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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...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2023
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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. |
format | Online Article Text |
id | pubmed-10383291 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
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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