REPRESSIT will generate a technology platform for off-the-shelf RIPR molecules (Receptor Inhibition by Phosphatase Recruitment) targeting any tyrosine phosphatase carrying inhibitory immune receptor.

The REPRESSIT consortium will create a Proof-of-Concept for full in vivo functionality of RIPR molecules against diverse T and NK cell receptors in preclinical tumor models.

Our expected outcomes will provide the foundation for our long-term vision of novel immune checkpoint therapeutics with unprecedented efficacy for more cancer patients.  

The starting point

Checkpoint blockage focuses on targeting inhibitory immune receptors with antibodies to prevent their activation by blocking ligand binding. This strategy has revolutionized immunotherapy helping millions of cancer patients with some spectacular results, providing a novel path to potentiate immune responses against tumor cells.  

Nevertheless, most patients fail to benefit from these antibody-based therapies highlighting a critical pitfall of the current checkpoint blockade approach:
blocking receptor-ligand interactions is insufficient to shut down inhibitory signaling completely. As such, there is still a huge unmet medical need to develop novel therapeutic approaches for the effective targeting of immune checkpoints. 

Our project was raised to target the need of developing a novel conceptual leap that not only targets unresponsive patients but also could be implemented as a general strategy to anyone. 

The strategy

We propose changing the current ligand-centric “blockade” paradigm and focusing on developing molecules that induce dephosphorylation of immune receptors to shut down their signaling entirely. 

Our approach termed REPRESSIT (Regulated phosphatase recruitment ends sustained signaling of inhibitory targets) can completely shut down even tonic IR signaling.

This concept arises from ligand-independent, phosphatase-mediated targeting of the most proximal intracellular signaling of immune receptors: receptor Tyrosine phosphorylation.

We will develop an innovative set of bispecific protein molecules called RIPR (Receptor Inhibition by Phosphatase Recruitment) that recruit phosphatases inducing receptors dephosphorylation and thereby enhancing cytotoxic immune cell activity for eliminating tumors in patients. 

The RIPR technology will broaden the scope of checkpoint inhibition to ultimately cure more patients with more diverse tumor types.

The REPRESSIT approach is unique because it is ligand-independent and is therefore applicable even in conditions where ligands are absent, poorly described, or non-existing. 

Our interdisciplinary consortium will develop and evaluate the innovative RIPR technology for cancer immunotherapy by combining protein engineering, biophysics, proteomics, in vitro tumor immunology models and humanized mouse models.

With this, REPRESSIT will generate the first preclinical proof-of-concept checkpoint therapeutics platform. 

REPRESSIT PUBLICATIONS

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Our previous publications