Activity of CNTO 530 in a Murine Model of Sickle Cell Anemia.

Abstract 4606

CNTO 530 is an erythropoietin receptor agonist MIMETIBODY^TM 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) and in a model of beta-thalassemia. Here we report on the activity of CNTO 530 in murine globin KO-human HbS transgenic (sickle cell) mice. Berkeley mice, as originally described by Pászty et al (Pászty et al. Science 1997), are knocked out for murine alpha and beta globin and are transgenic for human alpha, beta (sickle) and gamma globin genes. Thus, these mice express exclusively human hemoglobin A (HbAsickle) (or sickle hemoglobin, HbS) and can also express human fetal hemoglobin (HbF). To test the effectiveness of CNTO 530 in this model, mice received a single subcutaneous (s.c.) dose of CNTO 530 (0.3 mg/kg), epoetin-alpha (0.1 mg/kg) or darbepoetin-alpha (0.03 mg/kg) (as comparators) at 10,000 U/kg, a dose previously shown to increase hemoglobin in normal mice. Hematology, histology of the spleen, F-cells and expression of HbF were then evaluated over time. We show that these mice express a severe compensated hypochromic microcytic anemia and display the sickle cell phenotype. In addition, splenomegaly and extramedullary erythropoiesis were observed. Ten days after dosing, CNTO 530 but not epoetin-alpha or darbepoetin-alpha caused an increase in reticulocytes, red blood cells (RBC), F-cells, total hemoglobin (Hgb) and HbF. In conclusion, these results demonstrate that a single dose of CNTO 530 can increase expression of HbF in sickle cell mice and suggest that human treatment with CNTO 530 may have beneficial effects in sickle cell anemia patients.