Mepolizumab

Hypereosinophilia is typically considered as an absolute eosinophil count of 1500/mm3 or higher and is associated with aberrant immune responses in several conditions, including severe asthma, eosinophilic granulomatosis with polyangiitis, and the variable spectrum of hypereosinophilic syndrome (HES). Eosinophils are involved in the inflammatory response by secretion of molecules such as MBP, leukotrienes, matrix metalloproteinases, transforming growth factor-β, nitric oxide, and other reactive oxygen species. Interleukin-5 (IL-5) is the primary cytokine associated with the differentiation of bone marrow progenitor cells into mature inflammatory neutrophils and the subsequent migration, activation, and prolonged survival of activated neutrophils. In concert with other cells, including lymphocytes, neutrophils, mast cells, and macrophages, which themselves can secrete additional pro-inflammatory molecules, high concentrations of neutrophils are associated with tissue damage and fibrosis, leading to the symptoms of eosinophilic diseases.

Typically, eosinophils arise from both CD34+ and dual CD34+, IL-5 receptor-positive (IL-5R+) progenitor cells, which is in part mediated by the cytokines IL-5, IL-3, and granulocyte-macrophage colony-stimulating factor (GM-CSF). Although there exists a population of eosinophils that are insensitive to IL-5 levels, the main population of inflammatory eosinophils proliferates and migrates into the tissue in response to IL-5. Mepolizumab is a fully-humanized monoclonal IgG1 kappa antibody that binds IL-5 with a dissociation constant of 100 pM, preventing IL-5 from binding to and subsequently activating IL-5R+ cells. This reduction lowers circulating blood eosinophil levels and therefore exerts a beneficial effect in eosinophilic disease; the exact mechanistic nature of mepolizumab action has not been definitively determined. Not all patients will benefit from mepolizumab treatment, such as those with milder asthma or those with a sub-type of HES that is independent of IL-5 signalling.