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.

Recent developments in myelodysplastic syndromes

“…For example, sotatercept, a soluble activin receptor type 2A IgG-Fc fusion protein that acts as a ligand trap for members of the transforming growth factor b superfamily, is undergoing a multicenter trial in MDS, as is the JAK1 inhibitor INCB047986. 124 ARRY-614, a dual p38 mitogenactivated protein kinase/Tie2 kinase inhibitor, has been associated with hematologic improvements in patients for whom hypomethylating agents have failed yet who still meet IPSS criteria for lowerrisk disease; a few other kinase inhibitors are also being studied despite the relative rarity of activating kinase mutations in MDS. 125 Finally, advances in HSCT may make this potentially curative approach available to a wider variety of patients and improve outcomes.…”

Catching a Disease: A Molecular Trap as a Therapy for Pulmonary Arterial Hypertension

“…Only time will tell. Thus far, several protein traps that ensnare TGF-b superfamily ligands have shown efficacy in animal models of disease; for example, trapping Activin A and growth differentiation factor 11 corrects bone loss and anemia (18,19) and trapping BMP9 and BMP10 inhibits tumor angiogenesis (20). However, translation of ligand traps to clinical use is not assured.…”

RAP-011 improves erythropoiesis in zebrafish model of Diamond-Blackfan anemia through antagonizing lefty1

“…Understanding how an activin ligand trap such as RAP-011 can promote erythropoiesis remains difficult to explain, given the contribution of activin molecules to erythroid development. 17,48 Our work provides evidence to suggest RAP-011 can function to enhance activin signaling by antagonizing activin inhibitors such as Lft1. Therefore, RAP-011 can promote an increase in erythroid counts by maintaining homeostasis.…”

“…[17][18][19] This molecule antagonizes signaling downstream of ActRIIA through sequestering distinct members within the transforming growth factor-b (TGF-b) family, including bone morphogenetic proteins (BMPs), growth differentiation factors (GDFs), and Activin molecules, from binding to the endogenous receptor. Injection of RAP-011 (the murine form of ACE-011) into murine models of anemia can restore red blood cell parameters.…”

“…Injection of RAP-011 (the murine form of ACE-011) into murine models of anemia can restore red blood cell parameters. 17,20 Furthermore, a study using sotatercept in healthy volunteers demonstrated that it can increase hemoglobin levels. 18 Currently, sotatercept is being evaluated for efficacy in anemia associated with diseases such as b-thalassemia, myelodyspastic syndrome and renal disease.…”