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

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 64 Cu-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 64 Cu-DOTA-ECL1i PET. Measurements and Main Results: Mouse models established that increased 64 Cu-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 IL-1β 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.Clinical trial registered with www.clinicaltrials.gov (NCT03492762).