Pharmacodynamics Of Cnto 530 In A Murine Model Of B-Thalassemia

Abstract CNTO 530 is an erythropoietin (EPO) receptor agonist that links two EMP-1 peptides to a MIMETIBODYä scaffold. Here, we characterize the in vivo efficacy of CNTO 530 in a murine model of b-Thalassemia. Hematological analysis confirmed dysregulated erythropoiesis in these mice with decreased red blood cells (RBC), hemoglobin (Hgb), and hematocrit (Hct) indices compared to age matched C57BL/6 littermates. An increase in reticulocytes was also observed concurrent with decreased mean cell volume (MCV) and increased red cell distribution width (RDW) suggesting compensatory erythropoiesis. In addition, splenomegaly was observed consistent with increased hematopoiesis. To test the effectiveness of CNTO 530 in this model, a timecourse study was done comparing treatment with CNTO 530 to darbepoetin-a. A single subcutaneous (s.c.) dose of CNTO 530 at 10,000 U/kg dose stimulated a long-lived, approximately 4 g/dL increase in hemoglobin compared to the less than 1 g/dL, short lived increase in Hgb observed in response to darbepoetin-a at 10,000 U/kg. Mice dosed with CNTO 530 also showed an increase in RBC, Hct, and MCV where darbepoetin-a had no significant effect. Non-thalassemic littermates were also given a single s.c. dose of 10,000 U/kg of CNTO 530 or darbepoetin-a which showed these drugs indeed are efficacious in normal background animals. These results demonstrate that CNTO 530 caused a potent, reproducible and longer-lived response in Hgb than darbepoietin in a model of b-thalassemia.