|
|
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.
 Previous Article | Next Article 
Submitted April 5, 2007
Accepted June 26, 2007
A potent erythropoietin mimic human antibody
interacts through a novel binding site
Zhihong Liu, Vincent S Stoll, Peter J DeVries, Clarissa G Jakob, Nancy Xie, Robert L Simmer, Susan E Lacy, David A Egan, John E Harlan, Richard R Lesniewski, and Edward B Reilly*
Global Pharmaceutical Research & Development-R4CD, Abbott Laboratories, Abbott Park, IL, United States
Global Pharmaceutical Research & Development, Abbott Bioresearch Center, Worcester, MA, United States
* Corresponding author; email: ed.reilly{at}abbott.com.
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 to 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 to 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 3.2 Å, 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:
|
|
|
|
 
P. Sathyanarayana, E. Houde, D. Marshall, A. Volk, D. Makropoulos, C. Emerson, A. Pradeep, P. J. Bugelski, and D. M. Wojchowski
CNTO 530 functions as a potent EPO mimetic via unique sustained effects on bone marrow proerythroblast pools
Blood,
May 14, 2009;
113(20):
4955 - 4962.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. T. Alexandrescu
In Reply
J. Clin. Oncol.,
March 10, 2009;
27(8):
1340 - 1342.
[Full Text]
[PDF]
|
|
|
|
|
|
|
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]
|
|
|
|
|
