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Blood, 1 October 2007, Vol. 110, No. 7, pp. 2408-2413. Prepublished online as a Blood First Edition Paper on July 9, 2007; DOI 10.1182/blood-2007-04-083998. This Article Full Text Full Text (PDF) Erratum (v111,p996) All Versions of this Article: blood-2007-04-083998v1 110/7/2408    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Liu, Z. Articles by Reilly, E. B. Search for Related Content PubMed PubMed Citation Articles by Liu, Z. Articles by Reilly, E. B. Related Collections Hematopoiesis and Stem Cells Hemostasis, Thrombosis, and Vascular Biology Immunobiology Red Cells Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  HEMATOPOIESIS A potent erythropoietin-mimicking human antibody interacts through a novel binding site Zhihong Liu1, Vincent S. Stoll1, Peter J. DeVries1, Clarissa G. Jakob1, Nancy Xie1, Robert L. Simmer1, Susan E. Lacy2, David A. Egan1, John E. Harlan1, Richard R. Lesniewski1, and Edward B. Reilly1 1 Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL; 2 Global Pharmaceutical Research and Development, Abbott Bioresearch Center, Worcester, MA Recombinant human erythropoietin (rHu-EPO) is used to treat anemia by activating the erythropoietin receptor (EPOR) in erythroid progenitor cells, leading to proliferation and differentiation into mature red blood cells. To allow less frequent dosing, a hyperglycosylated version of EPO has been developed with a longer half-life. In principle, an agonistic antibody targeting EPOR would offer an even longer half-life, support robust monthly dosing, and, unlike EPO products, reduce the risk of pure red cell aplasia. The efficiency of signaling and corresponding potency of previously reported antibody mimics are generally suboptimal compared with EPO and not suitable for clinical use. Here we describe a potent, fully human, agonistic antibody (ABT007) targeting EPOR that supports potent, more sustained, and less pulsatile elevation of hematocrit in a human EPOR–expressing transgenic mouse model compared with standard doses of rHu-EPO while requiring less frequent dosing. Resolution of the crystal structure of the EPOR extracellular domain (ECD) complexed to the ABT007 Fab fragment, determined at 0.32 nm, identifies a binding site that is consistent with a novel mechanism of receptor activation based on a unique antibody-imposed conformational change. These results demonstrate that a symmetric molecule can serve as a potent activator of the EPOR. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: S. E. Lacy, P. J. DeVries, N. Xie, E. Fung, R. R. Lesniewski, and E. B. Reilly The Potency of Erythropoietin-Mimic Antibodies Correlates Inversely with Affinity J. Immunol., July 15, 2008; 181(2): 1282 - 1287. [Abstract] [Full Text] [PDF]

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