Identification and in vivo characterization of a brain-penetrating nanobody.
Fluids Barriers CNS
; 17(1): 62, 2020 Oct 14.
Article
en En
| MEDLINE
| ID: mdl-33054787
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.Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Temperatura Corporal
/
Receptores de Transferrina
/
Encéfalo
/
Neurotensina
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Transcitosis
/
Anticuerpos de Dominio Único
Tipo de estudio:
Diagnostic_studies
Límite:
Animals
Idioma:
En
Revista:
Fluids Barriers CNS
Año:
2020
Tipo del documento:
Article
País de afiliación:
Bélgica