DRUGS FOR THERAPY · High throughput development of drugs for immunotherapy of autoimmune diseases

Final Activity Report Summary - DRUGS FOR THERAPY (High throughput development of drugs for immunotherapy of autoimmune diseases)

The scientific goal was to work on high throughput development of drugs for immunotherapy of (auto) immune diseases. Work has been performed on all five tasks named in the original project proposal: 1) identification of drug targets; 2) computational design of drugs; 3) rational design of drugs; 4) in vitro testing of drugs; 5) in vivo testing of drugs. Most of the work has been carried out in cooperation between different participants. The first project that was initiated by the LUMC was aimed at the development of antagonistic molecules that occupy the HLA binding site from HLA-DQ2 (or HLA DQ-8). Potential candidates have been tested for the activity in functional assays to identify the most effective molecules. The resulting peptide has an at least 200 times higher affinity for HLA-DQ2 compared to the gluten peptides that are known to be involved in Celiac disease (CD). We aim to develop this lead peptide into a blocker of HLA-DQ2 that can be used as a novel therapeutic for CD. For this purpose, the peptide needs to be further optimised and stabilised in order to be appropriately bioactive in vivo. Such an approach may subsequently be also applied to other HLA-DQ molecules, know to predispose to type I diabetes. This project plans are made to set-up a spin-off company that will take this approach towards application. The collaboration of algonomics in this project was also beneficial for their site. They could increase the accuracy of the predictions of their software for computational design of drugs. Epibase now extracts knowledge from the experimental measurements of peptide binding affinity. These developments allow to further increase the accuracy of the predictions. The improvement in quality is so that algonomics will soon release a new version of epibase. The second project coordinated by the Karolinska Institutet resulted in the development of an assay for monitoring ubiquitin in living cells. This assay has given new insights in the dynamics of ubiquitin under various conditions and the role of histone ubiquitylation in DNA repair. Also an activity probe for the proteosome which had been developed by the group of participant 2 has been characterized. Furthermore the role of the AAA-ATPase VCP in the degradation of soluble short lived proteins has been studied. A model system described in this manuscript has been patented (US provisional 61/078,978). The economical impact of the above results will become clear in the coming years. In total, seven experienced researchers and seven early stage researchers were recruited within the network; one position for an ESR remained open during the whole project. In three institutes, the researchers were replaced during the project. Four of the early stage researchers will complete their thesis in the coming year. Most of the research fellows will continue their career in science; only in some cases a career change was made. The consortium was based on existing collaborations between partners; during the projects some new collaborations were established. For instance a collaboration between partners 3 (NKI) and 11 (Josef Stefan Institute) and a collaboration between partners 5 (MDC) and 8 (University of Oslo) were new. These collaborations could be established for a huge part because of the possibility that the recruited MC-RTN researchers could work for some time in the other institute. Project website: http://www.drugs-for-therapy.org

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