Natural Form of Noncytolytic Flexible Human Fc as a Long-Acting Carrier of Agonistic Ligand, Erythropoietin
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SCOPUS
- Title
- Natural Form of Noncytolytic Flexible Human Fc as a Long-Acting Carrier of Agonistic Ligand, Erythropoietin
- Authors
- Se Jin Lim; Yang, SI; Yang, SH; Choi, DH; Choi, SY; Kim, HS; Jang, DS; Jin, KS; Chung, YK; Kim, SH; Paik, SH; Park, YC; Chung, MK; Kim, YB; Han, KH; Choi, KY; Sung, YC
- Date Issued
- 2011-09-16
- 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
- https://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, 2011-09-16
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