Antibodies for the diagnosis and/or treatment of atherosclerosis

Atherosclerosis is a chronic inflammatory disease that underlies thrombosis and cardiovascular events, but it can remain asymptomatic for long periods of time. The presence of antibodies in the atherosclerotic plaque was described decades ago, and the connection between autoimmunity and atherosclerosis is well accepted. However, the immunogenic trigger and the impact of the antibody immune response during atherosclerosis are not well understood.

Atherosclerosis is triggered by the retention and oxidation of low-density lipoprotein (LDL) at the vessel sub-endothelium space, leading to an inflammatory immune response. In addition, B cells and the antibody immune response are known to be critical during atherosclerosis. Antibodies can be used as diagnostic and therapeutic agents. CNIC and DKFZ researchers have performed a highthroughput single cell analysis of the antibody repertoire associated with atherosclerosis.

They sequenced more than 1700 antibodies from LDLR-/- mice with high fat diet (HFD) and control mice, 18 of which showed reactivity against atherosclerotic plaques (AtherAbs). They found that one such antibody, A12, binds to atherosclerotic plaques in LDLR-/- HFD mouse model and in human carotid atherosclerosis lesions (Figure 1A). Deep proteomics analysis showed that A12 antibody recognizes a self-protein, A12Ag1 whose distribution they found altered during atherosclerosis. The researchers also found that A12Ag1 is increased in the plasma of atherosclerotic mice and of humans with atherosclerosis (Figure 1B-C). In addition, they have shown that treatment of LDLR-/- HFD mice with infusions of A12 antibody delays atherosclerosis progression and reduces circulating free cholesterol and LDL. These findings open the way for A12 antibody as a very promising diagnostic and therapeutic tool in cardiovascular disease.

Applications

- A12 and 17 additional identified AtherAbs have very specific reactivity patterns against the atherosclerotic plaque. These patterns differ from traditional markers of this disease, such as oxLDL.

- AtherAbs show specific reactivity against the atherosclerotic plaque from early stages of the disease, so they can potentially be used as diagnostic agents for the early detection of the disease, before the patients have symptoms. In addition, AtherAbs can be used to study the molecular physiology of atherosclerosis.

- AtherAbs were identified from LDLR-/- HFD atherogenic mice during the progression of the disease, thus, no toxicity is expected when used as a therapeutic agent.

- A12 AtherAb allows the detection of atherosclerotic plaque in vivo. Functional in vivo experiments showed that A12 infusion delays the progression of atheroma plaque in LDLR-/- HFD mice.

Current development status

Tested in animal models

Desired business relationship

Patent licensing

Scientific article

https://doi.org/10.1038/s41586-020-2993-2