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2 results on '"activin receptor IIA inhibition"'

1. An activin receptor IIA ligand trap promotes erythropoiesis resulting in a rapid induction of red blood cells and haemoglobin.

Author

Carrancio, Soraya, Markovics, Jennifer, Wong, Piu, Leisten, Jim, Castiglioni, Paola, Groza, Matthew C., Raymon, Heather K., Heise, Carla, Daniel, Tom, Chopra, Rajesh, and Sung, Victoria

Subjects
*ACTIVIN receptors, *ERYTHROCYTES, *HEMOGLOBINS, *ANEMIA treatment, *ERYTHROPOIESIS, *ERYTHROPOIETIN
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. [ABSTRACT FROM AUTHOR]

Published
2014
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2. An activin receptor IIA ligand trap promotes erythropoiesis resulting in a rapid induction of red blood cells and haemoglobin

Author

Carla Heise, Matthew C. Groza, Heather Raymon, Jennifer A. Markovics, Rajesh Chopra, Soraya Carrancio, Jim Leisten, Thomas O. Daniel, Victoria Sung, Piu Wong, and Paola Castiglioni

Subjects
Ineffective erythropoiesis, Erythrocyte Indices, medicine.medical_specialty, Erythrocytes, Activin Receptors, Type II, Recombinant Fusion Proteins, Bone Marrow Cells, medicine.disease_cause, Ligands, Colony-Forming Units Assay, Hemoglobins, Mice, activin receptor IIA inhibition, Transforming Growth Factor beta, Internal medicine, medicine, Animals, Humans, Erythropoiesis, Red Cells and Iron, Erythropoietin, Erythroid Precursor Cells, biology, Hematology, Activin receptor, Transforming growth factor beta, haemoglobin, Cell biology, Red blood cell, medicine.anatomical_structure, Endocrinology, Cellular Microenvironment, biology.protein, Female, medicine.drug, Transforming growth factor, Signal Transduction
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.

Published
2013

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