An Affibody Molecule Is Actively Transported into the Cerebrospinal Fluid via Binding to the Transferrin Receptor
Copyright policy )An Affibody Molecule Is Actively Transported into the Cerebrospinal Fluid via Binding to the Transferrin Receptor
The use of biotherapeutics for the treatment of diseases of the central nervous system (CNS) is typically impeded by insufficient transport across the blood–brain barrier. Here, we investigate a strategy to potentially increase the uptake into the CNS of an affibody molecule (ZSYM73) via binding to the transferrin receptor (TfR). ZSYM73 binds monomeric amyloid beta, a peptide involved in Alzheimer’s disease pathogenesis, with subnanomolar affinity. We generated a tri-specific fusion protein by genetically linking a single-chain variable fragment of the TfR-binding antibody 8D3 and an albumin-binding domain to the affibody molecule ZSYM73. Simultaneous tri-specific target engagement was confirmed in a biosensor experiment and the affinity for murine TfR was determined to 5 nM. Blockable binding to TfR on endothelial cells was demonstrated using flow cytometry and in a preclinical study we observed increased uptake of the tri-specific fusion protein into the cerebrospinal fluid 24 h after injection.
Models, Molecular, Recombinant Fusion Proteins, Molecular Conformation, blood–brain barrier, Article, Permeability, Mice, Structure-Activity Relationship, Receptors, Transferrin, Animals, Humans, Protein Interaction Domains and Motifs, Amyloid beta-Peptides, Biological Transport, transferrin receptor, Flow Cytometry, Protein Transport, Blood-Brain Barrier, neurodegenerative disorders, Drug Design, receptor-mediated transcytosis, affibody molecules, Protein Binding
Models, Molecular, Recombinant Fusion Proteins, Molecular Conformation, blood–brain barrier, Article, Permeability, Mice, Structure-Activity Relationship, Receptors, Transferrin, Animals, Humans, Protein Interaction Domains and Motifs, Amyloid beta-Peptides, Biological Transport, transferrin receptor, Flow Cytometry, Protein Transport, Blood-Brain Barrier, neurodegenerative disorders, Drug Design, receptor-mediated transcytosis, affibody molecules, Protein Binding
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