Journal
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
Volume 21, Issue 8, Pages -Publisher
MDPI
DOI: 10.3390/ijms21082999
Keywords
neurodegenerative disorders; affibody molecules; blood-brain barrier; receptor-mediated transcytosis; transferrin receptor
Funding
- Swedish Brain foundation [F02018-0094]
- Wallenberg Center for Protein Research [KAW 2019.0341]
- Tussilago foundation [FL-0002.025.551-7]
- Schorling Family foundation via the Swedish FTD Initiative
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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 (Z(SYM73)) via binding to the transferrin receptor (TfR). Z(SYM73) 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 Z(SYM73). 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.
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