Abstract
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.
Highlights
EPO receptor (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
A fulllength human agonistic antibody targeting the EPO receptor (EPOR) would offer a longer serum half-life and may support even less frequent dosing regimens that could better match with many chemotherapy regimens and may provide better convenience for both predialysis and peritoneal dialysis patients who need to attend the clinic only infrequently
The activation signal achieved with the symmetric molecule ABT007 is sufficient to support potent and more sustained erythropoiesis in animal models compared with standard doses of Recombinant human EPO (rHu-EPO)
Summary
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. Mouse monoclonal antibodies (mAbs) that are raised to the soluble extracellular domain (ECD) of the human EPOR and that mimic EPO activation by inducing ligand-dependent cell proliferation and differentiation have been described.[5,6] These mAbs, activate the EPOR less efficiently than the natural hormone does and are less potent agonists and unsuitable for clinical use. In vivo properties of ABT007 may be further enhanced by extended serum half-life of the human antibody and its fast off rate from the receptor, which permits continuous stimulation
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