REPRESSIT: A novel class of clinical immune checkpoint inhibitors

Project Information

REPRESSIT

Grant agreement ID: 101098965

DOI

10.3030/101098965

EC signature date 13 March 2023

Start date 1 May 2023

End date 30 April 2028

Funded under

• The European Innovation Council (EIC)

Total cost

€ 2 896 496,25

EU contribution

€ 2 896 496,00

Coordinated by

STICHTING NEDERLANDSE WETENSCHAPPELIJK ONDERZOEK INSTITUTEN
Netherlands

Periodic Reporting for period 2 - REPRESSIT (REPRESSIT: A novel class of clinical immune checkpoint inhibitors)

Reporting period: 2024-05-01 to 2025-08-31

Summary of the context and overall objectives of the project

In the complex world of cancer, immune cells such as T cells and natural killer (NK) cells play a critical role in eliminating tumour cells, particularly after treatments like chemotherapy or radiation., However, these cells can become “switched off” by inhibitory immune receptors (IRs), leading to therapy resistance and disease relapse. Current checkpoint blockade therapies aiming to interfere with this off-switch have transformed outcomes for some patients but remain ineffective for many others, especially when tumours lack the ligands for these drugs to block.
In this context, the REPRESSIT consortium aims to overcome this limitation by directly targeting the root cause of IR signalling: IR tyrosine phosphorylation. Our strategy harnesses the natural phosphatase activity already present at the cell surface and redirects it to the vicinity of inhibitory receptors, selectively dampening their signalling This innovative induced-proximity approach aims to reinvigorate exhausted T and NK cells, both in the presence or absence of IR ligands. With a consortium of experts in IR biology, tumor immunology, protein engineering, biophysics, and proteomics, REPRESSIT aims to deliver a new generation of precision immunotherapies capable of overcoming resistance and broadening the reach of immune-based cancer treatment.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

The consortium has successfully generated a portfolio of candidate molecules for our phosphatase recruitment–based checkpoint therapeutics. In parallel, we have established and optimized experimental platforms to refine these molecules and evaluate their ability to counteract inhibitory receptor (IR)-mediated T cell suppression. Candidate molecules targeting two distinct IRs have been developed and tested, alongside expanded libraries for a previously explored receptor.
Our in vitro and cell-based assays are now enabling systematic structure-function analyses, revealing key design principles for effective receptor inhibition via phosphatase recruitment. Importantly, RIPR-mediated receptor dephosphorylation has been demonstrated using single-molecule fluorescence microscopy in live cells, and proximity between phosphatases (CD45) and inhibitory receptors has been independently verified by mass spectrometry.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

While further research is needed to identify the most effective RIPR candidates for preclinical development, this approach opens an entirely new avenue for overcoming resistance to immunotherapy. We are actively securing intellectual property covering both the candidate molecules and the underlying design principles to ensure protection and future translational potential. These steps, together with ongoing validation and optimisation, will position the consortium for subsequent phases of preclinical testing and eventual partnership toward clinical application.