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.
Highlights
For many therapeutics, delivery to lysosomes must be carefully controlled, either to minimize or to maximize proteolytic degradation of the therapeutic, and/or its target
We initially investigated whether formation of biotin:SA complexes at the plasma membrane affects the endocytosis and traffic of the iron carrying protein Tf
We investigated whether the Tf-Bi-647:SA complexes formed at the plasma membrane are internalized, like Tf, via the canonical clathrin-mediated endocytosis route
Summary
Delivery to lysosomes must be carefully controlled, either to minimize or to maximize proteolytic degradation of the therapeutic, and/or its target. Antibodies that bind to transferrin receptor (TfR) for delivery across the blood– brain barrier (BBB) must avoid lysosomal degradation.[1,2,3] On the other hand, antibodies that target oncogenic receptors are often targeted toward lysosomes in order to provide therapeutic benefits, either by depleting the growth-inducing oncogenic receptors or by unleashing toxic drugs from antibody–drug conjugates (ADCs).[4]. The only ADCs that have demonstrated sufficient efficacy to gain and retain clinical approval are trastuzumab–emtansine and brentuximab–vedotin.[11]
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