ANTI-HEMOJUVELIN MONOCLONAL ANTIBODY REVERSES ANEMIA AND EXERTS DISEASE-MODIFYING EFFECTS IN A MOUSE MODEL OF INFLAMMATORY BOWEL DISEASE

Abstract

Abstract Anemia is a common complication of inflammatory bowel disease (IBD), driven by chronic inflammation, iron deficiency, intestinal blood loss, and impaired iron absorption. Despite the use of intravenous iron therapy, managing anemia in IBD remains clinically challenging. DISC-0974 is a humanized anti-hemojuvelin (HJV) monoclonal antibody designed to inhibit the HJV–bone morphogenetic protein receptor interaction, thereby suppressing hepcidin expression and increasing systemic iron availability. It is currently in clinical trials for anemia in myelofibrosis (NCT05320198) and chronic kidney disease (NCT05745883). The therapeutic potential of DISC-0974 was evaluated in a dextran sodium sulfate (DSS)-induced chronic colitis mouse model using DBIO-100, a murine analog of DISC-0974. Female C57BL/6J mice received 4 DSS cycles (each cycle consisted of 2.5% DSS in drinking water for 4 days, followed by 3 days off). DBIO-100 (20 mg/kg intravenously [IV] every 10 days) or vehicle treatment was initiated at the start of the second DSS cycle. Mesalamine (100 mg/kg/day orally [PO]), a standard IBD therapy, was used as a positive control. Cohort 1 was evaluated 10 days after the treatment initiation and Cohort 2 after 26 days. DBIO-100 suppressed serum hepcidin and increased serum iron and hemoglobin (Hgb), with Hgb rising by up to 6 g/dL in Cohort 2. Notably, even in Cohort 1, DBIO-100 increased red blood cell count and Hgb (by 2.9 g/dL) after only 10 days, suggesting additional disease-modifying effects beyond improved ineffective erythropoiesis. DBIO-100 also mitigated colitis symptoms, including body weight loss, disease activity index (DAI), colon shortening, and histopathologic injury. In Cohort 2, DBIO-100 reduced circulating white blood cells, neutrophils, and monocytes, and downregulated colonic tumor necrosis factor-α and interleukin-6 expression. Several benefits were partially recapitulated by mesalamine, but DBIO-100 led to greater improvements in body weight, colon length, mean corpuscular volume, and mean corpuscular hemoglobin. A second study tested combination therapy in the DSS-induced chronic colitis mouse model. Mice received vehicle, DBIO-100 (20 mg/kg IV), mesalamine (30 mg/kg/day PO), or both. DBIO-100 monotherapy and combination therapy lowered hepcidin and increased serum iron, transferrin saturation, and Hgb. While either DBIO-100 or mesalamine alone modestly improved weight and DAI, combination treatment led to further reduced DAI and mitigated weight loss. Both agents normalized monocyte counts, with enhanced benefit in combination. Collectively, DBIO-100 reversed anemia and iron deficiency and exerted disease-modifying, anti-inflammatory effects in DSS-induced colitis. These results support DISC-0974 as a promising therapeutic for anemia in IBD, either as monotherapy or in combination with mesalamine.