Periodic Reporting for period 1 - CAPSTONE (Training experts in antigen processing to deliver new drug prototypes for cancer and autoimmune diseases)
Période du rapport: 2021-01-01 au 2022-12-31
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 is 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 underlies 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 will deliver an international and interdisciplinary research and training programme for 15 early-stage researchers (ESRs) and prepare them for a career in academia or the pharmaceutical industry.
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 is 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 underlies 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 will deliver an international and interdisciplinary research and training programme for 15 early-stage researchers (ESRs) and prepare them for a career in academia or the pharmaceutical industry.
The first reporting period focused on recruiting the 15 ESRs. Significant efforts have been made to ensure a network-wide ideal environment to support researchers. This was also critical during the pandemic to maintain regular exchanges between all participants. Four networkwide meetings (two online, two physical) were organised, allowing updates on research progress and training of the ESRs on scientific themes, transferable skills, communication and outreach. Several ESRs have already conducted secondments at the labs of beneficiaries or partner organisations.
The three scientific work packages have already delivered important results. We have expanded our knowledge of ERAP/IRAP functions through a combination of allotypes production, X-Ray crystallography, structural dynamics and cellular assays. Construction and production of cell lines invalidated with the enzymes of interest or expressing disease-associated allotypes have been achieved. These cells are currently being used for the in vitro exploration of the roles of ERAP/IRAP in immunopeptidome modulation, immune cells activation, tumour microenvironment and diseases’ phenotypes, as well as for studying the effect of inhibitors. Acquisition of gene expression of ERAP-associated human inflammatory disease patients was been completed, and sets of biomarkers differentiating the wild type and autoimmune rodent model have been obtained. Three large screening campaigns using protein templated reactions, fragments or virtual screening have delivered hits. Optimisation and physico-chemical and biological characterisation of more advanced chemical series are ongoing. Several formulations were developed for a first series of inhibitors.
The three scientific work packages have already delivered important results. We have expanded our knowledge of ERAP/IRAP functions through a combination of allotypes production, X-Ray crystallography, structural dynamics and cellular assays. Construction and production of cell lines invalidated with the enzymes of interest or expressing disease-associated allotypes have been achieved. These cells are currently being used for the in vitro exploration of the roles of ERAP/IRAP in immunopeptidome modulation, immune cells activation, tumour microenvironment and diseases’ phenotypes, as well as for studying the effect of inhibitors. Acquisition of gene expression of ERAP-associated human inflammatory disease patients was been completed, and sets of biomarkers differentiating the wild type and autoimmune rodent model have been obtained. Three large screening campaigns using protein templated reactions, fragments or virtual screening have delivered hits. Optimisation and physico-chemical and biological characterisation of more advanced chemical series are ongoing. Several formulations were developed for a first series of inhibitors.
Preliminary results from the network show that the pharmacological inhibition of ERAP is now within reach and can effectively manipulate immune responses. Our innovative research approach based on ERAP targets the upstream molecular events that cause these diseases. This will provide unique opportunities for future treatment of unmet medical needs and innovative immunotherapies.
All of this will support the growth of European expertise in the field and supports its economy with the development of both methods/tools as well as drug candidates. To translate fundamental research directly into novel treatment avenues, we exploit established and to-be-developed unique patient-derived models, putting Europe at the forefront of this field.
Finally, it will prepare the CAPSTONE ESRs with scientific and transferable skills and high-value professional connections for exciting career perspectives in academia, the pharmaceutical industry, and biotechnology SMEs. More specifically, the excellent background in immunology and small-molecule immunotherapy (in all their aspects, from molecules to formulation and pharmacology) provided by CAPSTONE is highly demanded by professionals.
All of this will support the growth of European expertise in the field and supports its economy with the development of both methods/tools as well as drug candidates. To translate fundamental research directly into novel treatment avenues, we exploit established and to-be-developed unique patient-derived models, putting Europe at the forefront of this field.
Finally, it will prepare the CAPSTONE ESRs with scientific and transferable skills and high-value professional connections for exciting career perspectives in academia, the pharmaceutical industry, and biotechnology SMEs. More specifically, the excellent background in immunology and small-molecule immunotherapy (in all their aspects, from molecules to formulation and pharmacology) provided by CAPSTONE is highly demanded by professionals.