Rat cardiac tissue showing chronic rejection with cardiac allograft vasculopathy (left image) and interstitial fibrosis (right image): immunofluorescence double labelling of the endothelial cell marker CD31 (red fluorescence) in combination with ED-A domain containing fibronectin (ED-A+ Fn, green fluorescence). In contrast to normal healthy adult organs, ED-A+ Fn is overexpressed in chronically rejected cardiac tissue with a spatial association to vasculopathy and fibrosis. The insert in the left image shows a healthy vessel where ED-A+ Fn is virtually absent."
The project is also probing the extent to which antibody drugs – known as TNF blockers – can prevent the immune system’s over-exuberant action. This over reaction is the cause of the chronic inflammation seen in patients with rheumatoid arthritis. It can also lead to the rejection of transplanted organs.
“Understanding how and why some patients exhibit a substantial benefit from treatment represents the basis for achieving success in a larger number of cases,” says PRIAT’s coordinator, Professor Dario Neri of the Department of Chemistry and Applied Biosciences at the Swiss Federal Institute of Technology (ETH).
PRIAT focuses on three medical conditions: skin cancer, rheumatoid arthritis and the rejection of transplanted organs. Skin cancer and rheumatoid arthritis are already commonly treated with antibody therapies, although the results vary from patient to patient.
Under the microscope
In the first study of its kind in Europe, PRIAT is using Positron Emission Tomography (PET) – an imaging technique – to visualise, in three-dimensions, good or poor antibody uptake of drugs in places where inflammation occurs because of rheumatoid arthritis.
Such information is vital in deciding which patients with rheumatoid arthritis can best be treated with existing antibody therapies since a blocking action does not occur in all patients.
PRIAT has made good progress in developing mass spectrometry-based analysis, among other techniques, says Neri. This equipment can measure – with great precision – the masses of individual molecules. Combined with the analysis of actual specimens of disease, it will allow scientists to learn more about tumour-rejection activity in the body following antibody therapy.
“Some melanoma (skin cancer) patients appear to enjoy durable complete remissions after treatment with some immune-stimulatory antibodies. Understanding why this happens is vital to improving treatment,” he says.
He expects the ongoing research to help develop ‘tetramer technologies’ – new tools for profiling specific T cells (a type of white blood cell) in blood samples; those responding to and killing any foreign antigens.
PRIAT’s research is potentially far-reaching; the findings could provide information that would help doctors treat other medical conditions with existing antibody drugs – and ultimately lead to the development of new drugs.
“There is an urgent need to develop curative treatments to disseminated tumours (those which spread throughout the body from the original site of the tumour),” says Neri. “Understanding and exploiting the action of the immune system represents one of the most promising strategies to fight cancer.”
The potential benefits for patients are huge. Antibody therapies can act on tumours directly, unlike more conventional chemotherapy that can spread toxic substances to other organs.
PRIAT is also keeping Europe at the forefront of antibody therapy research and product development – an area where there is sharp competition from Asia and United States. The market for antibody drugs to treat rheumatoid arthritis is alone worth an annual €29 billion worldwide, he says.
The pooling of Europe-wide research expertise boosts research capacity. PRIAT brings together eight centres of excellence in the field across Europe.
“It is rare that a single centre has all the techniques necessary to tackle a complex problem, such as the success or failure of antibody therapies. Only an integrated approach allows us to adequately address this important biomedical problem in a productive fashion,” adds Neri.