The Medical Challenge –
treating inflammation in vascular disease

The treatment and prevention of vascular disease, including diseases and conditions affecting the heart as well as blood vessels in the brain, legs and other organs, have improved significantly, but morbidity and mortality remain high. More than 500 million worldwide suffer from various types of vascular disease, which is the leading cause of death in the world (WHO 2017). Several of the most prescribed drugs are directed against vascular disease, with sales of $130bn in 2015 (GBI Research, 2016).

Inflammation is a recognized component of vascular disease but is not specifically addressed.
A treatment that effectively inhibits vascular inflammation could greatly improve survival and reduce morbidity.

The Solution –
PC-mAb fully human therapeutic antibody

PC-mAb is a fully human monoclonal antibody that binds to phosphorylcholine (PC). PC is sometimes referred to as oxidized phospholipid, OxPL.

This drug target PC is exposed in blood vessels in vascular disease such as atherosclerosis or when injuries occur in the blood vessels, for example in a surgical procedure.

In the ‘Cryptic Epitope’, phosphorylcholine, PC (or oxidized phospholipid, OxPL, shown in blue) is hidden inside viable cells or native LDL and is inactive.
 
In the ‘Exposed Epitope’, modified or damaged cells, or oxidized lipid particles, carry PC (in red) on the outside. The exposed PC is the Danger Associated Molecular Pattern (DAMP) or ”eat-me”-signal for the immune system to clear out damaged cells and oxidized lipid particles.

Endogenous or natural antibodies to PC act to clean out damaged cells from the body, through the inflammatory challenge caused by exposed PC. Our therapeutic antibody PC-mAb is designed to mimic the anti-inflammatory role of endogenous antibodies against PC and further support the immune response to vascular inflammation challenges, thereby reducing the risk for complications in vascular disease.

High lipoprotein (a) level is an indicator of high target PC

Lipids containing PC, sometimes referred to as OxPL, are present in blood vessels and on the surface of other carriers, such as lipid particles that circulate in the blood. These include lipoprotein (a), or Lp(a), a very large particle that has considerable PC-carrying capacity. Lp(a) is a risk factor for cardiovascular disease and approximately 10 – 20 % of the population has high levels of Lp(a), defined as a level in blood above 50 mg/dL. The amount of circulating Lp(a) in a person is mainly inherited, and varies little over time, through changes in life style, or from effects from common medicines against increased cardiovascular risk. Due to the inheritance factor, it may be of special interest to measure Lp(a) if patients have one or more relatives who have suffered from heart attack before age 65.

Lipoprotein(a), Lp(a), is a very large composite lipid particle, made of an LDL particle and apolipoprotein(a), which is bound to the apolipoprotein B of the LDL particle. Phosphorylcholine, PC, also called oxidized phospholipid, OxPL, (in red) is carried on the large lipid particle lipoprotein (a), Lp(a).

Promising Clinical Trials and Excellent Patent Protection

Phase 1a and 1b studies in healthy volunteers and patients have delivered positive data,
and a Phase 2a trial has started. Key patents have been secured for PC-mAb. New patent applications have been filed for further therapeutic innovations.

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Blocking PC accumulation reduces inflammation

Our working hypothesis is that Lp(a) particles carry large amounts of the PC-containing lipids, thereby causing inflammation of the vessels. This results in impaired vascular function, i.e. increased risk of vascular disease. If PC exposure can be blocked then inflammation in vessels can be reduced and their vascular function improved.

Endogenous anti-PC is anti-inflammatory

There are natural antibodies in healthy individuals that bind to PC, thereby cleaning out damaged cells and suppressing inflammation. Clinical research has shown that low levels of natural antibodies to PCs are linked to a faster development of inflammation-related vascular disease, as well as increased complications of vascular disease.

PC-mAb acts to support the immune
response to vascular inflammation

PC-mAb is designed to mimic the anti-inflammatory role of endogenous antibodies against PC. PC-mAb binds to, and thus blocks, PC. This reduces the inflammation of the blood vessel and lessens the consequences of vascular disease. The therapeutic antibody PC-mAb supports the immune response to vascular inflammation challenges, thus reducing the risk of developing complications of atherosclerosis or damage to vessels driven by exposed PC. The therapeutic approach has proven preclinical efficacy, as PC-mAb has been effective in several preclinical models of vascular disease and inflammation.

Evidence that anti-inflammatory drugs
could reduce risk of second heart attack and stroke

A recent study has shown that treatment with an anti-inflammatory drug could lower the risk of secondary cardiovascular events after heart attack and have effect in addition to conventional treatment. The study, CANTOS (Canakinumab Anti-inflammatory Thrombosis Outcomes Study), involved 10,000 patients who had had a heart attack and a positive blood test for an inflammatory marker, hsCRP. Treatment with the human monoclonal antibody canakinumab over four years reduced their risk of an additional cardiovascular event by 15%.