CNTO 530 Increases Expression of HbA and HbF in Murine Models of β-Thalassemia and Sickle Cell Anemia

Title:CNTO 530 Increases Expression of HbA and HbF in Murine Models of β-Thalassemia and Sickle Cell Anemia

Volume: 14 Issue: 2

Author(s): Dorie A. Makropoulos, Ram Achuthanandam, Justin Avery, Krista Wilson, Kerry Brosnan, Andrew Miller, Thomas Nesspor, Denise Chroscinski, Mindi Walker, Devon Egenolf, ChiChi Huang and Peter J. Bugelski

Affiliation:

Keywords: Erythropoiesis, Flow Cytometry, Fusion protein, Hematology, Ion Exchange Chromatography, Pharmacodynamics

Abstract: CNTO 530 is an erythropoietin receptor agonist MIMETIBODYTM construct. CNTO 530 has been shown to be active in a number of rodent models of acquired anemia (e.g. renal insufficiency and chemotherapy induced anemia). We investigated the efficacy of CNTO 530 in murine models of β-thalassemia and sickle cell anemia (Berkeley mice). β- thalassemic mice are deficient in expression of α-globin chain and heterozygous mice are characterized by a clinical syndrome similar to the human β-thalassemia intermedia. Berkeley mice are knocked out for murine alpha and beta globin and are transgenic for human alpha, beta (sickle) and gamma globin genes. Berkeley mice thus express human sickle hemoglobin A (HbS) and can also express human fetal hemoglobin. These mice express a severe compensated hypochromic microcytic anemia and display the sickle cell phenotype. To test the effectiveness of CNTO 530, mice from both genotypes received a single subcutaneous (s.c.) dose of CNTO 530 or darbepoetin-α (as a comparator) at 10,000 U/kg, a dose shown to cause a similar increase in reticulocytes and hemoglobin in normal mice. Hematologic parameters were evaluated over time. CNTO 530, but not darbepoetin-α, increased reticulocytes, red blood cells and total hemoglobin in β- thalassemic mice. In Berkeley mice CNTO 530 showed an increase in reticulocytes, red blood cells, F-cells, total hemoglobin and fetal hemoglobin. In conclusion, CNTO 530 is effective in murine models of β-thalassemia and sickle cell anemia. These data suggest that CNTO 530 may have beneficial effects in patients with genetically mediated hemoglobinopathies.

Cite this article as:

A. Makropoulos Dorie, Achuthanandam Ram, Avery Justin, Wilson Krista, Brosnan Kerry, Miller Andrew, Nesspor Thomas, Chroscinski Denise, Walker Mindi, Egenolf Devon, Huang ChiChi and J. Bugelski Peter, CNTO 530 Increases Expression of HbA and HbF in Murine Models of β-Thalassemia and Sickle Cell Anemia, Current Pharmaceutical Biotechnology 2013; 14 (2) . https://dx.doi.org/10.2174/1389201011314020015