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

Authors:
Lintao Song
Lintao Song
Jilin Agricultural University
China
Yanlin Zhu
Yanlin Zhu
School of Pharmacy
China
Huiyan Wang
Huiyan Wang
Shandong University
China
Artur A Belov
Artur A Belov
New York University School of Medicine
United States
Jianlou Niu
Jianlou Niu
School of Pharmacy
China
Lu Shi
Lu Shi
UCLA School of Public Health
United States
Yaoyao Xie
Yaoyao Xie
School of Pharmacy
Lawrence | United States
Chaohui Ye
Chaohui Ye
Wuhan Institute of Physics and Mathematics
China

Biomaterials 2014 Jun 28;35(19):5206-15. Epub 2014 Mar 28.

School of Pharmacy, Wenzhou Medical University, Wenzhou 325035, Zhejiang, China. Electronic address:

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.

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http://dx.doi.org/10.1016/j.biomaterials.2014.03.023DOI Listing
June 2014
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