Key result
Anti-FAP BiTE reduces atherosclerotic plaque burden in mice by depleting FAP+ cells.
Why the study?
Molecular mechanisms governing cell state transitions in human coronary neo-intima remain poorly understood, and no lipid-independent therapies are approved for CAD.
Does targeting FAP+ modulated vascular smooth muscle cells with an anti-FAP bispecific T-cell engager reduce atherosclerotic plaque burden in preclinical models?
Does targeting FAP+ modulated vascular smooth muscle cells with an anti-FAP bispecific T-cell engager reduce atherosclerotic plaque burden in preclinical models?
Targeting modulated vascular smooth muscle cells via FAP-directed immunotherapy reduces atherosclerotic plaque burden in mouse models, presenting a potential novel lipid-independent therapeutic strategy for coronary artery disease.
Answers are grounded in this paper and cite their sources.
Hypothesis-generating for FAP-targeted BiTE in atherosclerosis; leaves open clinical translation pending human studies.
Vascular smooth muscle cell (VSMC) and immune cell diversification play a central role in driving atherosclerotic coronary artery disease (CAD) 1–3 . However, the molecular mechanisms governing cell state transitions within the neo-intima in human CAD remain poorly understood, and no lipid-independent therapies are currently approved for its treatment. Here, we performed multi-omic single-cell gene expression profiling, epitope mapping, and spatial transcriptomics from 27 human coronary arteries. Our analysis identified fibroblast activation protein (FAP) as a marker of modulated VSMCs within the neo-intima. Genetic lineage tracing in mice confirmed that FAP⁺ cells in the plaque originate from medial VSMCs. Additionally, non-invasive positron emission tomography (PET) imaging in patients with CAD revealed focal FAP uptake in atherosclerotic lesions. Spatial transcriptomics further delineated the distinct localization of VSMC and immune cell subsets within plaques, with FAP⁺ states enriched in the neo-intima. To explore the therapeutic potential of targeting de-differentiated VSMCs, we developed an anti-FAP bispecific T-cell engager (BiTE) and demonstrated that it significantly reduced the plaque burden in multiple mouse models of atherosclerosis. Collectively, our study provides the first single-cell and spatially resolved map of human CAD, establishes FAP as a marker of modulated smooth muscle cells, and demonstrates the broader potential of immunotherapeutics for lipid independent targets in atherosclerotic CAD.
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Amrute et al. (2025) studied Atherosclerotic coronary artery disease (CAD) (n=27). Anti-FAP bispecific T-cell engager (BiTE) vs. Control (Control BiTE/Vehicle) was evaluated on Atherosclerotic plaque burden in the aortic arch. Treatment with an anti-FAP bispecific T-cell engager (BiTE) significantly reduced atherosclerotic plaque burden and depleted FAP+ cells in multiple mouse models of atherosclerosis.
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