PHARMACOKINETICS AND PHARMACODYNAMICS OF AN ANTI-HEMOJUVELIN MONOCLONAL ANTIBODY IN MICE

Hemojuvelin (HJV/RGMc) is a BMP co-receptor that specifically regulates hepcidin gene expression. Hepcidin plays a major role in iron homeostasis. High hepcidin levels inhibit intestinal iron absorption and macrophage iron recycling, causing iron-restricted erythropoiesis and anemia. Conversely, low hepcidin levels lead to an increase in iron availability for enhanced erythropoiesis. 

 

DISC-0974 is a humanized anti-hemojuvelin (HJV) monoclonal antibody designed to block the interaction between HJV and bone morphogenetic protein (BMP) receptors leading to decreased hepcidin expression. DISC-0974 is currently in clinical trials to treat patients with anemia of myelofibrosis, and patients with NDD-CKD and anemia.

 

A murine analog of DISC-0974, PRO-1535, was developed to avoid immunogenicity in mouse studies. To evaluate the PK PD effects of PRO-1535, male C57/BL6 mice were dosed once with vehicle or PRO-1535 at 0.2, 2, or 20 mg/kg intravenously. Blood and liver samples were collected on days 1, 3, 7, and 10 post-dosing. PRO-1535 administration was well-tolerated. Dose proportional increase in PRO-1535 concentration in plasma was observed in treated mice. With respect to PD, PRO-1535 decreased serum hepcidin level, and its liver mRNA expression in a dose-dependent manner. Furthermore, PRO-1535 administration was associated with increased serum iron and TSAT.

 

Taken together, this study demonstrated that PRO-1535, a mouse anti-HJV monoclonal antibody, can inhibit hepcidin production and enhance serum iron level in vivo. PRO-1535 can be used in efficacy studies in mouse disease models and further support the therapeutic potential of DISC-0974 for the treatment of anemia.