Issue 22, 2022

Non-internalising antibody–drug conjugates


Antibody–drug conjugates (ADCs) typically require internalisation into cancer cells to release their cytotoxic payload. However, this places stringent constraints on therapeutic development, requiring cancer targets that have high expression of internalising antigens and efficient intracellular processing. An alternative approach is emerging whereby the payloads can be released extracellularly from cleavable linkers upon binding to poorly-internalising antigens or other tumoral components. This removes the reliance on high antigen expression, avoids potentially inefficient internalisation, and can greatly expand the range of cancer targets to components of the extracellular tumour matrix. This review gives an overview of recent developments towards non-internalising ADCs, including emerging cancer-associated cell surface and extracellular proteins, cancer stromal targeting and the linking chemistry that enables extracellular payload release.

Graphical abstract: Non-internalising antibody–drug conjugates

Article information

Article type
Tutorial Review
18 Aug 2022
First published
02 Nov 2022
This article is Open Access
Creative Commons BY license

Chem. Soc. Rev., 2022,51, 9182-9202

Non-internalising antibody–drug conjugates

N. Ashman, J. D. Bargh and D. R. Spring, Chem. Soc. Rev., 2022, 51, 9182 DOI: 10.1039/D2CS00446A

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