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Affibody Molecules Intended for Receptor-Mediated Transcytosis via the Transferrin Receptor

The development of biologics for diseases affecting the central nervous system has been less successful compared to other disease areas, in part due to the challenge of delivering drugs to the brain. The most well-investigated and successful strategy for increasing brain uptake of biological drugs i...

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Autores principales: Hjelm, Linnea Charlotta, Lindberg, Hanna, Ståhl, Stefan, Löfblom, John
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10383291/
https://www.ncbi.nlm.nih.gov/pubmed/37513868
http://dx.doi.org/10.3390/ph16070956
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author Hjelm, Linnea Charlotta
Lindberg, Hanna
Ståhl, Stefan
Löfblom, John
author_facet Hjelm, Linnea Charlotta
Lindberg, Hanna
Ståhl, Stefan
Löfblom, John
author_sort Hjelm, Linnea Charlotta
collection PubMed
description The development of biologics for diseases affecting the central nervous system has been less successful compared to other disease areas, in part due to the challenge of delivering drugs to the brain. The most well-investigated and successful strategy for increasing brain uptake of biological drugs is using receptor-mediated transcytosis over the blood–brain barrier and, in particular, targeting the transferrin receptor-1 (TfR). Here, affibody molecules are selected for TfR using phage display technology. The two most interesting candidates demonstrated binding to human TfR, cross-reactivity to the murine orthologue, non-competitive binding with human transferrin, and binding to TfR-expressing brain endothelial cell lines. Single amino acid mutagenesis of the affibody molecules revealed the binding contribution of individual residues and was used to develop second-generation variants with improved properties. The second-generation variants were further analyzed and showed an ability for transcytosis in an in vitro transwell assay. The new TfR-specific affibody molecules have the potential for the development of small brain shuttles for increasing the uptake of various compounds to the central nervous system and thus warrant further investigations.
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spelling pubmed-103832912023-07-30 Affibody Molecules Intended for Receptor-Mediated Transcytosis via the Transferrin Receptor Hjelm, Linnea Charlotta Lindberg, Hanna Ståhl, Stefan Löfblom, John Pharmaceuticals (Basel) Article The development of biologics for diseases affecting the central nervous system has been less successful compared to other disease areas, in part due to the challenge of delivering drugs to the brain. The most well-investigated and successful strategy for increasing brain uptake of biological drugs is using receptor-mediated transcytosis over the blood–brain barrier and, in particular, targeting the transferrin receptor-1 (TfR). Here, affibody molecules are selected for TfR using phage display technology. The two most interesting candidates demonstrated binding to human TfR, cross-reactivity to the murine orthologue, non-competitive binding with human transferrin, and binding to TfR-expressing brain endothelial cell lines. Single amino acid mutagenesis of the affibody molecules revealed the binding contribution of individual residues and was used to develop second-generation variants with improved properties. The second-generation variants were further analyzed and showed an ability for transcytosis in an in vitro transwell assay. The new TfR-specific affibody molecules have the potential for the development of small brain shuttles for increasing the uptake of various compounds to the central nervous system and thus warrant further investigations. MDPI 2023-07-03 /pmc/articles/PMC10383291/ /pubmed/37513868 http://dx.doi.org/10.3390/ph16070956 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Hjelm, Linnea Charlotta
Lindberg, Hanna
Ståhl, Stefan
Löfblom, John
Affibody Molecules Intended for Receptor-Mediated Transcytosis via the Transferrin Receptor
title Affibody Molecules Intended for Receptor-Mediated Transcytosis via the Transferrin Receptor
title_full Affibody Molecules Intended for Receptor-Mediated Transcytosis via the Transferrin Receptor
title_fullStr Affibody Molecules Intended for Receptor-Mediated Transcytosis via the Transferrin Receptor
title_full_unstemmed Affibody Molecules Intended for Receptor-Mediated Transcytosis via the Transferrin Receptor
title_short Affibody Molecules Intended for Receptor-Mediated Transcytosis via the Transferrin Receptor
title_sort affibody molecules intended for receptor-mediated transcytosis via the transferrin receptor
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10383291/
https://www.ncbi.nlm.nih.gov/pubmed/37513868
http://dx.doi.org/10.3390/ph16070956
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