Second-Generation Interferons: An Effective, Long-Lasting Hyperglycosylated IFN-alpha2 View Full Text


Ontology type: schema:Chapter     


Chapter Info

DATE

2011-07-25

AUTHORS

Natalia Ceaglio , Marina Etcheverrigaray , Ricardo Kratje , Harald S. Conradt , Marcos Oggero

ABSTRACT

Recombinant human interferon-alpha2 (rhIFN-alpha2) has proven useful for the treatment of a diversity of viral diseases and cancers. However, the standard E. coli-derived cytokine has the drawbacks of short serum half-life and rapid clearance, requiring daily or thrice weekly dosing to achieve sustained efficacy. In order to tailor its therapeutic properties, a second-generation IFN-alpha was developed by introducing N-glycosylation consensus sequences by site-directed mutagenesis. The glycoengineering approach, aided by the knowledge of structure and function of IFN, led to fourteen IFN-alpha analogs that were produced in CHO cells. Four suitable consensus sequences that fulfilled the criteria of retaining in vitro biological activity and displaying the highest glycosylation degree were combined into a single molecule: 4 N-IFN. A stable CHO clone expressing 4 N-IFN was isolated and used for large-scale production. The immunoaffinity-purified mutein was analyzed by HPAEC-PAD and MALDI-TOF-MS demonstrating the presence of complex type N-linked oligosaccharides, the major consisting in tri- and tetraantennary structures (31 and 57%, respectively). Glycans were mainly tri- and tetrasialylated consistent with a terminal sialylation ratio of 10.6 mol sialic acid/mol protein. The in vivo performance of the cytokine was then analyzed in murine models. A 20-fold decrease in systemic clearance and a 25-fold increase in elimination half-life after subcutaneous inoculation were assessed in comparison with non-glycosylated IFN. Moreover, despite its lower in vitro activity, 4 N-IFN showed a remarkable enhanced anti-proliferative effect on human prostate carcinomas implanted in nude mice. The higher in vivo potency also correlated with a greater in vitro resistance to serum protease inactivation, denoting an additional advantage conferred by glycosylation. This newly designed and long-acting IFN analog confirmed that glycoengineering represents a proper strategy for increasing the in vivo activity of naturally non N-glycosylated proteins, leading to a novel drug that might combine less administration frequency with improved therapeutic efficacy. More... »

PAGES

535-555

Book

TITLE

Proceedings of the 21st Annual Meeting of the European Society for Animal Cell Technology (ESACT), Dublin, Ireland, June 7-10, 2009

ISBN

978-94-007-0883-9
978-94-007-0884-6

Identifiers

URI

http://scigraph.springernature.com/pub.10.1007/978-94-007-0884-6_91

DOI

http://dx.doi.org/10.1007/978-94-007-0884-6_91

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1006025571


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Turtle is a human-readable linked data format.

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RDF/XML is a standard XML format for linked data.

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