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

Abstract

<b>Rationale:</b> 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.<b>Objectives:</b> To phenotype patients with IPF for potential targeted therapy, we developed ⁶⁴Cu-DOTA-ECL1i, a radiotracer to noninvasively track CCR2⁺ monocytes and macrophages using positron emission tomography (PET).<b>Methods:</b> 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 <i>Ccr2</i> RNA <i>in situ</i> hybridization and then correlated with parallel quantitation of lung uptake by ⁶⁴Cu-DOTA-ECL1i PET.<b>Measurements and Main Results:</b> Mouse models established that increased ⁶⁴Cu-DOTA-ECL1i PET uptake in the lung correlates with CCR2⁺ cell infiltration associated with fibrosis (<i>n</i> = 72). As therapeutic models, the inhibition of fibrosis by IL-1β blockade (<i>n</i> = 19) or antifibrotic pirfenidone (<i>n</i> = 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 (<i>n</i> = 21). Human imaging revealed little lung uptake in healthy volunteers (<i>n</i> = 7), whereas subjects with IPF (<i>n</i> = 4) exhibited intensive signals in fibrotic zones.<b>Conclusions:</b> 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.Clinical trial registered with www.clinicaltrials.gov (NCT03492762).