Chemokine receptor 2-targeted molecular imaging in pulmonary fibrosis
By
Steven L Brody,
Sean P. Gunsten,
Hannah P. Luehmann,
Debbie H. Sultan,
Michelle Hoelscher,
Gyu Seong Heo,
Jiehong Pan,
Jeffrey R Koenitzer,
Ethan C. Lee,
Tao Huang,
Cedric Mpoy,
Shuchi Guo,
Richard Laforest,
Amber Salter,
Tonya D. Russell,
Adrian Shifren,
Christophe Combadiere,
Kory J. Lavine,
Daniel Kreisel,
Benjamin D. Humphreys,
Buck E. Rogers,
David S. Gierada,
Derek E. Byers,
Robert J. Gropler,
Delphine L. Chen,
Jeffrey J Atkinson,
Yongjian Liu
Posted 05 Mar 2020
bioRxiv DOI: 10.1101/2020.03.04.960179
(published DOI: 10.1164/rccm.202004-1132OC)
Idiopathic pulmonary fibrosis (IPF) is a progressive, inflammatory lung disease that is monitored clinically by measures of lung function, without effective molecular markers of disease activity or therapeutic efficacy. Lung immune cells active in the pro-fibrotic process include inflammatory monocyte and interstitial macrophages that express the C-C motif chemokine receptor 2 (CCR2). CCR2+ monocyte lung influx is essential for disease phenotypes in models of fibrosis and identified in lungs from subjects with IPF. Here, we show that our peptide-based radiotracer 64Cu-DOTA-ECL1i identifies CCR2+ inflammatory monocytes and interstitial macrophages in multiple preclinical mouse models of lung fibrosis, using positron emission tomography (PET) imaging. Mice with bleomycin-induced fibrosis treated with blocking antibodies to interleukin-1β, a mediator of fibrosis associated with CCR2+ cell inflammation, or with pirfenidone, an approved anti-fibrotic agent, demonstrated decreased CCR2-dependent interstitial macrophage accumulation and reduced 64Cu-DOTA-ECL1i PET uptake, compared to controls. Lung tissues from patients with fibrotic lung disease demonstrated abundant CCR2+ cells surrounding regions of fibrosis, and an ex vivo tissue-binding assay showed correlation between radiotracer localization and CCR2+ cells. In a phase 0/1 clinical study of 64Cu-DOTA-ECL1i PET, healthy volunteers showed little lung uptake, while subjects with pulmonary fibrosis exhibited increased uptake, notably in zones of subpleural fibrosis, reflecting the distribution of CCR2+ cells in the profibrotic niche. These findings support a pathologic role of inflammatory lung monocytes/macrophages in fibrotic lung disease and the translational use of 64Cu-DOTA-ECL1i PET to track CCR2-specific inflammation for image-guided therapy.
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