Thalassemia syndromes are inherited hemoglobinopathies characterized by impaired or absent production of one of the globin chains of adult hemoglobin with subsequent accumulation of the unpaired chains. The most common form is β-thalassemia related to a defective production of the β-globin chains causing an unbalanced ratio of α-globin to β-globin. As a consequence, the unbound free α-globin chains precipitate in erythroid precursors, leading to ineffective erythropoiesis, chronic hemolytic anemia, and compensatory hemopoietic expansion.1 Ineffective erythropoiesis is the leading driver of clinical severity of β-thalassemias and, for many years, the standard of care to suppress it was red blood cell (RBC) transfusions.2 Bone marrow transplantation was introduced in the 1980s with the rationale of restoring the capability of producing functional hemoglobin.3 Gene therapy with globin lentiviral vectors and genome editing to inhibit the BCL11A gene are currently under investigation.4 These approaches, however, have several limitations, are feasible in a small subset of patients, and require transplantation conditioning. Thus, much effort has been devoted to finding new therapeutic options.
Luspatercept (formerly ACE-536; Acceleron Pharma, Celgene/Bristol Myers Squibb) is a ligand trap consisting of a modified form of the extracellular domain of the human activin type 2B receptor (ActR2B) linked to the fragment crystallizable (Fc) domain of human immunoglobulin G1, which binds to select transforming growth factor-β superfamily (TGF-β) ligands, blocks SMAD-2/3 signaling, and enhances erythroid maturation. Luspatercept was approved by the US Food and Drug Administration (FDA)5 in 2019 and by the European Medicines Agency6 in 2020 to treat anemia in adult patients with β-thalassemia who require regular RBC transfusions.
Luspatercept pharmacology
Members of the TGF-β superfamily ligands, which include TGF-β, activins, growth differentiation factors (GDFs), and bone morphogenetic proteins, have been shown to act as inhibitors of late-stage erythropoiesis.7,8 The activin receptor ligand traps sotatercept and luspatercept were designed to compete with the extracellular domains of activin receptor type 2A (ACVR2A) or 2B, to act as ligand traps for TGF-β–like molecules9 (Figure 1). Sotatercept was originally developed to treat bone loss disorders, but clinical studies unexpectedly revealed increased hematocrit and hemoglobin (Hb) levels in treated patients.10 Further studies showed that sotatercept and luspatercept, through their ability to reduce Smad-2/3 signaling, improve anemia in disorders characterized by ineffective erythropoiesis, such as β-thalassemia11 and myelodysplastic syndromes (MDSs).12 Luspatercept was tested in the Hbbth1/th1 transgenic mouse model of human β-thalassemia intermedia,11 which demonstrated an increase in RBC count, hematocrit, and Hb levels in a dose-dependent manner.13 Several studies in mouse models of anemia associated with ineffective erythropoiesis confirmed that Smad-2/3 and GDF-11 inhibition restores normal erythropoietic differentiation and improves anemia.14 On the basis of this observation, it was postulated that GDF-11 could be the target of luspatercept; however, in 2019, Guerra and colleagues15 clearly demonstrated that GDF-11 is not the only target of luspatercept; this observation was supported in a commentary by Camaschella.16 Subsequent to this observation, Martinez et al17 published consistent data showing that luspatercept enhances erythroid differentiation in murine β-thalassemia by increasing GATA-1 availability. Using differentiating murine erythroleukemia cells and GDF-11–induced overactivation of the Smad-2/3 pathway, they found a higher nuclear localization of pSmad-2/3 and Smad-4 and a concomitant reduced nuclear localization and expression of GATA-1 and TIF-1. In addition, ACE-536 (luspatercept) increased the nuclear localization of TIF1-γ and the expression of GATA-1.17 A consistent body of data has demonstrated that overactivation of the Smad-2/3 signaling pathway negatively regulates terminal erythroid differentiation in mouse models of β-thalassemia, partly by reducing GATA-1 expression. RAP-536 (murine ACE-536/luspatercept)-mediated inhibition of Smad-2/3 signaling enhances erythroid maturation in this context by increasing the expression and functional availability of GATA-1. It is well known that GATA-1 is indispensable for erythroid maturation.