Chemokine Receptor 2–targeted Molecular Imaging in Pulmonary Fibrosis. A Clinical Trial

Abstract

Rationale: Idiopathic pulmonary fibrosis (IPF) is a progressive inflammatory lung disease without effective molecular markers of disease activity or treatment responses. Monocyte and interstitial macrophages that express the C-C motif CCR2 (chemokine receptor 2) are active in IPF and central to fibrosis. Objectives: To phenotype patients with IPF for potential targeted therapy, we developed Cu-64-DOTA-ECL1i, a radiotracer to noninvasively track CCR2(+) monocytes and macrophages using positron emission tomography (PET). Methods: CCR2(+) cells were investigated in mice with bleomycin- or radiation-induced fibrosis and in human subjects with IPF. The CCR2(+) cell populations were localized relative to fibrotic regions in lung tissue and characterized using immunolocalization, single-cell mass cytometry, and Ccr2 RNA in situ hybridization and then correlated with parallel quantitation of lung uptake by Cu-64-DOTA-ECL1i PET. Measurements and Main Results: Mouse models established that increased Cu-64-DOTA-ECL1i PET uptake in the lung correlates with CCR2(+) cell infiltration associated with fibrosis (n = 72). As therapeutic models, the inhibition of fibrosis by IL1 beta blockade (n = 19) or antifibrotic pirfenidone (n = 18) reduced CCR2(+) macrophage accumulation and uptake of the radiotracer in mouse lungs. In lung tissues from patients with IPF, CCR2(+) cells concentrated in perifibrotic regions and correlated with radiotracer localization (n = 21). Human imaging revealed little lung uptake in healthy volunteers (n = 7), whereas subjects with IPF (n = 4) exhibited intensive signals in fibrotic zones. Conclusions: These findings support a role for imaging CCR2(+) cells within the fibrogenic niche in IPF to provide a molecular target for personalized therapy and monitoring.