Antibody treatment reprograms immune system after heart attack

A new drug being trialled in heart attack patients could reprogram the immune system to prevent inflammation and heart damage following severe heart attacks, as well as to promote repair.

Although modern clinical practice has reduced mortality from heart attacks by almost 90% over the last 50 years, no existing medicines have been able to safely address the excessive immune response that follows the most severe type of heart attack, known as ST-elevation myocardial infarction or a ‘widow maker’. These can happen suddenly when the main artery supplying blood to the heart is blocked.

Dr Daniel Donner, from Melbourne’s Baker Heart and Diabetes Institute, led an international team of more than 30 researchers to demonstrate a potential treatment that uses an antibody to reprogram the immune system response to prioritise healing instead of exacerbating damage. In a study published in JACC: Basic to Translational Science, Donner’s team showed how the antibody reprograms key immune cells called macrophages; this prevents the excessive immune system response from further damaging the heart after the heart attack and avoids further deterioration of heart function.

The study supports emerging evidence that the macrophages are master puppeteers of the immune response, which tends to overreact to a heart attack. This leads to excessive inflammation, recruitment of more immune cells, and long-term damage.

“The antibody we tested blocks CD14, a receptor on the surface of these macrophages that acts as an antenna receiving multiple signals that drive inflammation after a heart attack,” Donner explained. “Blocking this receptor rewires these key immune cells, preventing them from inflaming the heart muscle, and instead promoting repair and recovery.

“Broad-spectrum suppression of the entire immune response can be dangerous, as these key immune cells also play important roles in healing from a heart attack, and fighting everyday infections.”

Co-author Professor Kory Lavine, Director of the Center for Cardiovascular Research at Washington University School of Medicine, added, “The unique feature of targeting CD14 is that instead of removing these cells like other immune suppressants, it allows us to put these cells to work regulating the rest of the immune system, avoiding further deterioration of heart function.

“CD14 sits at the intersection of heart inflammation and scarring and serves as a regulator of different immune responses that each contribute to cardiac damage and heart failure. It is unique in that inhibition of CD14 does not cause immunosuppression. Targeting CD14 signalling has great potential in treating and preventing heart failure in these most at-risk patients.”

As part of clinical trials in the USA, sponsored by Australian drug development company Implicit Bioscience, a clinical-stage, CD14-targeting antibody known as atibuclimab has been approved to treat patients who have recently had a severe heart attack or deteriorating heart failure. All 14 patients involved in the trials are so far responding well, said Implicit Bioscience CEO Garry Redlich.

“We have also identified a very useful blood test that can predict whether this therapy is likely to work for a particular patient after their heart attack,” Redlich said. “No existing immune-modulating treatment like this has a precisely matched blood test that can assure cardiologists that they are treating the right patient with the right drug at the right time.”

If successful, there are plans for atibuclimab to be tested in larger phase 2 clinical studies around the world.

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