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Identification and in vivo characterization of a brain-penetrating nanobody

Identification and in vivo characterization of a brain-penetrating nanobody

Authors :
B. de Strooper
Yessica Wouters
Tom Jaspers
Maarten Dewilde
Source :
Fluids and Barriers of the CNS, Vol 17, Iss 1, Pp 1-10 (2020), Fluids and Barriers of the CNS
Publication Year :
2020
Publisher :
BMC, 2020.

Abstract

Background Preclinical models to determine blood to brain transport ability of therapeutics are often ambiguous. In this study a method is developed that relies on CNS target-engagement and is able to rank brain-penetrating capacities. This method led to the discovery of an anti-transferrin receptor nanobody that is able to deliver a biologically active peptide to the brain via receptor-mediated transcytosis. Methods Various nanobodies against the mouse transferrin receptor were fused to neurotensin and injected peripherally in mice. Neurotensin is a neuropeptide that causes hypothermia when present in the brain but is unable to reach the brain from the periphery. Continuous body temperature measurements were used as a readout for brain penetration of nanobody-neurotensin fusions after its peripheral administration. Full temperature curves were analyzed using two-way ANOVA with Dunnett multiple comparisons tests. Results One anti-transferrin receptor nanobody coupled to neurotensin elicited a drop in body temperature following intravenous injection. Epitope binning indicated that this nanobody bound a distinct transferrin receptor epitope compared to the non-crossing nanobodies. This brain-penetrating nanobody was used to characterize the in vivo hypothermia model. The hypothermic effect caused by neurotensin is dose-dependent and could be used to directly compare peripheral administration routes and various nanobodies in terms of brain exposure. Conclusion This method led to the discovery of an anti-transferrin receptor nanobody that can reach the brain via receptor-mediated transcytosis after peripheral administration. This method could be used to assess novel proteins for brain-penetrating capabilities using a target-engaging readout.

Details

Language :
English
ISSN :
20458118
Volume :
17
Issue :
1
Database :
OpenAIRE
Journal :
Fluids and Barriers of the CNS
Accession number :
edsair.doi.dedup.....d3aaf48a57ed92d3e0c297cfea31e152
Full Text :
https://doi.org/10.1186/s12987-020-00226-z