Abstract
The greatest challenges for therapeutic efficacy of many macromolecular drugs that act on intracellular are delivery to key organs and tissues and delivery into cells and subcellular compartments. Transport of drugs into critical cells associated with disease, including those in organs protected by restrictive biological barriers such as central nervous system (CNS), bone, and eye remains a significant hurdle to drug efficacy and impacts commercial risk and incentives for drug development for many diseases. These limitations expose a significant need for the development of novel strategies for macromolecule delivery. RTB lectin is the non-toxic carbohydrate-binding subunit B of ricin toxin with high affinity for galactose/galactosamine-containing glycolipids and glycoproteins common on human cell surfaces. RTB mediates endocytic uptake into mammalian cells by multiple routes exploiting both adsorptive-mediated and receptor-mediated mechanisms. In vivo biodistribution studies in lysosomal storage disease models provide evidence for the theory that the RTB-lectin transports corrective doses of enzymes across the blood–brain barrier to treat CNS pathologies. These results encompass significant implications for protein-based therapeutic approaches to address lysosomal and other diseases having strong CNS involvement.
Highlights
Biologics represent the fastest-growing sector for new drug development
This review highlights current unmet needs in treating the neurodegeneration and other central nervous system (CNS) manifestations prevalent in lysosomal diseases, the promise of the RTB lectin to support a new class of delivery-enhanced enzyme replacement therapies (ERTs) based on human enzyme:RTB fusions, and the broader implications of this emerging technology for delivery of biologic drugs
Pericytes were labeled with wheat germ agglutinin (WGA)-horseradish peroxidase (HRP) between 6 and 24 h after the injection. These results provided the first direct evidence of delivery of blood-borne molecules through the blood–brain barrier (BBB) into the brain using lectin-mediated uptake
Summary
Biologics represent the fastest-growing sector for new drug development. Most of these drugs, for example immuno-therapeutics, typically act on targets in the blood or localized at the cell surface. Mobilizing large therapeutic molecules into and across endothelial/epithelial cell layers to reach complex intracellular targets present in distal cells remains a challenge Delivering these products across the blood–brain barrier (BBB) to treat pathologies of the central nervous system is problematic and new strategies are clearly required to address diseases having severe neurological manifestations. Lectins such as the plant lectin RTB show significant promise as protein carriers with the potential to address delivery to CNS as well as delivery to other hard-to-treat tissues and cells. This review highlights current unmet needs in treating the neurodegeneration and other CNS manifestations prevalent in lysosomal diseases, the promise of the RTB lectin to support a new class of delivery-enhanced enzyme replacement therapies (ERTs) based on human enzyme:RTB fusions, and the broader implications of this emerging technology for delivery of biologic drugs
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