First-in-human PET imaging study using [⁶⁸Ga]-Folate tracer, [⁶⁸Ga]EC2115

Background: Macrophages provide the first line of host defense against invaders in the lungs by patrolling the airways, phagocytosing particulates and microbes, and activating the inflammatory cascade, when necessary. Persistent and/or dysregulated macrophage activation plays a key role in the pathogenesis of multiple inflammatory lung diseases, including chronic obstructive pulmonary disease (COPD). Studying this cell population in humans is complicated by the invasive methods currently required to obtain sufficient quantities of cells. Imaging activated macrophages using a non-invasive approach would allow frequent monitoring of disease progression and response to therapy. Conditions associated with chronic macrophage activation, including COPD, result in a dramatic increase in folate receptor β (FRβ)-expressing macrophages in mice and humans. We hypothesize that folate-based molecular imaging using positron emission tomography (PET) to detect activated macrophages can identify patients with COPD and determine those most likely to have rapid disease progression due to higher levels of chronic lung inflammation. Objectives: The purpose of this study is to evaluate the ability of a folate-based PET radiopharmaceutical ([⁶⁸Ga]EC2115) to differentiate COPD patients from control subjects and determine whether the PET signal correlates with measurements of inflammation, disease severity, and rate of disease progression. Human imaging with [⁶⁸Ga]EC2115 has not been performed previously so we will also determine the safety and biodistribution for this novel imaging agent.

Methods: We are conducting a phase I clinical study using [⁶⁸Ga]EC2115. The study is carried out in accordance with FDA IND 138443. Patients who are undergoing bronchoscopy for diagnosis of solitary pulmonary nodules are recruited from the Vanderbilt clinic. We plan to enroll a total of 30 patients with COPD and 15 non-smokers without COPD. [⁶⁸Ga]EC2115 is synthesized under cGMP procedures. Folate imaging is performed with [⁶⁸Ga]EC2115 prior to scheduled bronchoscopy, which is performed for clinical purposes. PET imaging is performed at multiple time points. To assess the safety of [⁶⁸Ga]EC2115, cardiac tracing is performed and vital signs and clinical laboratory tests are monitored. A portion of the bronchoalveolar lavage (BAL) is interrogated to compare PET imaging with parameters of inflammation in BAL, including the number/percentage of macrophages expressing FRβ. In addition, PET imaging data is compared with disease severity, based on pulmonary function testing.

Results: We have performed the first-in-human PET scans using [⁶⁸Ga]EC2115. The tracer exhibited the anticipated biodistribution, consistent with folic acid, with the highest signal being observed in organs involved in clearance. No signs of toxicity or adverse events were observed.

Conclusions: Development of novel approaches for detecting activated macrophages in patients could lead to important advances in studying and treating lung diseases, including COPD. Our studies will develop a novel imaging approach to monitor inflammation in COPD and provide information regarding disease severity and progression. Identifying patients with high levels of macrophage activation could delineate subgroups of patients who would benefit from anti-inflammatory or macrophage-targeted therapies. In addition, measuring macrophage activation in COPD will help to characterize the mechanistic roles of macrophages in this disease.