NDLI: Human erythropoietin dimers with markedly enhanced in vivo activity.

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Human erythropoietin dimers with markedly enhanced in vivo activity.

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Human erythropoietin dimers with markedly enhanced in vivo activity.

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Lunn, E. D. Sytkowski, A. J. Davis, K. L. Feldman, L. Siekman, S.
Description	Author Affiliation: Sytkowski AJ ( Laboratory for Cell and Molecular Biology, Division of Hematology and Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA. asytkows@west.bidmc.harvard.edu);
Abstract	Human erythropoietin, a widely used and important therapeutic glycoprotein, has a relatively short plasma half-life due to clearance by glomerular filtration as well as by other mechanisms. We hypothesized that an erythropoietin species with a larger molecular size would exhibit an increased plasma half-life and, potentially, an enhanced biological activity. We now report the production of biologically active erythropoietin dimers and trimers by chemical crosslinking of the conventional monomeric form. We imparted free sulfhydryl residues to a pool of erythropoietin monomer by chemical modification. A second pool was reacted with another modifying reagent to yield monomer with maleimido groups. Upon mixing these two pools, covalently linked dimers and trimers were formed that were biologically active in vitro. The plasma half-life of erythropoietin dimers in rabbits was >24 h compared with 4 h for the monomers. Importantly, erythropoietin dimers were biologically active in vivo as shown by their ability to increase the hematocrits of mice when injected subcutaneously. In addition, the dimers exhibited >26-fold higher activity in vivo than did the monomers and were very effective after only one dose. Dimeric and other oligomeric forms of Epo may have an important role in therapy.
ISSN	00278424
e-ISSN	10916490
Journal	Proceedings of the National Academy of Sciences of the United States of America
Issue Number	3
Volume Number	95
Language	English
Publisher	National Academy of Sciences
Publisher Date	1998-03-01
Publisher Place	United States
Access Restriction	Open
Subject Keyword	Erythropoietin Chemical Synthesis Animals Blotting, Western Chromatography, High Pressure Liquid Dimerization Blood Pharmacokinetics Half-Life Mice Protein Conformation Rabbits Research Support, U.S. Gov't, Non-P.H.S. Research Support, U.S. Gov't, P.H.S. Multidisciplinary
Content Type	Text
Resource Type	Article
Subject	Multidisciplinary

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