PMID: 9448306Mar 14, 1998Paper

Human erythropoietin dimers with markedly enhanced in vivo activity

Proceedings of the National Academy of Sciences of the United States of America
A J SytkowskiS Siekman

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...Continue Reading

References

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Citations

Jul 24, 2012·Applied Microbiology and Biotechnology·Jae Seong LeeGyun Min Lee
Apr 20, 2006·Amino Acids·M Werle, A Bernkop-Schnürch
Dec 2, 2008·Expert Reviews in Molecular Medicine·Constance Tom NoguchiYi Jia
Oct 29, 2008·Acta Pharmacologica Sinica·Jing-fa ZhangGuo-tong Xu
Oct 31, 2000·Bioscience, Biotechnology, and Biochemistry·R SasakiM Nagao
Jan 12, 2013·PloS One·Olga Kolaj-RobinTewfik Soulimane
Oct 8, 2004·Internal Medicine·Wolfgang Jelkmann
Mar 4, 2014·Expert Opinion on Biological Therapy·Lucia Del Vecchio, Francesco Locatelli
Dec 2, 2008·Expert Opinion on Drug Delivery·Zhi-Yang ChangMing-Kung Yeh
Jul 26, 2011·Biochemical Pharmacology·S ChateauvieuxM Diederich
Feb 14, 2009·International Journal of Pharmaceutics·Yan HuXianming Hu
Jul 28, 2007·Critical Reviews in Oncology/hematology·Vivien M HodgesA Peter Maxwell
Jan 27, 2007·European Journal of Haematology·Wolfgang Jelkmann
Apr 18, 2012·Drug Testing and Analysis·Nataša Debeljak, Arthur J Sytkowski
Jul 25, 2006·Protein Expression and Purification·Kornelia SchrieblKarola Vorauer-Uhl
Nov 30, 2005·Biochemical and Biophysical Research Communications·Dong Eok LeeOok Joon Yoo
Mar 25, 2014·Developmental and Comparative Immunology·Fumihiko KatakuraMiodrag Belosevic
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Jun 12, 2009·Electrophoresis·Max GassmannJohannes Vogel
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