Training experts in antigen processing to deliver new drug prototypes for cancer and autoimmune diseases

Projektinformationen

CAPSTONE

ID Finanzhilfevereinbarung: 954992

DOI

10.3030/954992

Projekt abgeschlossen

EK-Unterschriftsdatum 3 September 2020

Startdatum 1 Januar 2021

Enddatum 30 Juni 2025

Finanziert unter

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Gesamtkosten

€ 3 968 730,62

EU-Beitrag

€ 3 968 730,62

Koordiniert durch

UNIVERSITE DE LILLE
France

Periodic Reporting for period 2 - CAPSTONE (Training experts in antigen processing to deliver new drug prototypes for cancer and autoimmune diseases)

Berichtszeitraum: 2023-01-01 bis 2025-06-30

Zusammenfassung vom Kontext und den Gesamtzielen des Projekts

Cancer is still one of the leading causes of death in Europe despite the development of targeted therapies. Cancer immunotherapy has proven to be a new, effective strategy, but it is only effective in a fraction of patients. Modulation of the immune system is also the basis of the treatment of autoimmune diseases. These highly prevalent and complex diseases are increasing at an alarming rate across Europe. Small-molecule personalised treatments have the potential for tailor-made immune-oncology and to replace conventional unsatisfactory immunosuppressant approaches.
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/IRAP enzymes that generate antigenic peptides have thus emerged as promising targets for cancer immunotherapy and autoimmune disease treatments.

The main research objective of CAPSTONE was to deliver disruptive therapeutic innovation in two areas – autoimmune diseases and cancer, and, in particular, to
- Obtain a mechanistic and quantitative understanding of ERAP/IRAP antigen processing and its functional consequences.
- Characterise how ERAP/IRAP modulation and variation underlie antigen processing dysfunctions in diseases.
- Validate ERAP/IRAP as targets, develop pharmacological probes and bridge their early-stage development all the way to preclinical leads in diseases of urgent medical need.

To reach these objectives, CAPSTONE delivered an international and interdisciplinary research and training programme for 15 early-stage researchers (ESRs) and prepared them for a career in academia or the pharmaceutical industry.

Arbeit, die ab Beginn des Projekts bis zum Ende des durch den Bericht erfassten Berichtszeitraums geleistet wurde, und die wichtigsten bis dahin erzielten Ergebnisse

The CAPSTONE consortium has greatly advanced understanding of ERAP1, ERAP2, and IRAP in immunity, cancer, and autoimmunity. Structural and functional studies revealed how specific ERAP1 allotypes shape antigen presentation, while inhibitor design uncovered novel binding modes and led to potent, selective compounds with promising pharmacological profiles in vitro and in vivo.
Immunopeptidomic and in vivo studies demonstrated that modulating ERAP activity enhances anti-tumour immunity, improves immune infiltration, and reduces leukaemia growth, highlighting ERAPs as attractive therapeutic targets. In autoimmune models, ERAP deletion delayed the onset of type 1 diabetes, further underscoring its role in disease regulation.
Medicinal chemistry efforts delivered optimised inhibitors, novel chemotypes, nanoparticle formulations, and predictive drug-like properties models to accelerate therapeutic development. Biomarker and metabolomic analyses confirmed relevance and safety of the approach and provided tools for monitoring intervention.
Overall, CAPSTONE achieved its objectives, generating both mechanistic insights and translational advances that position ERAPs and IRAP as key nodes for therapeutic innovation.
Through collaborative research, the project has generated a wealth of new knowledge, which has been disseminated so far through 18 peer-reviewed publications and more are expected in the coming months.

Fortschritte, die über den aktuellen Stand der Technik hinausgehen und voraussichtliche potenzielle Auswirkungen (einschließlich der bis dato erzielten sozioökonomischen Auswirkungen und weiter gefassten gesellschaftlichen Auswirkungen des Projekts)

CAPSTONE has already made significant contributions to the scientific understanding of antigen processing, particularly focusing on the role of ERAP aminopeptidases in autoimmune diseases and cancer as a new paradigm in immunity modulation, upstream of current therapeutic interventions. Apart from scientific results, new experimental models, and exploring cross-disciplinary methodologies as well as validated protocols, reagents (compounds, cells, plasmids), and guidelines that can be used by the broader scientific community, ensuring that CAPSTONE’s innovations contribute to future research and therapeutic development beyond the project’s timeline.
CAPSTONE contributes to Europe’s innovation potential by accelerating the development of novel immunomodulatory therapies with strong commercial relevance. By focusing on early-stage drug discovery and target validation, the project may lead to cost savings in the drug development pipeline, particularly by identifying candidates with higher translational potential and a clearer understanding of the mechanism of action. The collaboration with seven industrial partners ensured that the technological outputs of CAPSTONE are closely aligned with the needs of pharmaceutical R&D.
CAPSTONE addressed diseases with a significant impact on both life expectancy and quality of life, aiming to deliver solutions that are not only scientifically innovative but also meaningfully improve patient outcomes. In the longer term, innovations generated through CAPSTONE have the potential to lead to more precise and effective ERAP-based treatments, reducing disease progression, improving management, and potentially lowering healthcare costs. Therapies represent a promising alternative to costly and side-effect-prone biologics. The project has also engaged with patient associations to ensure that research remains patient-centred.

CAPSTONE ESRs and the Coordinator, Rebecca Deprez, at the 3rd CAPSTONE Summit