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Natural Form of Noncytolytic Flexible Human Fc as a Long-Acting Carrier of Agonistic Ligand, Erythropoietin

Title
Natural Form of Noncytolytic Flexible Human Fc as a Long-Acting Carrier of Agonistic Ligand, Erythropoietin
Authors
Se Jin LimYang, SIYang, SHChoi, DHChoi, SYKim, HSJang, DSJin, KSChung, YKKim, SHPaik, SHPark, YCChung, MKKim, YBHan, KHChoi, KYSung, YC
POSTECH Authors
Choi, KYSung, YC
Date Issued
Sep-2011
Publisher
Public Library of Science
Abstract
Human IgG1 Fc has been widely used as a bioconjugate, but exhibits shortcomings, such as antibody-and complement-mediated cytotoxicity as well as decreased bioactivity, when applied to agonistic proteins. Here, we constructed a nonimmunogenic, noncytolytic and flexible hybrid Fc (hyFc) consisting of IgD and IgG4, and tested its function using erythropoietin (EPO) conjugate, EPO-hyFc. Despite low amino acid homology (20.5%) between IgD Fc and IgG4 Fc, EPO-hyFc retained "Y-shaped" structure and repeated intravenous administrations of EPO-hyFc into monkeys did not generate EPO-hyFc-specific antibody responses. Furthermore, EPO-hyFc could not bind to Fc gamma R I and C1q in contrast to EPO-IgG1 Fc. In addition, EPO-hyFc exhibited better in vitro bioactivity and in vivo bioactivity in rats than EPO-IgG1 Fc, presumably due to the high flexibility of IgD. Moreover, the mean serum half-life of EPO-hyFc(H), a high sialic acid content form of EPO-hyFc, was approximately 2-fold longer than that of the heavily glycosylated EPO, darbepoetin alfa, in rats. More importantly, subcutaneous injection of EPO-hyFc(H) not only induced a significantly greater elevation of serum hemoglobin levels than darbepoetin alfa in both normal rats and cisplatin-induced anemic rats, but also displayed a delayed time to maximal serum level and twice final area-under-the-curve (AUC(last)). Taken together, hyFc might be a more attractive Fc conjugate for agonistic proteins/peptides than IgG1 Fc due to its capability to elongate their half-lives without inducing host effector functions and hindering bioactivity of fused molecules. Additionally, a head-to-head comparison demonstrated that hyFc-fusion strategy more effectively improved the in vivo bioactivity of EPO than the hyperglycosylation approach.
Keywords
RECOMBINANT-HUMAN-ERYTHROPOIETIN; STIMULATING PROTEIN NESP; I-RELATED RECEPTOR; BIOLOGICAL-ACTIVITY; BINDING-SITE; HUMAN-IGG; ANTIBODIES; PHARMACOKINETICS; CELLS; PHARMACODYNAMICS
URI
http://oasis.postech.ac.kr/handle/2014.oak/16674
DOI
10.1371/JOURNAL.PONE.0024574
ISSN
1932-6203
Article Type
Article
Citation
PLOS ONE, vol. 6, no. 9, page. E24574 - E24574, 2011-09
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 SUNG, YOUNG CHUL
Div of Integrative Biosci & Biotech
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