title: An activin receptor IIA ligand trap promotes erythropoiesis resulting in a rapid induction of red blood cells and haemoglobin.
abstract: Sotatercept (ACE-011), a recombinant human fusion protein containing the extracellular domain of the human Activin receptor IIA, binds to and inhibits activin and other members of the transforming growth factor -β (TGF-β) superfamily. Administration of sotatercept led to a rapid and sustained increase in red blood cell (RBC) count and haemoglobin (Hb) in healthy volunteers (phase I clinical trials), but the mechanism is not fully understood. Mice treated with RAP-011 (murine ortholog of ACE-011) respond with a rapid (within 24 h) increase in haematocrit, Hb, and RBC count. These effects are accompanied by an equally rapid stimulation of late-stage erythroid precursors in the bone marrow (BM). RAP-011 also induces a significant increase in erythroid burst-forming units and erythropoietin, which could contribute to additional, sustained effects on RBC production. Further in vitro co-culture studies demonstrate that BM accessory cells are required for RAP-011 effects. To better understand which TGF-β family ligand(s) mediate RAP-011 effects, we evaluated the impact of several of these ligands on erythroid differentiation. Our data suggest that RAP-011 may act to rescue growth differentiation factor 11/Activin A-induced inhibition of late-stage erythropoiesis. These data define the mechanism of action of a novel agent that regulates RBC differentiation and provide the rationale to develop sotatercept for the treatment of anaemia and ineffective erythropoiesis.
authors.affiliation: Celgene Corporation, San Francisco, CA, USA.
authors.forename: Soraya
authors.initials: S
authors.lastname: Carrancio
authors.forename: Jennifer
authors.initials: J
authors.lastname: Markovics
authors.forename: Piu
authors.initials: P
authors.lastname: Wong
authors.forename: Jim
authors.initials: J
authors.lastname: Leisten
authors.forename: Paola
authors.initials: P
authors.lastname: Castiglioni
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Groza
authors.forename: Heather K
authors.initials: HK
authors.lastname: Raymon
authors.forename: Carla
authors.initials: C
authors.lastname: Heise
authors.forename: Tom
authors.initials: T
authors.lastname: Daniel
authors.forename: Rajesh
authors.initials: R
authors.lastname: Chopra
authors.forename: Victoria
authors.initials: V
authors.lastname: Sung
mesh_terms: D030301:Activin Receptors, Type II / Q000378:metabolism*; D000818:Animals; D001854:Bone Marrow Cells / Q000187:drug effects / Q000378:metabolism; D060833:Cellular Microenvironment / Q000502:physiology; D003114:Colony-Forming Units Assay; D004909:Erythrocyte Indices / Q000187:drug effects; D004912:Erythrocytes / Q000187:drug effects* / Q000378:metabolism*; D015672:Erythroid Precursor Cells / Q000187:drug effects / Q000378:metabolism; D004920:Erythropoiesis / Q000187:drug effects* / Q000502:physiology*; D004921:Erythropoietin / Q000096:biosynthesis; D005260:Female; D006454:Hemoglobins / Q000096:biosynthesis*; D006801:Humans; D008024:Ligands; D051379:Mice; D011993:Recombinant Fusion Proteins / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D030301:Activin Receptors, Type II; D004921:Erythropoietin; D006454:Hemoglobins; D008024:Ligands; D011993:Recombinant Fusion Proteins; D016212:Transforming Growth Factor beta; C542017:sotatercept; C425585:activin receptor type II-A
keywords: activin receptor IIA inhibition; erythropoiesis; haemoglobin