A solid-phase PEGylation strategy for protein therapeutics using a potent FGF21 analog

Abstract Fibroblast growth factor 21 (FGF21) is an endocrine-acting hormone that has the potential to treat metabolic diseases, such as type 2 diabetes and obesity. Development of FGF21 into a therapeutic has been hindered due to its low intrinsic bio-stability, propensity towards aggregation and it...

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Bibliographic Details
Published in:Biomaterials 2014-06, Vol.35 (19), p.5206-5215
Main Authors: Song, Lintao, Zhu, Yanlin, Wang, Huiyan, Belov, Artur A, Niu, Jianlou, Shi, Lu, Xie, Yaoyao, Ye, Chaohui, Li, Xiaokun, Huang, Zhifeng
Format: Article
Language:English
Subjects:
3T3-L1 Cells
Advanced Basic Science
Animals
Biological
Biomedical materials
Biostability
Blotting, Western
Conjugates
Cysteine
Dentistry
Diabetes Mellitus, Type 2 - drug therapy
Fibroblast Growth Factors - chemistry
Fibroblast Growth Factors - therapeutic use
Human fibroblast growth factor 21
Humans
Male
Mice
Mutation
Polyethylene Glycols - chemistry
Proteins
Rats
Recombinant Proteins - chemistry
Recombinant Proteins - therapeutic use
Residues
Solid-phase PEGylation
Strategy
Surgical implants
Type 2 diabetes
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Summary:Abstract Fibroblast growth factor 21 (FGF21) is an endocrine-acting hormone that has the potential to treat metabolic diseases, such as type 2 diabetes and obesity. Development of FGF21 into a therapeutic has been hindered due to its low intrinsic bio-stability, propensity towards aggregation and its susceptibility to in vivo proteolytic degradation. In order to address these shortcomings, we’ve developed recombinant human FGF21 variants by strategically introducing cysteine residues via site-directed mutagenesis, and have also developed a solid-phase nickel affinity PEGylation strategy, whereby engineered, surface-exposed cysteine residues of immobilized proteins were used as a platform to efficiently and site-selectively conjugate with PEG-maleimide. The engineered PEGylated FGF21 conjugates retained its biological functions, as well as demonstrated an increase in half-life by over 211.3 min. By demonstrating the biological activity of the FGF21 analog as a prototype, we have also provided a “generalized” solid-phase approach to effectively increase serum half-life of protein therapeutics.
ISSN:0142-9612
1878-5905
DOI:10.1016/j.biomaterials.2014.03.023