ineffective erythropoiesis

Blood

Beta thalassemia is an inherited hemoglobinopathy caused by a genetic defect in beta-globin gene and characterised by ineffective erythropoiesis, iron overload, splenomegaly and anemia. Excessive EPO production, resulting from the anemia, has a suppressive effect on the iron regulator hepcidin leading to increased iron absorption from the gut and release from internal stores. This in turn leads to tissue iron overload in transfusion independent (NTDT) patients and exacerbates the situation in transfusion dependent (TDT) patients. Primary standard of care treatment for TDT patients involves regular blood transfusions resulting in secondary iron overload and toxic tissue damage caused by non-transferrin bound iron (NTBI), which requires iron chelator treatment. Although transfusions and iron chelation have improved TDT patient prognosis, the iron overload experienced by some patients today still represents an unmet clinical need. The role of TMPRSS6 in iron regulation is already well established and reducing Tmprss6 expression was shown to increase hepcidin expression, correcting the iron overload, splenomegaly and anemia in Hbbth3/+ mice (Guo et al, JCI, 2013). Here we describe a first-in-class antibody targeting MTP-2, termed KY1066, for the treatment of diseases of iron overload, such as beta thalassemia. Through immunising mice transgenic for human immunoglobin heavy and light chain variable regions with purified human MTP-2 extra-cellular domain (ECD) and full-length human MTP-2 expressed on cells, we were able to obtain cross-reactive, MTP-2-specific monoclonal antibodies (mAbs). Our lead molecule, KY1066, was found to be a cross-reactive neutraliser of MTP-2 enzymatic activity both in vitro and in vivo and mechanistically blocks MTP-2 through binding to the serine protease (SP) domain active site, preventing cleavage of substrates. As a result, it was seen to increase BMP/SMAD signalling and elevate levels of hepcidin expression from hepatocyte cells following a single I.P. dose (10 mg/kg) in C57BL/6J mice. ...

Generation and Characterisation of KY1066, a Fully Human Antibody Targeting the Enzymatic Activity of Matriptase-2 for the Treatment of Iron Overload in Beta Thalassemia