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

Pegg, Cassandra L., Cooper, Leanne T., Zhao, Jing, Gerometta, Michael, Smith, Fiona M., Yeh, Michael, Bartlett, Perry F., Gorman, Jeffrey J. and Boyd, Andrew W. (2017) Glycoengineering of EphA4 Fc leads to a unique, long-acting and broad spectrum, Eph receptor therapeutic antagonist. Scientific Reports, 7 1: 6519. doi:10.1038/s41598-017-06685-z


Author Pegg, Cassandra L.
Cooper, Leanne T.
Zhao, Jing
Gerometta, Michael
Smith, Fiona M.
Yeh, Michael
Bartlett, Perry F.
Gorman, Jeffrey J.
Boyd, Andrew W.
Title Glycoengineering of EphA4 Fc leads to a unique, long-acting and broad spectrum, Eph receptor therapeutic antagonist
Journal name Scientific Reports   Check publisher's open access policy
ISSN 2045-2322
Publication date 2017-08-26
Year available 2017
Sub-type Article (original research)
DOI 10.1038/s41598-017-06685-z
Open Access Status DOI
Volume 7
Issue 1
Start page 6519
Total pages 11
Place of publication London, United Kingdom
Publisher Nature Publishing Group
Language eng
Subject 1000 General
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.
Keyword Multidisciplinary
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

 
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