Project description
What if we could kill diseased cells without harming normal tissues?
Scientists have been searching for a ‘magic bullet’ to selectively target disease causing cells for decades, but current treatments for cancer and chronic inflammatory diseases fall short of this ideal. Monoclonal antibodies, while providing specific targeting, are often not curative as single agents, and attempts to ‘arm’ them with drugs or cytokines have resulted in unacceptable toxicities. In this context, the ground-breaking European Research Council-funded ZAUBERKUGEL project proposes a solution that could change the game entirely. This involves the controlled release of cytotoxic drugs or stepwise non-covalent assembly of cytokines. Innovative proteomic methodologies, based on human leucocyte antigen-peptidome analysis, will be used to profile response to therapy. This approach holds considerable potential for treating serious diseases with ‘activity on demand’ pharmaceutical agents.
Objective
"Paul Ehrlich was the first scientist to postulate that if a compound could be made that selectively targeted disease-causing cells, then this agent could be used for the delivery of a toxin, which would enable a pharmacotherapy of unprecedented potency and selectivity. With this procedure, a ""magic bullet"" (Zauberkugel, his term for an ideal therapeutic agent) would be created, that killed diseased cells while sparing normal tissues.
The concept of a ""magic bullet"" was to some extent realized by the invention of monoclonal antibodies, as these molecules provide a very specific binding affinity to their cognate target. However, monoclonal antibodies used as single agents are typically not able to induce cures for cancer or chronic inflammatory diseases. More recently, intense academic and industrial research activities have aimed at “arming” monoclonal antibodies with drugs or cytokines, in order to preferentially deliver these therapeutic payloads to the site of disease. Unfortunately, in most cases, ""armed"" antibody products still cause unacceptable toxicities, which prevent escalation to potentially curative dose regimens.
In this Project, I outline a therapeutic strategy, which relies on the use of extremely specific tumor targeting agents, for the selective delivery of payloads, which can be conditionally activated at the site of disease. Methodologies for the conditional generation of active payloads include the stepwise non-covalent assembly of cytokines and the controlled release of cytotoxic drugs at suitable time points after injection, when the concentration of therapeutic agent in normal organs is acceptably low. Response to therapy will be profiled using innovative proteomic methodologies, based on HLA-peptidome analysis.
Pharmaceutical agents with “activity on demand” hold a considerable potential not only for the therapy of cancer, but also for the treatment of other serious diseases, including certain highly debilitating chronic inflammatory condition"
Fields of science
- medical and health scienceshealth sciencesinflammatory diseases
- medical and health sciencesbasic medicinepharmacology and pharmacypharmaceutical drugs
- medical and health sciencesclinical medicineoncologylung cancer
- medical and health sciencesclinical medicineoncologyskin cancermelanoma
- medical and health sciencesbasic medicineimmunology
Programme(s)
Topic(s)
Funding Scheme
ERC-ADG - Advanced GrantHost institution
8092 Zuerich
Switzerland