Novel BiTE Immunotherapy Reduces Arterial Plaque in Preclinical Atherosclerosis Study
核心洞察
Researchers at Washington University School of Medicine developed a bispecific T cell engager (搜索) (BiTE) immunotherapy that significantly reduced atherosclerotic plaque in mouse models of coronary artery disease (搜索).
The therapy targets modulated smooth muscle cells (搜索) expressing fibroblast activation protein (搜索), which drive inflammation and dangerous plaque formation in arterial walls.
Single-cell analysis of 27 human coronary arteries identified these harmful cells in plaque-vulnerable areas, with PET/CT imaging successfully detecting them in patients with coronary artery disease (搜索).
Scientists at Washington University School of Medicine in St. Louis have developed a novel immunotherapy that significantly reduces arterial plaque in mouse models of atherosclerosis (搜索), offering a potential breakthrough treatment for coronary artery disease (搜索). The study, published January 29 in Science, demonstrates how a bispecific T cell engager (搜索) (BiTE) molecule can eliminate harmful cells that drive dangerous plaque formation in arteries.
Targeting Modulated Smooth Muscle Cells
The research team, led by senior author Kory J. Lavine, MD, PhD, professor of medicine in WashU Medicine's Cardiovascular Division, focused on a specific type of dysfunctional cell called modulated smooth muscle cells (搜索). These cells migrate from their normal arterial locations and release inflammatory signals that attract immune cells, driving ongoing plaque formation and instability.
"This type of antibody therapy was originally designed to target cancers, such as lymphoma, and we imagine a similar precision medicine approach for cardiovascular disease," Lavine explained. "Cholesterol-lowering medications are mainly preventive, which does not substantially reduce plaques that are already there. An immunotherapy that can reduce inflammation and dangerous plaque in patients with more advanced atherosclerosis (搜索) is an exciting prospect."
Advanced Single-Cell Analysis Reveals Target
To identify the molecular signature of these harmful cells, Lavine's team performed cutting-edge single-cell profiling analysis of 27 human coronary arteries from patients undergoing heart transplantation. The technique revealed active genes and proteins in each of the 150,000-plus cells from these samples, combined with spatial data specifying cell locations within the 3D arterial structure.
Using this comprehensive "atlas" of human coronary artery disease (搜索), investigators identified fibroblast activation protein (搜索) (FAP) on the surface of modulated smooth muscle cells (搜索) as an ideal target for BiTE molecules. The engineered BiTE molecule (搜索) draws T cells to these target cells, enlisting the immune system's destructive power to eliminate them.
Promising Preclinical Results
In mouse models of atherosclerosis (搜索), eliminating modulated smooth muscle cells (搜索) with BiTE molecules significantly reduced atherosclerosis compared with untreated mice. The treatment reduced plaque amount, diminished inflammation, and improved plaque stability - a crucial factor in preventing heart attacks.
"We found that these cells are located in areas of the plaque that are particularly vulnerable to rupture, which is the primary cause of heart attacks," said Lavine, who also directs the WashU Medicine Center for Cardiovascular Research. "What this BiTE molecule (搜索) seems to be doing in removing these damaging cells is leading to an improved wound healing process, reducing inflammation and the amount of plaque, and increasing the stability of any plaque that remains."
Clinical Translation Potential
The research team, working in collaboration with biotech company Amgen, also developed an imaging tracer molecule targeting FAP that enables PET/CT scanning to locate modulated smooth muscle cells (搜索). Testing this tracer in patients with coronary artery disease (搜索) successfully identified coronary plaques in scans, demonstrating clinical feasibility.
This immunotherapy approach could particularly benefit patients who already have established coronary artery plaque and remain at high risk of heart attack (搜索) despite achieving low cholesterol levels through current treatments. The therapy represents a potential complement to traditional cholesterol-lowering approaches using diet modifications or statin medications.
Future Development Plans
Lavine and his team are planning additional imaging studies and further optimization of the BiTE molecule (搜索) to explore its potential as a safe and effective atherosclerosis (搜索) treatment. They also aim to determine whether their imaging tracer could distinguish stable versus unstable plaques, potentially enabling prevention of heart attacks in highest-risk patients.
The research was supported by multiple funding sources including the American Heart Association, National Institutes of Health, and an Amgen-sponsored research agreement. Several co-authors are Amgen employees, highlighting the collaborative industry-academic approach to developing this novel cardiovascular therapy.