Cargando…
Identification of lamprey variable lymphocyte receptors that target the brain vasculature
The blood–brain barrier (BBB) represents a significant bottleneck for the delivery of therapeutics to the central nervous system. In recent years, the promise of coopting BBB receptor-mediated transport systems for brain drug delivery has increased in large part due to the discovery and engineering...
Autores principales: | , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2022
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9001667/ https://www.ncbi.nlm.nih.gov/pubmed/35411012 http://dx.doi.org/10.1038/s41598-022-09962-8 |
_version_ | 1784685724910485504 |
---|---|
author | Lajoie, Jason M. Katt, Moriah E. Waters, Elizabeth A. Herrin, Brantley R. Shusta, Eric V. |
author_facet | Lajoie, Jason M. Katt, Moriah E. Waters, Elizabeth A. Herrin, Brantley R. Shusta, Eric V. |
author_sort | Lajoie, Jason M. |
collection | PubMed |
description | The blood–brain barrier (BBB) represents a significant bottleneck for the delivery of therapeutics to the central nervous system. In recent years, the promise of coopting BBB receptor-mediated transport systems for brain drug delivery has increased in large part due to the discovery and engineering of BBB-targeting antibodies. Here we describe an innovative screening platform for identification of new BBB targeting molecules from a class of lamprey antigen recognition proteins known as variable lymphocyte receptors (VLRs). Lamprey were immunized with murine brain microvessel plasma membranes, and the resultant repertoire cloned into the yeast surface display system. The library was screened via a unique workflow that identified 16 VLR clones that target extracellular epitopes of in vivo-relevant BBB membrane proteins. Of these, three lead VLR candidates, VLR-Fc-11, VLR-Fc-30, and VLR-Fc-46 selectively target the brain vasculature and traffic within brain microvascular endothelial cells after intravenous administration in mice, with VLR-Fc-30 being confirmed as trafficking into the brain parenchyma. Epitope characterization indicates that the VLRs, in part, recognize sialylated glycostructures. These promising new targeting molecules have the potential for brain targeting and drug delivery with improved brain vascular specificity. |
format | Online Article Text |
id | pubmed-9001667 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-90016672022-04-13 Identification of lamprey variable lymphocyte receptors that target the brain vasculature Lajoie, Jason M. Katt, Moriah E. Waters, Elizabeth A. Herrin, Brantley R. Shusta, Eric V. Sci Rep Article The blood–brain barrier (BBB) represents a significant bottleneck for the delivery of therapeutics to the central nervous system. In recent years, the promise of coopting BBB receptor-mediated transport systems for brain drug delivery has increased in large part due to the discovery and engineering of BBB-targeting antibodies. Here we describe an innovative screening platform for identification of new BBB targeting molecules from a class of lamprey antigen recognition proteins known as variable lymphocyte receptors (VLRs). Lamprey were immunized with murine brain microvessel plasma membranes, and the resultant repertoire cloned into the yeast surface display system. The library was screened via a unique workflow that identified 16 VLR clones that target extracellular epitopes of in vivo-relevant BBB membrane proteins. Of these, three lead VLR candidates, VLR-Fc-11, VLR-Fc-30, and VLR-Fc-46 selectively target the brain vasculature and traffic within brain microvascular endothelial cells after intravenous administration in mice, with VLR-Fc-30 being confirmed as trafficking into the brain parenchyma. Epitope characterization indicates that the VLRs, in part, recognize sialylated glycostructures. These promising new targeting molecules have the potential for brain targeting and drug delivery with improved brain vascular specificity. Nature Publishing Group UK 2022-04-11 /pmc/articles/PMC9001667/ /pubmed/35411012 http://dx.doi.org/10.1038/s41598-022-09962-8 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Lajoie, Jason M. Katt, Moriah E. Waters, Elizabeth A. Herrin, Brantley R. Shusta, Eric V. Identification of lamprey variable lymphocyte receptors that target the brain vasculature |
title | Identification of lamprey variable lymphocyte receptors that target the brain vasculature |
title_full | Identification of lamprey variable lymphocyte receptors that target the brain vasculature |
title_fullStr | Identification of lamprey variable lymphocyte receptors that target the brain vasculature |
title_full_unstemmed | Identification of lamprey variable lymphocyte receptors that target the brain vasculature |
title_short | Identification of lamprey variable lymphocyte receptors that target the brain vasculature |
title_sort | identification of lamprey variable lymphocyte receptors that target the brain vasculature |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9001667/ https://www.ncbi.nlm.nih.gov/pubmed/35411012 http://dx.doi.org/10.1038/s41598-022-09962-8 |
work_keys_str_mv | AT lajoiejasonm identificationoflampreyvariablelymphocytereceptorsthattargetthebrainvasculature AT kattmoriahe identificationoflampreyvariablelymphocytereceptorsthattargetthebrainvasculature AT waterselizabetha identificationoflampreyvariablelymphocytereceptorsthattargetthebrainvasculature AT herrinbrantleyr identificationoflampreyvariablelymphocytereceptorsthattargetthebrainvasculature AT shustaericv identificationoflampreyvariablelymphocytereceptorsthattargetthebrainvasculature |