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  • Review Article
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Exploring the next generation of antibody–drug conjugates

Nature Reviews Clinical Oncology volume 21, pages 203–223 (2024)Cite this article

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Abstract

Antibody–drug conjugates (ADCs) are a promising cancer treatment modality that enables the selective delivery of highly cytotoxic payloads to tumours. However, realizing the full potential of this platform necessitates innovative molecular designs to tackle several clinical challenges such as drug resistance, tumour heterogeneity and treatment-related adverse effects. Several emerging ADC formats exist, including bispecific ADCs, conditionally active ADCs (also known as probody–drug conjugates), immune-stimulating ADCs, protein-degrader ADCs and dual-drug ADCs, and each offers unique capabilities for tackling these various challenges. For example, probody–drug conjugates can enhance tumour specificity, whereas bispecific ADCs and dual-drug ADCs can address resistance and heterogeneity with enhanced activity. The incorporation of immune-stimulating and protein-degrader ADCs, which have distinct mechanisms of action, into existing treatment strategies could enable multimodal cancer treatment. Despite the promising outlook, the importance of patient stratification and biomarker identification cannot be overstated for these emerging ADCs, as these factors are crucial to identify patients who are most likely to derive benefit. As we continue to deepen our understanding of tumour biology and refine ADC design, we will edge closer to developing truly effective and safe ADCs for patients with treatment-refractory cancers. In this Review, we highlight advances in each ADC component (the monoclonal antibody, payload, linker and conjugation chemistry) and provide more-detailed discussions on selected examples of emerging novel ADCs of each format, enabled by engineering of one or more of these components.

Key points

  • Antibody–drug conjugates (ADCs) are an effective cancer therapy, although responses to these agents are often limited by acquired resistance and treatment-related adverse effects.

  • Advances in the various ADC components (namely the antibody, linker, payload and conjugation chemistry) will be key to improving both the efficacy and safety of these agents.

  • To address these challenges, several novel ADC formats have been developed, including bispecific ADCs, probody–drug conjugates, immune-stimulating ADCs, protein-degrader ADCs and dual-drug ADCs.

  • Probody–drug conjugates are expected to have improved tumour specificity, whereas bispecific ADCs and dual-drug ADCs have the potential to combat drug resistance and tumour heterogeneity.

  • Integrating immune-stimulating ADCs and protein-degrader ADCs with current treatment regimens might enable multimodal treatment, potentially through several distinct mechanisms of action.

  • Patient stratification and biomarker identification will be crucial to maximize the clinical benefits of these emerging ADCs.

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Fig. 1: Components, molecular properties and novel designs of antibody–drug conjugates.
Fig. 2: Bispecific antibody–drug conjugates currently under clinical investigation.
Fig. 3: Probody–drug conjugates.
Fig. 4: Immune-stimulating antibody conjugates.
Fig. 5: Degrader–antibody conjugates.
Fig. 6: Dual-drug ADCs.

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Acknowledgements

The authors acknowledge support from the US NIH (R35GM138264 and R01CA283876 to K.T.) and the US Department of Defense Breast Cancer Research Program (W81XWH-19-1-0598 to K.T.).

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Authors and Affiliations

  1. Texas Therapeutics Institute, The Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center at Houston, Houston, TX, USA

    Kyoji Tsuchikama, Yasuaki Anami, Summer Y. Y. Ha & Chisato M. Yamazaki

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  1. Kyoji Tsuchikama
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  2. Yasuaki Anami
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  3. Summer Y. Y. Ha
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  4. Chisato M. Yamazaki
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Correspondence to Kyoji Tsuchikama.

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Competing interests

All authors are named inventors on all or some of the patent applications (WO2018218004A1, US11629122B2, EP3630189A4 and WO2023122587A3) relating to the linker technologies described in this article. K.T. is a co-founder of and holds equity in CrossBridge Bio.

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Tsuchikama, K., Anami, Y., Ha, S.Y.Y. et al. Exploring the next generation of antibody–drug conjugates. Nat Rev Clin Oncol 21, 203–223 (2024). https://doi.org/10.1038/s41571-023-00850-2

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