Clinical translation of targeted intracoronary imaging for inflammatory activity

Inflammatory activity plays a major role in the development and progression of coronary artery disease (CAD), the major cause of mortality in the US and around the world. Until now, there has been no way to visualize and quantify coronary inflammation with the precision required to impact patient management. There is an opportunity for this capability gap to change, as a new clinical near-infrared fluorescence (NIRF) imaging agent called LUM015 has recently been introduced for cancer applications. LUM015 fluoresces following active cathepsin cleavage and thus appears promising as a highly specific targeted agent for inflammatory activity in atherosclerosis, as cathepsins are key mediators of plaque progression and coronary thrombosis risk. In this grant, we propose to investigate a first-in-human use of LUM015 NIRF for intracoronary CAD assessment. We will accomplish this objective by developing and clinically validating a multimodality imaging system and catheter that simultaneously obtains co-localized, intracoronary optical coherence tomography (OCT) images of lesional microanatomy and LUM015 NIRF to evaluate cathepsin-mediated plaque inflammatory activity. This technology will be clinically translated by investigating the targeting profile and dosing parameters for LUM015 in animal models of atherosclerosis and in humans undergoing carotid endarterectomy (Aim 1). Technology will be developed to spectrally unmix LUM015 NIRF from NIR autofluorescence (NIRAF) that is prevalent in advanced CAD (Aim 2.1). We also will advance NIRF-OCT technology by creating an innovative two-fiber catheter/rotary junction that removes fiber autofluorescence background. The resultant increase in LUM015 NIRF sensitivity will allow the time between injection and imaging to be minimized, which is important to capture many patients undergoing cardiac catheterization (Aim 2.2). The new catheter will also improve OCT image quality, which is inferior in current multimodality systems. After completion of Aims 1 and 2, the intravascular LUM015 NIRF-OCT technology will be tested in patients undergoing cardiac catheterization to show that NIRF- OCT can predict CAD severity (Aim 3). By establishing a new clinical imaging methodology for evaluating coronary microstructure and inflammatory activity in vivo, this work will have a major impact on CAD research, drug development, and personalized CAD management aimed at improving clinical outcomes.