Immune therapies: The next frontier in battle against atherosclerosis

March 30, 2012, European Society of Cardiology

New strategies injecting cardiovascular disease (CVD) patients with vaccines and monoclonal antibodies to combat atherosclerosis could soon change the treatment landscape of heart disease. Both approaches, Professor Jan Nilsson told delegates at the Frontiers in CardioVascular Biology (FCVB) 2012 meeting, can be considered truly ground breaking since for the first time they target the underlying cause of CVD. The FCVB meeting, organised by the Council on Basic Cardiovascular Science (CBCS) of the European Society of Cardiology (ESC), held 30 March to 1 April at the South Kensington Campus of Imperial College in London.

"People at high risk of MI are likely to be the first candidates for immune approaches. Such treatments, since they've totally different modes of action, could be used in addition to the current therapies," explained Nilsson, who is professor of Experimental at Lund University, Sweden, and a key player in the development of immune treatments.

Speaking at the session "Atherosclerosis and the immune system: Expanding beyond inflammation"¹, Nilsson said that with phase 2a trials on recombinant antibodies currently ongoing in the US and Canada and results expected to be announced Quarter IV 2012, such treatments could soon become a clinical reality. "If all goes well, the first in class of these treatments could be licensed within four to five years," he added.

Undoubtedly there is an urgent need for new approaches to tackle CHD, a condition that kills two million people across Europe each year. Established therapies against atherosclerosis almost exclusively focus on risk factor modification – that is reduction of dyslipidaemia, hypertension and hyperglycaemia. "Existing treatments only reduce the risk of patients experiencing a CVD event by 40%. Although such results are encouraging, it shouldn't be forgotten that 60% of CVD events continue to occur," said Nilsson.

It was in the early 1990s that identification of antibodies against oxidised low density lipoproteins (LDL) in artery plaques, first gave rise to the concept that CVD might be an autoimmune disease where the attacks oxidised LDL. To test this hypothesis Nilsson and colleagues conducted experiments immunizing rabbits with high blood cholesterol with their own oxidised LDL. "We had anticipated that immunization would result in the atherosclerosis becoming more aggressive, but to our initial disappointment found that immunization appeared to be activating protection against atherosclerosis. At the time this made no sense to us at all," he recalled.

The team subsequently discovered that through serendipitous use of an adjuvant (agent added to vaccines to increase the immune response) they had in fact stumbled upon a way to shift the T cells from pro-inflammatory Th1 responses towards protective Th2 and regulatory T cell responses. "This had the overall effect of dampening down inflammation and reducing the plaque severity," said Nilsson.

Since it is impractical to develop vaccines based on oxidised LDL (due to difficulty of standardising the particle) Nilsson looked to identify structures within the oxidised LDL that triggered the desired protective response. Working with Prediman Shah, from Cedars-Sinai Heart Institute (Los Angeles, CA), the team screened a number of different apolipoprotein (apo) B peptides (the only protein permanently associated with LDL) sequences. The team were able to identify three 20 amino acid long apo B peptides, which when formulated with a carrier and adjuvant, reduced development of atherosclerosis in mice by 60 to 70%.

The resulting CVX-210 , currently in development by CardioVax, involves one of these three amino acid fragments (residues 3136 to 3155). CardioVax are currently awaiting FDA clearance to start phase 1 clinical trials with the vaccine, which will be given subcutaneously. Also in development is a second vaccine using the same amino acid sequence that has been formulated in a way that makes it possible to give intranasally.

Further along the development pathway, and already in clinical trials, is an altogether different immune approach involving injection of antibodies directly targeting oxidised LDL. "The rationale is that since oxidised LDL plays a major role in the development of atherosclerotic plaques and harmful inflammatory processes, directly targeting oxidised LDL should prevent plaque formation and reduce inflammation," explained Nilsson.

Preclinical studies show that administration of the BI-204 monoclonal antibody, developed jointly by BioInvent and Genentech, reduced the formation of atherosclerotic plaques and plaques already present by 50%. In the phase I study, which took place in 80 healthy volunteers with elevated levels of LDL, BI-204 was found to be safe and well tolerated.

Now for the current phase 2a double blind GLACIER (Goal of oxidised Ldl and Activated maCrophage Inhibition by Exposure to a Recombinant antibody) study, BI-204 is being delivered intravenously to 144 patients with stable coronary artery disease in addition to standard care. The study, which is taking place at 20 centres in the US and Canada, has been designed to demonstrate reduction in in the carotid artery quantified by FDG-PET imaging (18Fluoro-2-deoxyglucose positron emission tomography) at weeks four and 12 following initiation of treatment. At the beginning of March, the companies announced that patient recruitment was completed.

Looking to the future, Nilsson said it was unlikely that either the or vaccine would be given as "one off jabs" during childhood against CVD. "Both these treatments are far more like drugs – to be effective they'd need to be given long term. The antibody therapy in particularly is likely to be expensive so you could probably only afford to give it to high risk populations rather than everyone," he said.

Explore further: Low levels of lipid antibodies increase complications following heart attack

More information: 1. Session Atherosclerosis and the immune system –Expanding beyond inflammation. 30 March 2012. 14.30- 16.00. Clore Lecture Theatre.

Related Stories

Low levels of lipid antibodies increase complications following heart attack

February 6, 2012
Coronary patients with low levels of an immune system antibody called anti-PC, which neutralises parts of the "bad" cholesterol, run a greater risk of suffering complications following an acute cardiac episode and thus of ...

Lowering LDL, the earlier the better

March 26, 2012
Coronary atherosclerosis – a hardening of the arteries due to a build-up of fat and cholesterol – can lead to heart attacks and other forms of coronary heart disease (CHD). Lowering low-density lipoprotein (LDL), ...

Recommended for you

Biomechanical mapping method aids development of therapies for damaged heart tissue

January 23, 2018
Researchers have developed a new way to capture the detailed biomechanical properties of heart tissue. The high-resolution optical technique fills an important technology gap necessary to develop and test therapies that might ...

Researchers borrow from AIDS playbook to tackle rheumatic heart disease

January 22, 2018
Billions of US taxpayer dollars have been invested in Africa over the past 15 years to improve care for millions suffering from the HIV/AIDS epidemic; yet health systems on the continent continue to struggle. What if the ...

A nanoparticle inhalant for treating heart disease

January 18, 2018
A team of researchers from Italy and Germany has developed a nanoparticle inhalant for treating people suffering from heart disease. In their paper published in the journal Science Translational Medicine, the group describes ...

Starting periods before age of 12 linked to heightened risk of heart disease and stroke

January 15, 2018
Starting periods early—before the age of 12—is linked to a heightened risk of heart disease and stroke in later life, suggests an analysis of data from the UK Biobank study, published online in the journal Heart.

'Decorated' stem cells could offer targeted heart repair

January 10, 2018
Although cardiac stem cell therapy is a promising treatment for heart attack patients, directing the cells to the site of an injury - and getting them to stay there - remains challenging. In a new pilot study using an animal ...

Exercise is good for the heart, high blood pressure is bad—researchers find out why

January 10, 2018
When the heart is put under stress during exercise, it is considered healthy. Yet stress due to high blood pressure is bad for the heart. Why? And is this always the case? Researchers of the German Centre for Cardiovascular ...


Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.