Current antibody-drug conjugates (ADCs) target internalising receptors on cancer cells leading to intracellular drug release. Typically, only a subset of patients with solid tumours has sufficient expression of such a receptor, while there are suitable non-internalising receptors and stroma targets. Here, we demonstrate potent therapy in murine tumour models using a non-internalising ADC that releases its drugs upon a click reaction with a chemical activator, which is administered in a second step. This was enabled by the development of a diabody-based ADC with a high tumour uptake and very low retention in healthy tissues, allowing systemic administration of the activator 2 days later, leading to efficient and selective activation throughout the tumour. In contrast, the analogous ADC comprising the protease-cleavable linker used in the FDA approved ADC Adcetris is not effective in these tumour models. This first-in-class ADC holds promise for a broader applicability of ADCs across patient populations.
CITATION STYLE
Rossin, R., Versteegen, R. M., Wu, J., Khasanov, A., Wessels, H. J., Steenbergen, E. J., … Robillard, M. S. (2018). Chemically triggered drug release from an antibody-drug conjugate leads to potent antitumour activity in mice. Nature Communications, 9(1). https://doi.org/10.1038/s41467-018-03880-y
Mendeley helps you to discover research relevant for your work.