Cited by 660Monoclonal and Polyclonal Antibodies ResearchProtein Degradation and InhibitorsToxin Mechanisms and Immunotoxins

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Exploring the next generation of antibody–drug conjugates

Tsuchikama, Kyoji, Anami, Yasuaki, Ha, Summer Y. Y., Yamazaki, Chisato M.·2024·Nature Reviews Clinical Oncology

DOI 10.1038/s41571-023-00850-2

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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.

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CytomX Therapeutics Inc. CytomX therapeutics presents overview of conditionally-activated antibody-drug conjugate (ADC) programs including next generation EpCAM-targeting CX-2051. CytomX Press Release Details https://ir.cytomx.com/news-releases/news-release-details/cytomx-therapeutics-presents-overview-conditionally-activated/ (2022).

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See all 660

Authors: Tsuchikama, K., Anami, Y., Ha, S. Y. Y., & Yamazaki, C. M.
Affiliations: Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases (US)
Corresponding author: Tsuchikama, Kyoji
ORCID: Tsuchikama, Kyoji
Anami, Yasuaki
Ha, Summer Y. Y.
Yamazaki, Chisato M.
Venue: Nature Reviews Clinical Oncology
Publisher: Springer Science and Business Media LLC
Published: 2024-01-08
Volume: 21
Issue: 3
Pages: 203-223
ISSN: 1759-4774 (ISSN-L)
1759-4782
DOI: 10.1038/s41571-023-00850-2
OpenAlex: W4390673654
Cited by: 659
References: 248
Citations by year: 2026: 282 · 2025: 270 · 2024: 106
FWCI: 42.66
Type: journal article
Language: en
Open access: closed
Licence: www.springernature.com/gp/researchers/text-and-data-mining (tdm)
www.springernature.com/gp/researchers/text-and-data-mining (vor)
Locations: Nature Reviews Clinical Oncology (publishedVersion)
PubMed (publishedVersion)
Funders: U.S. Department of Defense (W81XWH1910598, W81XWH)
National Institutes of Health (W81XWH)
Topics: Life Sciences › Immunology and Microbiology › Immunology › Monoclonal and Polyclonal Antibodies Research
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
Life Sciences › Immunology and Microbiology › Immunology › Toxin Mechanisms and Immunotoxins
Keywords: antibody-drug conjugates, drug resistance, tumor heterogeneity, linker chemistry, chemical conjugation, payload design, patient stratification, biomarkers, treatment-refractory cancer, multimodal cancer therapy
MeSH terms: Antibodies, Monoclonal, Antineoplastic Agents, Pharmaceutical Preparations, Humans, Neoplasms, Immunoconjugates

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Exploring the next generation of antibody–drug conjugates

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