title: 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.
authors.affiliation: Biologics Toxicology, Center of Excellence in Biotechnology, Centocor R & D, Radnor, PA 19087, USA. dmakropo@its.jnj.com
authors.forename: Dorie A
authors.initials: DA
authors.lastname: Makropoulos
authors.forename: Ram
authors.initials: R
authors.lastname: Achuthanandam
authors.forename: Justin
authors.initials: J
authors.lastname: Avery
authors.forename: Krista
authors.initials: K
authors.lastname: Wilson
authors.forename: Kerry
authors.initials: K
authors.lastname: Brosnan
authors.forename: Andrew
authors.initials: A
authors.lastname: Miller
authors.forename: Thomas
authors.initials: T
authors.lastname: Nesspor
authors.forename: Denise
authors.initials: D
authors.lastname: Chroscinski
authors.forename: Mindi
authors.initials: M
authors.lastname: Walker
authors.forename: Devon
authors.initials: D
authors.lastname: Egenolf
authors.forename: ChiChi
authors.initials: C
authors.lastname: Huang
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Bugelski
mesh_terms: D000755:Anemia, Sickle Cell / Q000097:blood / Q000188:drug therapy*; D000818:Animals; D000068256:Darbepoetin alfa; D004195:Disease Models, Animal; D004906:Erythrocyte Count; D004921:Erythropoietin / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D006397:Hematinics / Q000494:pharmacology / Q000627:therapeutic use; D006454:Hemoglobins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017467:Receptors, Erythropoietin / Q000819:agonists*; D011993:Recombinant Fusion Proteins / Q000494:pharmacology / Q000627:therapeutic use*; D017086:beta-Thalassemia / Q000097:blood / Q000188:drug therapy*
chemical_list: C541126:CNTO 530; D006397:Hematinics; D006454:Hemoglobins; D017467:Receptors, Erythropoietin; D011993:Recombinant Fusion Proteins; D004921:Erythropoietin; D000068256:Darbepoetin alfa