Prolonged half-life of small-sized therapeutic protein using serum albumin-specific protein binder

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Many small-sized proteins and peptides, such as cytokines and hormones, are clinically used for the treatment of a variety of diseases. However, their short half-life in blood owing to fast renal clearance usually results in a low therapeutic efficacy and frequent dosing. Here we present the development of a human serum albumin (HSA)specific protein binder with a binding affinity of 4.3 nM through a phage display selection and modular evolution approach to extend the blood half-life of a small-sized therapeutic protein. As a proof-of-concept, the protein binder composed of LRR (Leucine-rich repeat) modules was genetically fused to the N-terminus of Glucagon-like Peptide-1 (GLP-1). The fused GLP-1 was shown to have a significantly improved pharmacokinetic property: The terminal half-life of the fused GLP-1 increased to approximately 10 h, and the area under the curve was 5-times higher than that of the control. The utility and potential of our approach was demonstrated by the efficient control of the blood glucose level in type-2 diabetes mouse models using the HSA-specific protein binder-fused GLP-1 over a prolonged time period. The present approach can be effectively used in enhancing the efficacy of small-sized therapeutic proteins and peptides through an enhanced blood circulation time.
Publisher
ELSEVIER
Issue Date
2019-12
Language
English
Article Type
Article
Citation

JOURNAL OF CONTROLLED RELEASE, v.315, pp.31 - 39

ISSN
0168-3659
DOI
10.1016/j.jconrel.2019.09.017
URI
http://hdl.handle.net/10203/270278
Appears in Collection
BS-Journal Papers(저널논문)
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