Antibody-Based Therapeutics for Atherosclerosis and Cardiovascular Diseases

Abstract

Cardiovascular disease is the leading cause of death worldwide, and its prevalence is increasing due to the aging of societies. Atherosclerosis, a type of chronic inflammatory disease that occurs in arteries, is considered to be the main cause of cardiovascular diseases such as ischemic heart disease or stroke. In addition, the inflammatory response caused by atherosclerosis confers a significant effect on chronic inflammatory diseases such as psoriasis and rheumatic arthritis. Here, we review the mechanism of action of the main causes of atherosclerosis such as plasma LDL level and inflammation; furthermore, we review the recent findings on the preclinical and clinical effects of antibodies that reduce the LDL level and those that neutralize the cytokines involved in inflammation. The apolipoprotein B autoantibody and anti-PCSK9 antibody reduced the level of LDL and plaques in animal studies, but failed to significantly reduce carotid inflammation plaques in clinical trials. The monoclonal antibodies against PCSK9 (alirocumab, evolocumab), which are used as a treatment for hyperlipidemia, lowered cholesterol levels and the incidence of cardiovascular diseases. Antibodies that neutralize inflammatory cytokines (TNF-α, IL-1β, IL-6, IL-17, and IL-12/23) have shown promising but contradictory results and thus warrant further research.

Keywords: antibody therapy; atherosclerosis; inflammation.

Figure 1

Mechanism of atherosclerosis formation.The development of atherosclerosis begins when low-density lipoprotein (LDL) particles infiltrate the intima layer and accumulate. Within the intima, LDLs form oxidized LDL (oxLDL) through myeloperoxidase and lipoxygenase, bind to the scavenger receptor of macrophage-derived foam cells, and activate the foam cells. Activated foam cells induce inflammation by secreting cytokines through several downstream signals. Concurrently, smooth muscle cells in the media layer migrate to the intima and are transdifferentiated into macrophage-like cells, and under the influence of the cytokines secreted from foam cells, secrete cytokines such as IL-6 to promote inflammation. In the intima, oxLDL increases the expression of adhesion molecules at the endothelial cell surface, leading to the recruitment of monocytes and other immune cells, and promote synergy with the aforementioned phenomena to induce the formation of atherosclerotic plaques.

Figure 2

Antibodies targeting cytokines and cytokines acting on atherosclerotic plaque. Atherosclerotic plaque consists of lipid, apoptotic cells, immune cells, smooth muscle cells, and endothelial cells. These cells induce inflammation by secreting specific cytokines. Among them, IL-1β, TNF-α, IL-17, IL-6, and IL-12/23 are under investigation as therapeutic targets for atherosclerosis, and a number of antibodies have been developed to target each cytokine.