A potent erythropoietin-mimicking human antibody interacts through a novel binding site.
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.
Liu
Zhihong
Z
Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL 60064-6199, USA.
Stoll
Vincent S
VS
Devries
Peter J
PJ
Jakob
Clarissa G
CG
Xie
Nancy
N
Simmer
Robert L
RL
Lacy
Susan E
SE
Egan
David A
DA
Harlan
John E
JE
Lesniewski
Richard R
RR
Reilly
Edward B
EB
D000818:Animals; D000906:Antibodies / Q000276:immunology*; D001665:Binding Sites; D002460:Cell Line; D018360:Crystallography, X-Ray; D004920:Erythropoiesis; D004921:Erythropoietin / Q000378:metabolism*; D006400:Hematocrit; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008958:Models, Molecular; D018716:Molecular Mimicry; D020836:Protein Structure, Quaternary; D017434:Protein Structure, Tertiary; D017467:Receptors, Erythropoietin / Q000737:chemistry / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D040681:Structural Homology, Protein
D000906:Antibodies; D017467:Receptors, Erythropoietin; D004921:Erythropoietin