April 6, 2012

Immune Therapy for Atherosclerosis

(Ivanhoe Newswire) — Atherosclerosis is when plaque builds up in the arteries; and it can cause serious problems in the heart. However new strategies are helping patients combat atherosclerosis; and could change the treatment landscape of heart disease, all together.

It was in the early 1990s that identification of antibodies against oxidized low density lipoproteins (LDL) in artery plaques, first gave rise to the concept that cardiovascular disease (CVD) might be an autoimmune disease where the immune system attacks oxidized LDL. To test this hypothesis Nilsson, a professor of Experimental Cardiovascular Research at Lund University, Sweden, and a key player in the development of immune treatments, and colleagues conducted experiments immunizing rabbits with high blood cholesterol with their own oxidized LDL.

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 oxidized LDL (due to difficulty of standardizing the particle) Nilsson looked to identify structures within the oxidized 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 was 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 vaccine, 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 oxidized LDL. "The rationale is that since oxidized LDL plays a major role in the development of atherosclerotic plaques and harmful inflammatory processes, directly targeting oxidized 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 oxidized 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 centers across the US and Canada, has been designed to demonstrate reduction in inflammation 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 monoclonal antibodies 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.

SOURCE: New England Journal of Medicine, April 2012