NIH CCR2 AAA Study
CCR2 Targeted Molecular Imaging and Treatment of Abdominal Aortic Aneurysms
Abdominal aortic aneurysm (AAA) is a degenerative vascular disease, which is typically asymptomatic until rupture, resulting in high mortality. AAAs are more prevalent in men over age 65, though rupture is disproportionately higher in women. Due to nonlinear and unpredictable aortic dilatation, it is challenging to predict the AAA rupture using clinical diagnostics based on morphology. No medical therapy is used clinically to treat AAA, and there is an unmet need for clinically translatable, molecular biomarkers of AAA disease activity for surveillance and patient-specific management. The goal of this proposal is to develop a new approach for the diagnosis and targeted therapy of AAA.
This project addresses the absence of a reliable diagnostic modality and medical therapy to prevent abdominal aortic aneurysm (AAA) growth and rupture in patients, leading to high mortality in those over the age of 65 years old. Due to the pathogenic role of the monocyte chemoattractant protein-1 / C-C chemokine receptor type 2 (MCP-1/CCR2) axis in AAA, we propose to study the ability of 64Cu-DOTA-ECL1i PET/CT to predict the murine AAA rupture and serve as a companion diagnostic to assess CCR2 molecular therapy of murine AAA. We will perform the first-in-patient evaluation of 64Cu-DOTA-ECL1i PET/CT to image and detect AAA inflammation in a preoperative setting and acquire key biological information from AAA specimens collected at the time of open AAA repair, in order to assess the potential of 64Cu-DOTA-ECL1i PET in the management of AAA patients. Preclinical and clinical research demonstrated that monocyte chemotactic protein-1/ chemokine (C-C motif) receptor 2 (MCP-1/CCR2) plays an important role in the pathogenesis of AAAs. This axis specifically promotes AAA formation and development by mediating the recruitment of circulating LY6Chigh monocytes and infiltration of macrophages, which leads to the degradation of elastic and collagen. In AAA mouse models, the genetic depletion or specific inhibition of CCR2 significantly decreased the production of matrix metalloproteinases (MMPs) and formation of aneurysms, suggesting the potential of CCR2 as a biomarker for AAA imaging and pre-screening for targeted intervention. We have developed a specific CCR2 binding radiotracer, 64Cu-DOTA-ECL1i, for targeted imaging of CCR2 positive pro-inflammatory monocytes/macrophages, in multiple animal inflammatory models using positron emission tomography (PET). This investigational PET tracer is being used under Exploratory IND 137620 for research imaging studies in human subjects. In patients with inflammatory diseases, 64Cu-DOTA-ECL1i PET revealed specific detection of CCR2+ cells in inflammatory tissues. In a rat AAA model, 64Cu-DOTA-ECL1i PET revealed specific localization within the aneurysm, as well as sensitive detection of CCR2+ inflammatory cells. Human AAA specimens demonstrated specific binding of 64Cu-DOTA-ECL1i to CCR2 by autoradiography. Thus, we hypothesize that 64Cu-DOTA-ECL1i detect CCR2+ cells mediated aneurysmal activity and can be utilized for AAA molecular imaging. We propose to assess the potential of 64Cu-DOTA-ECL1i as a biomarker for AAA patients imaging.
Early Phase 1
Determine the binding characteristics of 64Cu-DOTA-ECL1i in ex vivo human AAA specimens and correlate with associated histopathological features
Abdominal Aortic Aneurysm (AAA)
AAA Group (Aim 3A)
Study Arms / Comparison Groups
AAA Group (Aim 3A)
Description: 40 (20 men; 20 women) participants with a diagnosis of AAA (above 40 years) will undergo a PET/CT scan prior to their scheduled surgical repair of their condition. The radiotracer, 64Cu-DOTA-ECL1i, will be injected to detect CCR2+ inflammatory cells. A dosage range of 8-10 mCi (296-370 MBq) is planned for 64Cu-DOTA-ECL1i. A PET-certified medical professional will draw and administer the 64Cu-DOTA-ECL1i tracer. The dosage will be assayed in a dose calibrator before and after the administration.
* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.
February 17, 2021
Primary Completion Date
Inclusion Criteria: - 40 years old and above - With or without active tobacco use - Asymptomatic patients with known AAAs by CT angiogram (men ≥ 5.5 cm, women ≥ 5.0cm). - Non-AAA volunteers will have a documented absence of AAA by exam and recent screening ultrasound (US). - Able to comprehend and willing to follow instructions for the study procedures as called for by the protocol Exclusion Criteria: - Inability to receive and sign informed consent. - Patients with Stage ≥ 4 chronic renal failure (calculated by modification of diet in renal disease eGFR equation [to minimize confounding imaging variables]) - Documented allergy to iodinated contrast and/or shellfish. - Patients with an unstable clinical condition that in the opinion of the principal investigators or designee precludes participation in the study. - Inability to tolerate 60 minutes in a supine position with arms down at sides, as necessary for PET/CT. - Positive pregnancy test or lactating. - Other conditions such as symptomatic/recently treated coronary disease, cancer requiring oncologic management, or autoimmune/inflammatory diseases (e.g., rheumatoid arthritis or multiple sclerosis) that are known to have increased associated CCR2 expression. - Non-AAA volunteers may not carry a diagnosis of aortoiliac occlusive disease, as documented by their treating vascular surgeon, as significantly progressed atherosclerotic disease may demonstrate exaggerated, associated CCR2 expression.
40 Years - N/A
Accepts Healthy Volunteers
Mohamed M. Zayed, MD, (314) 362-6257, [email protected]
Washington University School of Medicine
Mohamed M. Zayed, MD, Principal Investigator, Washington University of Medicine