July 26, 2008 The chemist Dario Neri has carried out research for more than 15 years to find antibodies suitable as drug delivery vehicles for selective anti-cancer treatment. In his most recent publication he presents a new marker together with three associated monoclonal antibodies as further promising candidates for cancer therapy.
Up to now, monoclonal antibodies have only lived up to their expectations in the chemotherapeutic fight against cancer to a limited extent. Although these therapies are effective in prolonging the lives of patients who have types of cancer with a small chance of survival, for example advanced lung cancer, they cannot cure them. One of the main problems with current antibody chemotherapies is that the medicines lack selectivity. The active ingredients become distributed throughout the whole body and also attack healthy tissues in the liver, lungs or heart as well as the actual tumour that is to be treated.
Targeted anti-tumour treatment via the blood supply
By using “targeting”, Dario Neri from the Institute of Pharmaceutical Sciences at ETH Zurich has followed a promising path in cancer therapy. “Targeting” employs antibodies as delivery vehicles for medicines to carry their active ingredients through the blood circulation and into the tumour. Blood vessels that grow together with the tumour as a result of what is known as angiogenesis (neo-vascularization) and supply the tumour with nutrients enable drugs to be transported via the body’s own blood circulation and into the centre of the tumour.
The researchers use markers to help the antibodies find their way into the diseased cells. These markers can be thought of as a kind of antibody dock to which only proteins with specific characteristics can attach themselves. If the matching proteins are now loaded with an anti-cancer agent, the markers enable the drugs to be positioned highly selectively in the tumour as well as in the metastases, thus protecting the remainder of the healthy body. Among other things, Neri’s group is searching for such markers, i.e. protein characteristics that occur solely in the tumour’s blood circulatory system.
Neri’s colleague Luciano Zardi had already found such a marker 21 years ago in the shape of the extra-domain B (EDB) of the protein fibronectin. EDB is a variant of the fibronectin protein that occurs practically exclusively in the blood supply of tumours and their metastases. Today EDB is one of the best characterised markers in cancer research. In the past 10 years Neri and his team have developed two very promising antibodies, F16 und L19, that can “dock on to” tumour blood vessels and can be readily loaded with an anti-cancer active agent.
A large number of markers and antibodies is needed for therapy
In the “International Journal of Cancer”, Neri has described another marker, the fibronectin extra-domain A (EDA), together with three monoclonal antibodies that bind selectively to EDA. Explaining the relevance of the new results, Neri says, “Because each type of cancer has its own molecular characteristics, it is important that we make various different markers and antibodies available for therapy.” The publication describes the antibody F8 in particular as a promising candidate for this cancer therapy.
Tests on laboratory mice have shown that F8 accumulates very selectively in the tumour and in cancerous metastases, while healthy organs remain largely protected against the antibodies. According to Neri, “We believe that the F8 antibody could become an important building block in the development of selective and effective anti-cancer bio-pharmaceuticals.” Up to now, F8 has been tested only on mice. However, in collaboration with two pharmaceutical companies, clinical studies on humans are already taking place for the EDB antibodies F16 and L19, which have been known for longer. Initial results should be published soon, and, according to Neri, these are very promising. Neri says “We have good reason to assume that F8 could soon prove in clinical studies to be just as promising a cancer therapy candidate as F16 and L19.”
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- Villa A., Trachsel E., Kaspar M., Schliemann C., Sommavilla R., Rybak J.N., Rösli C., Borsi L. and Neri D. A high-affinity human monoclonal antibody specific to the alternatively spliced EDA domain of fibronectin efficiently target tumor neo-vasculature in vivo. Int J Cancer, Jun 1;122(11):2405-13 DOI: 10.1002/ijc.23408
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