Deciphering KY1066: A Human Antibody's Role in Beta Thalassemia Iron Overload Management

Beta thalassemia is a genetic disorder affecting hemoglobin, leading to symptoms like ineffective blood cell production, iron overload, an enlarged spleen, and anemia. The condition often results in high levels of EPO, which suppresses the iron-regulating hormone hepcidin, causing increased iron absorption and storage. This can lead to tissue damage in both non-transfusion dependent and transfusion dependent patients. While regular blood transfusions and iron chelation therapy have improved outcomes for transfusion dependent patients, some still face challenges with iron overload. TMPRSS6's role in iron regulation is recognized, and reducing its expression has been shown to increase hepcidin levels, correcting iron overload and other symptoms in a mouse model.

A novel antibody, KY1066, has been developed to target MTP-2 for treating iron overload diseases like beta thalassemia. The antibody was produced by immunizing mice with human MTP-2 and resulted in MTP-2-specific monoclonal antibodies. KY1066 neutralizes MTP-2's enzymatic activity, blocking its function and leading to increased BMP/SMAD signaling and hepcidin production. This single dose treatment in mice increased hepcidin, reducing serum iron and transferrin saturation by promoting ferroportin internalization and degradation. In a mouse model, it significantly decreased serum iron and transferrin saturation levels and consistently restricted iron levels with repeated dosing. These findings suggest KY1066's potential to treat iron overload in diseases like beta thalassemia, potentially improving anemia and reducing the need for transfusions and iron chelation.

The study's authors have disclosed their affiliations and interests with Kymab Ltd, including employment, equity ownership, consultancy, and research funding.