Lung inflammation is perhaps the most constant feature of acute and chronic lung disease, and immune cell types have been used to attempt to classify patient phenotypes. However, the ability to reliably detect and monitor this pathologic feature has been a challenge. Chemokines guide the migration of populations of inflammatory cells that harbor their cognate receptor. Cell surface chemokine (C-C motif) receptor 2 (CCR2) and ligand CCL2 are essential mediators of inflammatory monocyte migration and modulate the maturation of immune cell populations. The CCR2/CCL2 axis is active in both acute and chronic lung diseases, such as acute lung injury, primary graft dysfunction following lung transplantation, asthma and chronic obstructive pulmonary disease (COPD). We have identified a 7 amino acid peptide, ECL1i, which specifically binds to the CCR2 receptor. When assembled as a radiotracer, 64Cu-DOTA-ECL1i, was stable in mice and rapidly excreted. When assessed in multiple models of acute and chronic lung injury, intravenous injection of 64Cu- DOTA-ECL1i provided a robust positron emission tomography (PET) signal in the lung associated with monocyte migration. PET imaging in preclinical mouse models of lung disease that utilized CCR2 sufficient and deficient mice demonstrated that 64Cu-DOTA-ECL1i is sensitive for the detection of low levels of inflammation and specific for identifying PET signals related to CCR2-expressing immune cells. Moreover, in human lung tissues from subjects with advanced COPD displaying increased CCR2 levels, ECL1i probes detected increased CCR2 expression and bound immune cells, suggesting an affinity for human CCR2. We hypothesize that 64Cu-DOTA-ECL1i performs as a sensitive, specific and safe radiotracer for PET detection of CCR2- directed inflammation in lung disease.
Our aims will (1) test the specificity, sensitivity and stability in mouse lung injury models, (2) characterize bindig to human CCR2 in cells and human lung tissue and (3) translate 64Cu-DOTA-ECL1i to humans in a Phase 0 clinical safety trial. We propose that non-invasive PET imaging of CCR2 in the lung can specifically characterize an individual's inflammatory status and disease activity. This will provide a unique opportunity to define the immunologic response for personalized management in acute and chronic lung diseases.
Acute and chronic lung diseases are often associated with active inflammation, but it is difficult to quantify the problem using current methods. We have developed and propose to test a new radiotracer that can be used for PET scan to establish the extent of a defined type of inflammation in the lung. The radiotracer recognizes a specific protein called CCR2 that is also a target for therapies. We propose that PET imaging with this radiotracer can be used to diagnose the level of lung inflammation and as a marker for targeted drug therapy.
