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Directed evolution of broadly crossreactive chemokine-blocking antibodies efficacious in arthritis

Chemokine receptors typically have multiple ligands. Consequently, treatment with a blocking antibody against a single chemokine is expected to be insufficient for efficacy. Here we show single-chain antibodies can be engineered for broad crossreactivity toward multiple human and mouse proinflammato...

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Autores principales: Angelini, Alessandro, Miyabe, Yoshishige, Newsted, Daniel, Kwan, Byron H., Miyabe, Chie, Kelly, Ryan L., Jamy, Misha N., Luster, Andrew D., Wittrup, K. Dane
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5899157/
https://www.ncbi.nlm.nih.gov/pubmed/29654232
http://dx.doi.org/10.1038/s41467-018-03687-x
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author Angelini, Alessandro
Miyabe, Yoshishige
Newsted, Daniel
Kwan, Byron H.
Miyabe, Chie
Kelly, Ryan L.
Jamy, Misha N.
Luster, Andrew D.
Wittrup, K. Dane
author_facet Angelini, Alessandro
Miyabe, Yoshishige
Newsted, Daniel
Kwan, Byron H.
Miyabe, Chie
Kelly, Ryan L.
Jamy, Misha N.
Luster, Andrew D.
Wittrup, K. Dane
author_sort Angelini, Alessandro
collection PubMed
description Chemokine receptors typically have multiple ligands. Consequently, treatment with a blocking antibody against a single chemokine is expected to be insufficient for efficacy. Here we show single-chain antibodies can be engineered for broad crossreactivity toward multiple human and mouse proinflammatory ELR(+) CXC chemokines. The engineered molecules recognize functional epitopes of ELR(+) CXC chemokines and inhibit neutrophil activation ex vivo. Furthermore, an albumin fusion of the most crossreactive single-chain antibody prevents and reverses inflammation in the K/BxN mouse model of arthritis. Thus, we report an approach for the molecular evolution and selection of broadly crossreactive antibodies towards a family of structurally related, yet sequence-diverse protein targets, with general implications for the development of novel therapeutics.
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spelling pubmed-58991572018-04-16 Directed evolution of broadly crossreactive chemokine-blocking antibodies efficacious in arthritis Angelini, Alessandro Miyabe, Yoshishige Newsted, Daniel Kwan, Byron H. Miyabe, Chie Kelly, Ryan L. Jamy, Misha N. Luster, Andrew D. Wittrup, K. Dane Nat Commun Article Chemokine receptors typically have multiple ligands. Consequently, treatment with a blocking antibody against a single chemokine is expected to be insufficient for efficacy. Here we show single-chain antibodies can be engineered for broad crossreactivity toward multiple human and mouse proinflammatory ELR(+) CXC chemokines. The engineered molecules recognize functional epitopes of ELR(+) CXC chemokines and inhibit neutrophil activation ex vivo. Furthermore, an albumin fusion of the most crossreactive single-chain antibody prevents and reverses inflammation in the K/BxN mouse model of arthritis. Thus, we report an approach for the molecular evolution and selection of broadly crossreactive antibodies towards a family of structurally related, yet sequence-diverse protein targets, with general implications for the development of novel therapeutics. Nature Publishing Group UK 2018-04-13 /pmc/articles/PMC5899157/ /pubmed/29654232 http://dx.doi.org/10.1038/s41467-018-03687-x Text en © The Author(s) 2018 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/.
spellingShingle Article
Angelini, Alessandro
Miyabe, Yoshishige
Newsted, Daniel
Kwan, Byron H.
Miyabe, Chie
Kelly, Ryan L.
Jamy, Misha N.
Luster, Andrew D.
Wittrup, K. Dane
Directed evolution of broadly crossreactive chemokine-blocking antibodies efficacious in arthritis
title Directed evolution of broadly crossreactive chemokine-blocking antibodies efficacious in arthritis
title_full Directed evolution of broadly crossreactive chemokine-blocking antibodies efficacious in arthritis
title_fullStr Directed evolution of broadly crossreactive chemokine-blocking antibodies efficacious in arthritis
title_full_unstemmed Directed evolution of broadly crossreactive chemokine-blocking antibodies efficacious in arthritis
title_short Directed evolution of broadly crossreactive chemokine-blocking antibodies efficacious in arthritis
title_sort directed evolution of broadly crossreactive chemokine-blocking antibodies efficacious in arthritis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5899157/
https://www.ncbi.nlm.nih.gov/pubmed/29654232
http://dx.doi.org/10.1038/s41467-018-03687-x
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