Noninvasive Quantification of Radiation-Induced Lung Injury using a Targeted Molecular Imaging Probe

RATIONALE: Radiation-induced lung injury (RILI) is a progressive inflammatory process commonly seen following irradiation for lung cancer. The disease can be insidious, often characterized by acute pneumonitis followed by chronic fibrosis with significant associated morbidity. No therapies are approved for RILI, and accurate disease quantification is a major barrier to improved management. OBJECTIVE: To noninvasively quantify RILI, utilizing a molecular imaging probe that specifically targets type 1 collagen in mouse models and patients with confirmed RILI. METHODS: Using a murine model of lung radiation, mice were imaged with EP-3533, a type 1 collagen probe to characterize the development of RILI and to assess disease mitigation following losartan treatment. The human analog probe targeted against type 1 collagen, (68)Ga-CBP8, was tested on excised human lung tissue containing RILI and quantified via autoradiography. Finally, (68)Ga-CBP8 PET was used to assess RILI in vivo in six human subjects. RESULTS: Murine models demonstrated that probe signal correlated with progressive RILI severity over six-months. The probe was sensitive to mitigation of RILI by losartan. Excised human lung tissue with RILI had increased binding vs unirradiated control tissue and (68)Ga-CBP8 uptake correlated with collagen proportional area. Human imaging revealed significant (68)Ga-CBP8 uptake in areas of RILI and minimal background uptake. CONCLUSIONS: These findings support the ability of a molecular imaging probe targeted at type 1 collagen to detect RILI in preclinical models and human disease, suggesting a role for targeted molecular imaging of collagen in the assessment of RILI. Clinical trial registered with www.clinicaltrials.gov (NCT04485286, NCT03535545)