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

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.

Targeting EPO and EPO receptor pathways in anemia and dysregulated erythropoiesis

“…Such dimeric mimetibody EMPs exhibit high ESA potency, and sustained erythropoietic activity in mouse and rat models 98 . As recently reported, this includes mimetibody EMP-induced increases in HbF and HbA as assessed in a mouse model of beta-thalassemia 99 . Beyond this, and as a notable proof of principle for a fully synthetic mimetic of a complex glycoprotein hormone, PEG-scaffolded dimeric EMPs also have been developed that further proved in initial clinical trials to be non-inferior to rhEPO in treating the anemia of end-stage CKD 100 .…”

“…The murine EPOR is efficiently activated by rhEPO, and has 86% identity with the hEPO including eight of nine pY signaling motifs. For mouse models, genetic approaches in particular are time intensive, but nonetheless have been advantageous via the development, for example, of useful models for the anemia of chronic renal disease 110 , chemotherapy 98 , sublethal irradiation 136 , blood loss 110 and hemoglobinopathies 99 . In addition, mEPOR-KO mice expressing the hEPOR have been generated and employed in studies of EPOR agonists 89 .…”

“…Promise also continues to exist for the development of ESAs that efficiently activate preassembled EPOR dimers 89, 90, 96-99 . This prospectively includes scaffolded dimeric EPO mimetic peptides that bind EPORs at EPO binding sites as well as small molecule dimerizing agents that might act additively with rhEPO.…”