Long-Acting Anti-Matriptase-2 Antibody As a Potentially Best-in-Class Therapy for Iron Overload Diseases

Introduction Iron overload occurs when there are excess stores of iron in the body. This excess iron is stored in various organs and can lead to serious and life-threatening conditions. Many diseases and conditions are associated with iron overload, include polycythemia vera (PV), myelodysplastic syndrome (MDS), beta-thalassemia (BT) amongst others. The current standard of care for iron overload diseases primarily revolves around reducing the excess iron accumulated in the body includes phlebotomy or iron chelation therapy, depending on the etiology, to prevent or minimize organ damage. While effective in many cases, this course of treatment presents challenges such as adverse side effects and increases chance of developing anemia. Hepcidin is a key regulatory hormone in iron metabolism, playing a critical role in maintaining iron homeostasis within the body. Matriptase-2 (MTP-2), an enzyme encoded by the transmembrane protease serine 6 (TMPRSS6) gene, is involved in the regulation of iron metabolism by modulating hepcidin expression. Rallybio has developed a potent and specific anti-MTP-2 antibody, a fully humanized monoclonal antibody designed to extend serum half-life relative to conventional monoclonal antibodies. Administering the anti-MTP-2 antibody enhances Hepcidin mRNA expression, thus decreasing serum iron and transferrin saturation, which are clinical indicators for iron overload conditions. Methods We assessed the Pharmacokinetic (PK), Pharmacodynamic (PD), and safety profiles of anti-MTP-2 antibody using a specific humanized FcRn (Tg32) mouse model. This included administering doses of 0 (control), 1, and 3 mg/kg of the antibody via intravenous injection to groups of mice. This study measured mortality, clinical observations, body weights, clinical pathology parameters (focused on iron metrics for PD analysis), pharmacokinetics, and macroscopic examinations. Results The half-life of anti-MTP-2 antibody was reported as 204 hours with 1 mg/kg dosage and 348 hours with the 3 mg/kg dosage. Both the maximum concentration (Cmax) and the area under the curve (AUC) of the antibody increased proportionally with dosage, indicating dose-dependent pharmacokinetics. Notably, the anti-MTP-2 antibody administration resulted in rapid, significant, sustained pharmacological effects without unscheduled mortality or notable clinical side effects. Serum iron level and transferrin saturation reached approximately 70% reduction from baseline within 24 hours of dosing and remained at the low levels throughout the study period (4 weeks). Conclusions The antibody targeting MTP-2, is a promising candidate for treatment of iron overload disorders. In our study, single intravenous injections of the antibody were well tolerated in humanized FcRn mice at doses tested, whilst demonstrating significant and sustained pharmacological effects. These findings support the continued preclinical and clinical development of anti-MTP-2 antibody as a potentially best-in-class therapeutic molecule for managing iron overload diseases.