Anti-Hemojuvelin Monoclonal Antibody Reverses Anemia and Exerts Disease-Modifying Effects in a Mouse Model of Inflammatory Bowel Disease

Anemia is the most common complication of inflammatory bowel disease (IBD). Its etiology is multifactorial, caused by factors such as chronic inflammation, iron deficiency, intestinal blood loss, and reduced iron absorption. Despite approved intravenous iron therapy, management of anemia in IBD patients remains a challenge in clinical practice.

DISC-0974 is a humanized anti-hemojuvelin (HJV) monoclonal antibody. It was designed to disrupt the interaction between HJV and the bone morphogenetic protein (BMP) receptor complex, leading to decreased hepcidin expression and increased iron availability for enhanced erythropoiesis. DISC-0974 is currently in clinical studies to treat anemia in patients with myelofibrosis (NCT05320198) and chronic kidney disease (NCT05745883).

In this study, the effect of DISC-0974 on improving anemia was evaluated in a mouse model of IBD. The dextran sodium sulfate (DSS)-induced colitis mouse model provides a powerful tool for investigating the pathophysiology of IBD and evaluating the efficacy of therapeutic agents. Chronic colitis was induced in female C57BL/6J mice by 4 cycles of DSS treatment. In each cycle, the mice were given drinking water containing 2.5% DSS for 4 days, followed by 3 days of washout (ie, no DSS in the drinking water). At the start of the 2nd DSS cycle, either vehicle or DBIO-100 (murine analog of DISC-0974; 20 mg/kg) was administered intravenously every 10 days. Mesalamine, the first-line therapy of IBD, was included as a positive control. It was administered at 100 mg/kg daily via oral gavage at the beginning of the 2nd DSS cycle.

DSS induced extensive colitis in C57BL/6J mice, as measured by substantial weight loss, high disease activity index score, shortened colons, and remarkable colon histopathology. Moreover, DSS caused anemia in mice, as evidenced by hemoglobin (Hgb) levels between 6.8 and 10.5 g/dL at the end of the 1st and 4th DSS cycles. DBIO-100 increased Hgb level by as much as 6 g/dL and effectively alleviated anemia induced by DSS. Consistent with its mechanism of action, DBIO-100 suppressed serum hepcidin levels and increased serum iron and transferrin saturation levels to be higher than in control mice. In addition, DBIO-100 exhibited protective effects against DSS-induced colitis, reflected by attenuated weight loss, decreased disease activity index score, preserved colon length, and improved colon histopathology. DBIO100 also displayed anti-inflammatory effects by reducing circulating WBC/neutrophil/monocyte counts, as well as modestly down-regulating colonic TNFa and IL-6 gene expression. Notably, some of the beneficial effects associated with DBIO-100 were also observed in the mesalamine group. Importantly, DBIO-100-induced improvements in body weight, colon length, colon histopathology, mean corpuscular volume, and mean corpuscular hemoglobin were superior to mesalamine. Finally, an IgG control antibody did not have any impact on body weight or disease activity index score.

Taken together, this study demonstrated that DBIO-100, a mouse anti-HJV monoclonal antibody, not only reversed DSS-induced anemia and iron deficiency, but also exhibited disease-modifying therapeutic effects on chronic colitis in vivo. Of note, while some beneficial effects of DBIO-100 were equivalent to those of mesalamine, others showed superiority. The findings highlight the therapeutic potential of DISC-0974 in the treatment of anemia of chronic inflammatory disease such as IBD.

Xu:Disc Medicine Inc.: Current Employment, Current equity holder in publicly-traded company. MacDonald:Disc Medicine Inc.: Consultancy, Current equity holder in publicly-traded company, Ended employment in the past 24 months. Wu:Disc Medicine: Current Employment, Current equity holder in publicly-traded company.