Paul Ehrlich was a pioneering 19th century German physician who found the cure for syphilis and was awarded the Nobel Prize for his contributions to immunology. He also conceived the idea of a Zauberkugel, or ‘magic bullet’ – something that would attack disease in the body without affecting healthy tissue. The EU-funded ZAUBERKUGEL project sought to make this a reality through the development of advanced therapies for cancer and other diseases. “Ehrlich had a vision that you could have drugs targeted at the site of disease,” says project coordinator Dario Neri. “To a certain extent, monoclonal antibodies are such tools. These are molecules of exquisite specificity, and they can be used to deliver a payload to the site of disease.”
More sophisticated tools
For over 20 years, monoclonal antibodies that target diseased tissue have been used to deliver two principal classes of drugs: cytokines, which modulate activity of the immune system, and cytotoxic agents, which kill tumour cells. However, these do not quite fulfil Ehrlich’s dream of a magic bullet. “We have good antibodies with good specificity, but there is a misunderstanding even among experts, that because we have high specificity, the tumour would be like a sponge and everything you inject ends up there,” explains Neri. “In reality it’s different. It takes time to distribute in the body, and the process of preferential accumulation is low, despite good specificity.” Because the cytokines and cytotoxic agents carried by monoclonal antibodies are active from the moment they are injected, they have a negative impact on all tissues as they are transported around the body. This effect gradually decreases as the agent accumulates at the site of disease. “With antibodies that deliver cytokines and drugs, we want an even further level of sophistication – activity on demand,” notes Neri. This involves not simply using antibodies to deliver a payload, but ensuring those drugs are inactive until they reach the site of disease. The ZAUBERKUGEL project, hosted by ETH Zurich in Switzerland, explored several possibilities for generating this kind of conditional activity in monoclonal therapies. The first was the ‘split cytokine’ approach, where the molecule arrives in two inert parts which reform at the site of disease to become active. “We published a very good implementation of this in cranial tumours in PNAS,” adds Neri. Other techniques involved ‘masking’ molecules which detach at the site of disease to reveal the active agent, and antibodies which cleaved at the tumour face to liberate a drug held within. Neri and his team also investigated the use of ligands, small molecules which can penetrate deep into tumour tissue before delivering chemotherapy agents.
The project was supported by the European Research Council. “This helped enormously, allowing the group to be creative and develop prototypes for 5 years without worrying about funding,” says Neri. “The day has 24 hours, and you can spend it writing applications or conducting experiments. This grant allowed us to concentrate on research.” Next, Neri plans to develop the prototypes discovered through ZAUBERKUGEL. “We have a good number of therapeutic agents that cure tumours in mice, and many of them deserve to be moved to clinical trials,” he explains. To achieve this, Neri has moved to working full-time in industry, through the company he co-founded, Philogen. He says his plans are “very simple: to see which drugs work in clinical trials, and translation, translation, translation!!”
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