A human anti-matriptase-2 antibody limits iron overload, α-globin aggregates, and splenomegaly in β-thalassemic mice

• DOI: 10.1182/bloodadvances.2023012010
• Publication Date: 2024-01-19T20:01:16Z
• Authors: Matthew Wake; Anaïs Palin; Audrey Belot; Mathieu Berger; Megane Lorgouilloux; Margot Bichon; Jonathan Papworth; Luke Bayliss; Benjamin Grimshaw; Natalie Rynkiewicz; Jemima Paterson; Alicia Poindron; Erin Spearing; Emily Carter; Robyne Hudson; Millie Campbell; Verena Petzer; Céline Besson-Fou...; Chloé Latour; Amélie Largounez; Ophélie Gourbeyre; Alexis Fay; Hélène Coppin; Marie-Paule Roth; Igor Theurl; Volker Germaschewski; Delphine Meynard
• Keywords: Ineffective erythropoiesis; Transferrin receptor; TMPRSS6; Beta thalassemia

Iron plays a major role in the deterioration of β-thalassemia. Indeed, high levels transferrin saturation and iron delivered to erythroid progenitors are associated with production α-globin precipitates that negatively affect erythropoiesis. Matriptase-2/TMPRSS6, membrane-bound serine protease expressed hepatocytes, modulates hepcidin thus is key target prevent overload To address safety concerns raised by suppression Tmprss6 antisense oligonucleotides or small interfering RNA, we tested fully human anti-matriptase-2 antibody, RLYB331, which blocks activity matriptase-2. When administered weekly Hbbth3/+ mice, RLYB331 induced expression, reduced loading, prevented formation toxic α-chain/heme aggregates, ros oxygen species formation, improved reticulocytosis splenomegaly. increase effectiveness β-thalassemia treatment even further, combination RAP-536L, ligand-trapping protein contains extracellular domain activin receptor type IIB alleviates anemia promoting differentiation late-stage precursors. RAP-536L alone did not but significantly apoptosis populations bone marrow, normalized red blood cell counts, hemoglobin hematocrit levels. Interestingly, association entirely reversed phenotype mice simultaneously corrected overload, ineffective erythropoiesis, splenomegaly, hematological parameters, suggesting multifunctional molecule consisting fusion luspatercept (human version RAP-536L) would allow administration single medication addressing different pathophysiological aspects