Chemically triggered drug release from an antibody-drug conjugate leads to potent antitumour activity in mice

Raffaella Rossin, Ron M. Versteegen, Jeremy Wu, Alisher Khasanov, Hans J. Wessels, Erik J. Steenbergen, Wolter ten Hoeve, Henk M. Janssen, Arthur H. A. M. van Onzen, Peter J. Hudson, Marc S. Robillard

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.