Beta-thalassemia is a hereditary iron-independent anemia, caused by a reduction of β-globin, affecting millions of people globally. Current treatments such as blood transfusions and iron chelation show significant toxicities and add to organ damage. Luspatercept (Acvr2b(L79D)-Fc) is a novel treatment for transfusion-dependent β-thalassemia patients that improves erythropoiesis independent of erythropoietin. The exact mechanism of action remains unknown, and it is controversially discussed if growth differentiation factor 11 (GDF11) is the main target of this drug. Genetic models raised doubts that GDF11 is the target of Acvr2b(L79D)-Fc. Here we tested if a GDF11 specific blocking antibody improves β-thalassemia intermedia in mice. Our findings support the genetic data that GDF11 does not play a role in the ineffective erythropoiesis in β-thalassemia. Anti-GDF11 treatment did not change hematocrit, hemoglobin and red blood cell number and it did not improve erythropoiesis. Ex vivo treatment of erythroblasts with recombinant GDF11 did not inhibit red blood cell maturation. Lastly, we identified that inhibiting GDF8 in β-thalassemia mice has a small effect on erythropoiesis and increased hemoglobin levels without being as effective as Acvr2b(L79D)-Fc. Of note, wild-type animals treated with anti-GDF8 did not show changes in any hematology parameters and therefore the small effect we observed might be due to the disease phenotype, but not due to a physiological mechanism involved in erythropoiesis. Taken together, GDF11 is not involved in erythropoiesis but GDF8 may have a minor role in the regulation of ineffective erythropoiesis. Given the small effect of anti-GDF8 on erythropoiesis compared to Acvr2b(L79D)-Fc, we conclude that either there is another target or several targets of Acvr2b(L79D)-Fc driving ineffective erythropoiesis, or that Acvr2b(L79D)-Fc efficacy is due to it altering the overall BMP/GDF/Activin ligand and receptor balance.

Disclosures

Lob:Regeneron Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Kravets:Regeneron Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Miloscio:Regeneron Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Mastaitis:Regeneron Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Economides:Regeneron Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Hatsell:Regeneron Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company.

Author notes

*

Asterisk with author names denotes non-ASH members.