神経，免疫，血液脳関門を制御する治療薬の開発

抄録

Repulsive guidance molecule–a (RGMa), which is a glycosylphosphatidylinositol–linked glycoprotein, is expressed in glial cells and immune cells. RGMa was previously recognized as the protein that regulates axon growth negatively in the adult central nervous system (CNS). Enhanced recovery of skilled forelimb movement as well as neural rewiring was observed after spinal cord injury (SCI) in adult macaque monkey following anti–RGMa antibody treatment. Based on the findings by the preclinical studies, the international clinical trials of humanized anti–RGMa monoclonal antibody (Unasnemab) for SCI is ongoing currently.

Furthermore, RGMa was shown to be involved in immune regulation. RGMa expressed in dendritic cells promotes activation of T cells, leading to deterioration of autoimmune encephalomyelitis. Further, under the condition of neuromyelitis optica (NMO), RGMa was expressed by the spared neurons and astrocytes, whereas its receptor neogenin was expressed by infiltrating macrophages. Aquaporin4–IgG–induced astrocytopathy and clinical exacerbation in NMO rats were ameliorated by anti–RGMa antibody treatment. Anti–RGMa antibody treatment significantly suppressed neutrophil infiltration, and decreased the expression of neutrophil chemoattractants. Neogenin–expressing macrophages accumulated in the lesion expressed CXCL2, a strong neutrophil chemoattractant, and further analysis revealed that RGMa directly regulated CXCL2 expression in macrophages.

In addition to the roles of RGMa in immune regulation, we recently reported that RGMa also regulates blood–brain barrier integrity and cell survival in the CNS. The multiple modes of actions of anti–RGMa antibody may explain the potent effects on the neurodegenerative and neuroimmune diseases as well as the CNS injuries. The clinical trial of Unasnemab for HTLV–1–associated myelopathy is also ongoing.