Glycoengineering of EphA4 Fc leads to a unique, long-acting and broad spectrum, Eph receptor therapeutic antagonist

Abstract Eph receptors have emerged as targets for therapy in both neoplastic and non-neoplastic disease, however, particularly in non-neoplastic diseases, redundancy of function limits the effectiveness of targeting individual Eph proteins. We have shown previously that a soluble fusion protein, wh...

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Autores principales:	Cassandra L. Pegg, Leanne T. Cooper, Jing Zhao, Michael Gerometta, Fiona M. Smith, Michael Yeh, Perry F. Bartlett, Jeffrey J. Gorman, Andrew W. Boyd
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/8eef0bce7cd74492b8bf629ada41ee50
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spelling	oai:doaj.org-article:8eef0bce7cd74492b8bf629ada41ee502021-12-02T15:05:13ZGlycoengineering of EphA4 Fc leads to a unique, long-acting and broad spectrum, Eph receptor therapeutic antagonist10.1038/s41598-017-06685-z2045-2322https://doaj.org/article/8eef0bce7cd74492b8bf629ada41ee502017-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-06685-zhttps://doaj.org/toc/2045-2322Abstract Eph receptors have emerged as targets for therapy in both neoplastic and non-neoplastic disease, however, particularly in non-neoplastic diseases, redundancy of function limits the effectiveness of targeting individual Eph proteins. We have shown previously that a soluble fusion protein, where the EphA4 ectodomain was fused to IgG Fc (EphA4 Fc), was an effective therapy in acute injuries and demonstrated that EphA4 Fc was a broad spectrum Eph/ephrin antagonist. However, a very short in vivo half-life effectively limited its therapeutic development. We report a unique glycoengineering approach to enhance the half-life of EphA4 Fc. Progressive deletion of three demonstrated N-linked sites in EphA4 progressively increased in vivo half-life such that the triple mutant protein showed dramatically improved pharmacokinetic characteristics. Importantly, protein stability, affinity for ephrin ligands and antagonism of cell expressed EphA4 was fully preserved, enabling it to be developed as a broad spectrum Eph/ephrin antagonist for use in both acute and chronic diseases.Cassandra L. PeggLeanne T. CooperJing ZhaoMichael GeromettaFiona M. SmithMichael YehPerry F. BartlettJeffrey J. GormanAndrew W. BoydNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-11 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Cassandra L. Pegg Leanne T. Cooper Jing Zhao Michael Gerometta Fiona M. Smith Michael Yeh Perry F. Bartlett Jeffrey J. Gorman Andrew W. Boyd Glycoengineering of EphA4 Fc leads to a unique, long-acting and broad spectrum, Eph receptor therapeutic antagonist
description	Abstract Eph receptors have emerged as targets for therapy in both neoplastic and non-neoplastic disease, however, particularly in non-neoplastic diseases, redundancy of function limits the effectiveness of targeting individual Eph proteins. We have shown previously that a soluble fusion protein, where the EphA4 ectodomain was fused to IgG Fc (EphA4 Fc), was an effective therapy in acute injuries and demonstrated that EphA4 Fc was a broad spectrum Eph/ephrin antagonist. However, a very short in vivo half-life effectively limited its therapeutic development. We report a unique glycoengineering approach to enhance the half-life of EphA4 Fc. Progressive deletion of three demonstrated N-linked sites in EphA4 progressively increased in vivo half-life such that the triple mutant protein showed dramatically improved pharmacokinetic characteristics. Importantly, protein stability, affinity for ephrin ligands and antagonism of cell expressed EphA4 was fully preserved, enabling it to be developed as a broad spectrum Eph/ephrin antagonist for use in both acute and chronic diseases.
format	article
author	Cassandra L. Pegg Leanne T. Cooper Jing Zhao Michael Gerometta Fiona M. Smith Michael Yeh Perry F. Bartlett Jeffrey J. Gorman Andrew W. Boyd
author_facet	Cassandra L. Pegg Leanne T. Cooper Jing Zhao Michael Gerometta Fiona M. Smith Michael Yeh Perry F. Bartlett Jeffrey J. Gorman Andrew W. Boyd
author_sort	Cassandra L. Pegg
title	Glycoengineering of EphA4 Fc leads to a unique, long-acting and broad spectrum, Eph receptor therapeutic antagonist
title_short	Glycoengineering of EphA4 Fc leads to a unique, long-acting and broad spectrum, Eph receptor therapeutic antagonist
title_full	Glycoengineering of EphA4 Fc leads to a unique, long-acting and broad spectrum, Eph receptor therapeutic antagonist
title_fullStr	Glycoengineering of EphA4 Fc leads to a unique, long-acting and broad spectrum, Eph receptor therapeutic antagonist
title_full_unstemmed	Glycoengineering of EphA4 Fc leads to a unique, long-acting and broad spectrum, Eph receptor therapeutic antagonist
title_sort	glycoengineering of epha4 fc leads to a unique, long-acting and broad spectrum, eph receptor therapeutic antagonist
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/8eef0bce7cd74492b8bf629ada41ee50
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Glycoengineering of EphA4 Fc leads to a unique, long-acting and broad spectrum, Eph receptor therapeutic antagonist

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