Abstract
CNTO 530 and darbepoetin-a are long lived erythropoietin receptor agonists (ERAs). Clinically, anemia of chronic disease (ACD) is associated with increased expression of tumor necrosis factor-a (TNF-a) and mice transgenic for human TNF-a develop ACD. The purpose of this investigation was to compare the effects of these agents in a murine model of ACD. Human TNF-a expressing (Tg 197) mice were administered a single subcutaneous dose of CNTO 530 or darbepoetin-a and the pharmacodynamic response in bone marrow spleen and peripheral blood evaluated. RBC life span and reticulocyte age distribution were also evaluated. CNTO 530 induced a dose responsive increase in reticulocytes, RBCs and Hgb in both wild type and Tg197 mice. Although the reticulocyte response was similar to wild types, the RBC and Hgb response to CNTO 530 in Tg197 mice was blunted. There was no statistically significant difference in RBC life span with either compound. Darbepoetin-α caused a greater peak in % dead Pro/basophilic erythroblasts, greater peak EMH in the spleen and a greater increase in reticulocyte maturation time. In contrast, despite a similar peak increase, CNTO 530 caused a more sustained response of reticulocyte, EMH, RBC and Hgb, consistent with increased exposure. In conclusion, CNTO 530 and darbepoetin-a increased RBC and hemoglobin in a murine model of ACD. Compared to darbepoetin-a, CNTO 530 had a more sustained effect, consistent with increased exposure.
Highlights
Anemia of chronic disease (ACD) is an important cause of co-morbidity in rheumatoid arthritis (RA), a systemic autoimmune disease afflicting 1-2% of the population [1,2]
CNTO 530 includes two EMP1 sequences, a 20-amino acid peptide that binds to EPO receptors (EPO-R), on a human IgG4 Fc framework and expresses EPO-like bioactivity [9,10] The purpose of this study was to determine if darbepoetin- and CNTO 530 had beneficial effects in a murine model of anemia of chronic disease (ACD)
In our studies in huTNF- transgenic mice, it was observed that CNTO 530 and darbepoetin- caused a dose responsive stimulus of erythropoiesis
Summary
Anemia of chronic disease (ACD) is an important cause of co-morbidity in rheumatoid arthritis (RA), a systemic autoimmune disease afflicting 1-2% of the population [1,2]. Tumor necrosis factor- (TNF- ) has been shown to play a central role in disease progression in RA (see review by Sfikakis and Kollias [3]) and has been implicated in the pathogenesis of ACD. Darbepoetin- and CNTO 530 are long-lived erythropoietin receptor agonists. CNTO 530 is a 58 kD glycoprotein MIMETIBODYTM construct that has been shown to cause a long-lived stimulation of erythropoiesis in mice and rats [7,8]. CNTO 530 has no sequence homology with erythropoietin (EPO). CNTO 530 includes two EMP1 sequences, a 20-amino acid peptide that binds to EPO receptors (EPO-R), on a human IgG4 Fc framework and expresses EPO-like bioactivity [9,10] The purpose of this study was to determine if darbepoetin- and CNTO 530 had beneficial effects in a murine model of ACD
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
