Current trends in immunotherapy are to develop immuno-modulatory small molecules for intracellular targets for single therapy or combination with existing treatments. CAPSTONE scientists have recently identified the key pathway of intracellular antigen processing for modulating the immune response. ERAP enzymes that generate antigenic peptides have thus emerged as promising targets for the cancer immunotherapy and autoimmune diseases treatments. Our innovative research approach based on ERAP, targets the upstream molecular events that cause these diseases. We aim at fully understanding this pathway, deciphering the mechanisms of antigen processing dysfunctions in diseases, and developing innovative therapeutic drugs. This will provide unique opportunities for future treatment of unmet medical needs and innovative immunotherapies. CAPSTONE will thus be an excellent scientific environment to train the next generation of 15 Early Stage Researchers (ESRs) and establish an innovative cross-fertilisation between oncology and auto-immunity. Our fellows will be able to perform outstanding research at the forefront of transdisciplinary science within a high-calibre international network of academics, industries and patient associations. CAPSTONE brings together an intersectorial and multidisciplinary group of researchers in medicinal chemistry, X-Ray crystallography, cellular biology, oncology, autoimmunity, bioanalysis, mass spectrometry imaging, formulation, systems biology, personalised medicine that will expose the ESRs to key R&D stages, from basic research to pre-clinical development. CAPSTONE will prepare the ESRs for exciting career perspectives in academia, the pharmaceutical industry, biotechnology SMEs, and provide them with scientific and transferable skills and high-value professional connections. Industrial secondments and public engagement will add to a broad skill set to ensure employability in the higher ranks of academia and industry.

The European Regimen Accelerator for Tuberculosis (ERA4TB) has the explicit goal of developing a new combination therapy to treat all forms of TB starting from ~20 leads and drug candidates provided by EFPIA. Since details of these are as yet unavailable, we will implement an agile drug development algorithm that entails profiling and portfolio construction. Profiling involves characterisation and ranking molecules in preclinical studies comprising in vitro drug combination assays, hollow fiber and single cell analysis, innovative murine and non-human primate models, PK/PD studies, combined with biomarker discovery and non-invasive NIR or PET/CT imaging to monitor disease progression and response to treatment. Modelling, simulation and artificial intelligence tools will help progress compounds from early preclinical to clinical development and to predict drug exposure, human doses and the best combinations. After extensive preclinical profiling, selected compounds will enter portfolio development for first time in human tests and phase I clinical trials in order to ensure that they are safe, well-tolerated and bioavailable with negligible drug-drug interactions. If needed, formulation studies will be conducted to improve pharmacological properties. ERA4TB has assembled the best expertise and resources available in Europe, to build a highly effective and sustainable drug development consortium with a flexible and dynamic management system to execute the profiling and portfolio strategy, aided by clearly defined go/no-go decision points. The expected outcome of ERA4TB is a series of highly active, bactericidal, orally available drugs to constitute two or more new combination regimens with treatment-shortening potential ready for Phase II clinical evaluation. These regimens will be compatible with drugs used to treat common comorbidities, such as HIV-AIDS and diabetes, and should impact UN Sustainable Development Goal 3, namely, ending TB by 2030.