Receptor Crosslinking in Drug Delivery: Detour to the Lysosome?

Abstract

A universal method for delivery of bioactive molecules to lysosomes is highly desirable for a broad range of clinical applications. For instance, lysosomal targeting is important for delivery of ligand–drug conjugates and therapeutic strategies that involve degradation of growth-inducing oncogenic receptors. In this issue of Molecular Therapy, Moody and colleagues report a simple and generic method to achieve crosslinking of cell-surface receptors, which triggers internalization and subsequent redirected trafficking of the ligand–cargo complex to lysosomes.1 Crosslinking was achieved by employing biotinylated ligands that were caused to form complexes using (multivalent) streptavidin after receptor binding. The authors show that this method is applicable to otherwise noninternalized ligand–receptor complexes, such as trastuzumab, the antibody specific to Her2 (used for therapy of Her2-positive breast cancer). Similarly, the method was also able to target transferrin (Tf) to lysosomes. Although the method has only limited in vivo applications, the results should spur the development of alternative crosslinking methods and agents that could facilitate the development of more efficient strategies of macromolecular and/or targeted drug delivery, immunotherapy of cancer, and receptor ablation therapy.