Orticumab: the potential to harness oxidized LDL to reduce coronary inflammation with plaque-targeted therapy

Figures

• 

  Box 1. no caption available

• 

  FIGURE 1. Pro-atherogenic roles of oxidized LDL and macrophages in driving inflammation, growth and instability of established atherosclerotic plaques. (1) Circulating LDL diffuses through the endothelium into plaque. (2) LDL is oxidized via enzymatic and nonenzymatic pathways. (3) Oxidized LDL promotes activation of endothelial cells through binding to the LOX-1 receptor resulting in proinflammatory cytokine secretion and expression of adhesion receptors. Leukocytes bind these receptors and enter the plaque. (4 and 5) Oxidized LDL activates infiltrating monocytes and resting macrophages. (6) Oxidized LDL is taken up by Trem2+ anti-inflammatory macrophage foam cells via scavenger receptors, but exposure of these cells to high levels of oxidized LDL will transition them into perilipinhi/Trem1hi proinflammatory macrophages. (7) Proinflammatory macrophages can be activated by multiple proinflammatory cytokines via their respective receptors expressed by macrophages. (8) Proinflammatory macrophages can also be activated by multiple pathways that activate Toll-like receptors on macrophages, including PAMPs (Pathogen-Associated Molecular Patterns), DAMPs (Damage-Associated Molecular Patterns),…

• 

  FIGURE 2. Abnormal perivascular adipose tissue near inflamed plaques increases fat attenuation index. Normal artery: Healthy perivascular fat is comprised of normal adipocytes which have a normal lipid content resulting in a normal fat attenuation index (FAI) on coronary CCTA imaging. Mildly inflamed plaque: Inflamed plaques are characterized by increased numbers of proinflammatory macrophages and secretion of proinflammatory cytokines. Nearby perivascular fat responds to these proinflammatory signals by increasing lipolysis, fibrosis, and angiogenesis and reduction of adipogenesis resulting in smaller adipocyte size and shift of the composition of the perivascular space from the lipid-phase to the aqueous phase. Changes in the balance between lipid and aqueous phases of the perivascular tissue leads to an increase in perivascular FAI on CCTA imaging. Markedly inflamed plaque: More inflamed plaques contain a larger number of proinflammatory macrophages and other inflammatory components. Increased inflammatory signaling causes nearby perivascular adipose tissue (PVAT) adipocytes to be more intensely affected by reducing their size and lipid content further which leads to higher FAI on CCTA…

• 

  FIGURE 3. Proposed mechanism of action of orticumab. Oxidized LDL-targeted macrophage inhibition reduces plaque inflammation, growth, and instability. (1) Circulating orticumab diffuses into plaque. (2) Orticumab binds to densely aggregrated oxidized LDL molecules forming orticumab-oxidized LDL complexes. (3) Orticumab inhibits monocyte cytokine release induced by multiple different pro-inflammatory stimuli by negatively regulating NF-κB activity. (4) Inhibition of proinflammatory macrophages reduces plaque inflammation, growth, and instability.

• 

  FIGURE 4. Reduction in coronary inflammation as assessed by CCTA FAI-Score in subjects with psoriasis treated with orticumab. Absolute change in mean FAI-Score (arbitrary units; AU) from baseline (mean change ± standard deviation) in the whole study population and in the high inflammation subgroup. Mean FAI-Score is calculated as the average of the analyzable FAI-Scores (valid baseline and postbaseline FAI-Score) across the three main coronary arteries (RCA, LAD and LCX). Changes in mean FAI-Score versus baseline were analyzed using a mixed effects linear model (PROC MIXED in SAS), including fixed effects for treatment and site with corresponding or appropriate baseline measures as a covariate. P < 0.05 was considered statistically significant and significant differences are highlighted in red. Data is derived from reference [43▪▪].