be essential for further optimization. This Review provides a broad overview of the recent advances and challenges in ADC development for cancer treatment.

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Fig. 1: Structure and mechanism of action of conventional ADCs.
Fig. 2: Main characteristics of approved ADCs.
Fig. 3: Payload diversity in ADC pipeline.
Fig. 4: Number of new ADCs reaching clinical trials between 2012 and 2022.

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Acknowledgements

The authors thank the French National Cancer Institute (INCA) for its support.

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Authors and Affiliations

  1. CRCL INSERM 1052/CNRS 5286, University of Lyon, Hospices Civils de Lyon, Lyon, France

    Charles Dumontet

  2. The Antibody Society, Inc, Bothell, WA, USA

    Janice M. Reichert

  3. Seagen, Inc., Bothell, WA, USA

    Peter D. Senter

  4. Independent Consultant, Cambridge, MA, USA

    John M. Lambert

  5. Institut de Recherche Pierre Fabre, CIPF, Saint-Julien-en-Genevois, France

    Alain Beck

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Contributions

C.D., J.M.R. and A.B. researched data for the article and wrote the article. All authors contributed substantially to discussion of the content and/or edited the manuscript before submission.

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Correspondence to Charles Dumontet.

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Competing interests

C.D. has received research funding from Pierre Fabre and Sanofi, and has worked as a consultant for Sanofi and Bristol-Myers Squibb. He is shareholder and co-founder of Mablink Pharma. J.M.R. is employed by The Antibody Society, a non-profit trade association funded by corporate sponsors that develop antibody therapeutics or provide services to companies that develop antibody therapeutics, and she is Editor-in-Chief of mAbs, a biomedical journal focused on topics relevant to antibody therapeutics development. P.D.S. is an employee of Seattle Genetics. J.M.L. was an employee of ImmunoGen, Inc. from 1987 to 2017, Waltham, MA, USA. ImmunoGen developed the maytansinoid linker-payload technology utilized in the ADCs trastuzumab emtansine and mirvetuximab soravtansine discussed in this paper. Since 2018, J.M.L. has consulted for ImmunoGen and several other biotechnology companies developing ADCs. A.B. is an employee of the Pierre Fabre Research Institute, Saint-Julien en Genevois, France, which has licensed telisotuzumab (ABT-700) anti-cMet antibody to AbbVie and developed the ADC telisotuzumab vedotin.

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Supplementary information

Glossary

Bystander effect

A biological effect in which a payload released from a dying tumour cell that has internalized an antibody–drug conjugate will destroy neighbouring cells independently of their target antigen expression.

C’Dot–drug conjugates

Nanoparticle–drug conjugates of very small size in comparison to antibodies.

Drug-to-antibody ratios (DARs)

The average number of drug molecules that are conjugated to an antibody in an antibody–drug conjugate.

Linker

The chemical connector between the antibody and payload; it may be non-cleavable, cleavable or self-immolative; cleavage can take place with proteases, hydrolysis or reduction mechanisms.

Payload

A small-molecule cytotoxic chemotherapeutic (also known as a warhead).

Probodies

Proteolytically activated antibodies engineered to remain inert until activated locally in target tissue.

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Dumontet, C., Reichert, J.M., Senter, P.D. et al. Antibody–drug conjugates come of age in oncology. Nat Rev Drug Discov 22, 641–661 (2023). https://doi.org/10.1038/s41573-023-00709-2

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