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Nat Commun. 2018 May 4;9(1):1484. doi: 10.1038/s41467-018-03880-y.

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

Author information

1
Tagworks Pharmaceuticals, Geert Grooteplein Zuid 10, 6525 GA, Nijmegen, The Netherlands.
2
SyMO-Chem B.V., Den Dolech 2, 5612 AZ, Eindhoven, The Netherlands.
3
Avipep Pty Ltd, 343 Royal Parade, Parkville, VIC, 3052, Australia.
4
Levena Biopharma, 4955 Directors Place, Suite 300, San Diego, CA, 92121, USA.
5
Radboud Proteomics Centre, Department of Laboratory Medicine, Radboud University Medical Center, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands.
6
Department of Pathology, Radboud University Medical Center, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands.
7
Syncom B.V., Kadijk 3, 9747 AT, Groningen, The Netherlands.
8
Tagworks Pharmaceuticals, Geert Grooteplein Zuid 10, 6525 GA, Nijmegen, The Netherlands. marc.robillard@tagworkspharma.com.

Abstract

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.

PMID:
29728559
PMCID:
PMC5935733
DOI:
10.1038/s41467-018-03880-y
[Indexed for MEDLINE]
Free PMC Article

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