Receptor crosslinking: a general method to trigger internalization and lysosomal targeting of therapeutic receptor: ligand complexes

Moody, Paul R.; Alexander, Cameron; Sayers, Edward J.; Magnusson, Johannes P.; Borri, Paola; Watson, Peter; Jones, Arwyn T.

Abstract

A major unmet clinical need is a universal method for subcellular targeting of bioactive molecules to lysosomes. Delivery to this organelle enables either degradation of oncogenic receptors that are overexpressed in cancers, or release of prodrugs from antibody–drug conjugates. Here, we describe a general method that uses receptor crosslinking to trigger endocytosis and subsequently redirect trafficking of receptor:cargo complexes from their expected route, to lysosomes. By incubation of plasma membrane receptors with biotinylated cargo and subsequent addition of streptavidin to crosslink receptor:cargo–biotin complexes, we achieved rapid and selective lysosomal targeting of transferrin, an anti-MHC class I antibody, and the clinically approved anti-Her2 antibody trastuzumab. These three protein ligands each target a receptor with a distinct cellular function and intracellular trafficking profile. Importantly, we confirmed that crosslinking of trastuzumab increased lysosomal degradation of its cognate oncogenic receptor Her2 in breast cancer cell lines SKBR3 and BT474. These data suggest that crosslinking could be exploited for a wide range of target receptors, for navigating therapeutics through the endolysosomal pathway, for significant therapeutic benefit.

Citation

Moody, P. R., Alexander, C., Sayers, E. J., Magnusson, J. P., Borri, P., Watson, P., & Jones, A. T. (2015). Receptor crosslinking: a general method to trigger internalization and lysosomal targeting of therapeutic receptor: ligand complexes. Molecular Therapy, 23(12), 1888-1898. https://doi.org/10.1038/mt.2015.178

• Journal Article Type: Article
• Acceptance Date: Aug 12, 2015
• Online Publication Date: Dec 14, 2016
• Publication Date: Dec 1, 2015
• Deposit Date: May 31, 2018
• Publicly Available Date: Nov 29, 2018
• Print ISSN: 1525-0016
• Electronic ISSN: 1525-0024
• Publisher: Elsevier (Cell Press)
• Peer Reviewed: Peer Reviewed
• Volume: 23
• Issue: 12
• Pages: 1888-1898
• DOI: https://doi.org/10.1038/mt.2015.178
• Public URL: https://nottingham-repository.worktribe.com/output/1108855
• Publisher URL: https://www.sciencedirect.com/science/article/pii/S1525001616302052?via%3Dihub
• PMID: 00036699