Deciphering ALK2's Role in Anemia of Inflammation: Insights from a Monoclonal Antibody Approach

The study explores the role of ALK2 signaling in iron regulation and its potential as a therapeutic target for anemia of inflammation (AI). Hepcidin, a hormone produced mainly in the liver, regulates iron homeostasis by promoting the breakdown of ferroportin, an iron exporter. Hepcidin expression is influenced by signaling from the type I TGF-β receptor ALK2 and is upregulated by IL-6, a cytokine often elevated in chronic kidney disease (CKD) and other inflammatory states, leading to reduced serum iron availability and AI.

Previous research has shown that inhibiting ALK2 can reduce hepcidin expression in various species, including humans, and a small molecule ALK2 kinase inhibitor (KTI-2338) has been shown to reverse hepcidin and iron changes in a mouse CKD model. Another strategy is the use of a neutralizing ALK2 antibody, KTI-018, which has been shown to decrease hepcidin and increase serum iron in non-human primates.

The aim of this study was to investigate the specific impact of ALK2 signaling in AI and the therapeutic potential of the antibody KTI-018 using a CKD mouse model. The study involved male C57Bl/6 mice, with the CKD group treated with adenine to induce kidney inflammation and fibrosis, and a control group receiving a vehicle. After disease confirmation, the CKD group was split into a treatment group receiving KTI-018 and a control group receiving tris-buffered saline (TBS), while healthy mice received only TBS.

At the end of the study, hematologic parameters, serum hepcidin, iron, and IL-6 levels were measured. The CKD-TBS group showed signs of AI with increased hepcidin, decreased serum iron, and reduced hematologic parameters. In contrast, the CKD-KTI-018 group showed a decrease in serum hepcidin and an increase in serum iron, which corresponded to improvements in red blood cells, hemoglobin, and reticulocyte hemoglobin content.

The study concludes that the neutralizing ALK2 antibody KTI-018 can decrease serum hepcidin, increase serum iron, and reverse AI in a mouse model of CKD. These findings support the involvement of ALK2 signaling in AI and suggest that ALK2 inhibition could be a potential treatment for anemia caused by CKD and other chronic inflammatory diseases. Further research will examine the potential of ALK2 inhibition in preventing or treating the progression of CKD and its role in other chronic inflammatory conditions characterized by elevated hepcidin levels.