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Extending the use of biologics to mucous membranes by attachment of a binding domain
Biologics are almost exclusively administered systemically, but localized delivery is preferable as it minimizes off-target exposure and allows more aggressive treatments. Topical application of biologics to epithelia is generally ineffective because most are covered with fluids and biologics are wa...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10154311/ https://www.ncbi.nlm.nih.gov/pubmed/37130912 http://dx.doi.org/10.1038/s42003-023-04801-6 |
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author | Shanks, Robert M. Q. Romanowski, Eric G. Romanowski, John E. Davoli, Katherine McNamara, Nancy A. Klarlund, Jes K. |
author_facet | Shanks, Robert M. Q. Romanowski, Eric G. Romanowski, John E. Davoli, Katherine McNamara, Nancy A. Klarlund, Jes K. |
author_sort | Shanks, Robert M. Q. |
collection | PubMed |
description | Biologics are almost exclusively administered systemically, but localized delivery is preferable as it minimizes off-target exposure and allows more aggressive treatments. Topical application of biologics to epithelia is generally ineffective because most are covered with fluids and biologics are washed out too quickly to have significant therapeutic effects. Here we explore the idea that attaching a binding domain can serve as an “anchor” to extend the residency time of biologics on wet epithelia, allowing their effective use even with infrequent applications. We use topical application to the ocular surface as a challenging test since foreign substances are washed out especially efficiently by tear flow and blinking. Our results demonstrate that conjugation of antibodies to wheat germ agglutinin, which binds GlcNAc and sialic acid that are ubiquitously present in tissues, increases their half-life 350-fold upon application to the ocular surface in a mouse model of dry eye, a common and onerous disease in humans. Importantly, antibodies to IL-17A, IL-23, and IL-1β conjugated to the agglutinin reduces manifestations of dry eye, even when applied just once daily. In contrast, unconjugated antibodies are ineffective. Attaching an anchor to biologics is a simple means to overcome washout and to extend their therapeutic use. |
format | Online Article Text |
id | pubmed-10154311 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-101543112023-05-04 Extending the use of biologics to mucous membranes by attachment of a binding domain Shanks, Robert M. Q. Romanowski, Eric G. Romanowski, John E. Davoli, Katherine McNamara, Nancy A. Klarlund, Jes K. Commun Biol Article Biologics are almost exclusively administered systemically, but localized delivery is preferable as it minimizes off-target exposure and allows more aggressive treatments. Topical application of biologics to epithelia is generally ineffective because most are covered with fluids and biologics are washed out too quickly to have significant therapeutic effects. Here we explore the idea that attaching a binding domain can serve as an “anchor” to extend the residency time of biologics on wet epithelia, allowing their effective use even with infrequent applications. We use topical application to the ocular surface as a challenging test since foreign substances are washed out especially efficiently by tear flow and blinking. Our results demonstrate that conjugation of antibodies to wheat germ agglutinin, which binds GlcNAc and sialic acid that are ubiquitously present in tissues, increases their half-life 350-fold upon application to the ocular surface in a mouse model of dry eye, a common and onerous disease in humans. Importantly, antibodies to IL-17A, IL-23, and IL-1β conjugated to the agglutinin reduces manifestations of dry eye, even when applied just once daily. In contrast, unconjugated antibodies are ineffective. Attaching an anchor to biologics is a simple means to overcome washout and to extend their therapeutic use. Nature Publishing Group UK 2023-05-02 /pmc/articles/PMC10154311/ /pubmed/37130912 http://dx.doi.org/10.1038/s42003-023-04801-6 Text en © The Author(s) 2023 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 license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license 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 license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Shanks, Robert M. Q. Romanowski, Eric G. Romanowski, John E. Davoli, Katherine McNamara, Nancy A. Klarlund, Jes K. Extending the use of biologics to mucous membranes by attachment of a binding domain |
title | Extending the use of biologics to mucous membranes by attachment of a binding domain |
title_full | Extending the use of biologics to mucous membranes by attachment of a binding domain |
title_fullStr | Extending the use of biologics to mucous membranes by attachment of a binding domain |
title_full_unstemmed | Extending the use of biologics to mucous membranes by attachment of a binding domain |
title_short | Extending the use of biologics to mucous membranes by attachment of a binding domain |
title_sort | extending the use of biologics to mucous membranes by attachment of a binding domain |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10154311/ https://www.ncbi.nlm.nih.gov/pubmed/37130912 http://dx.doi.org/10.1038/s42003-023-04801-6 |
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