REPRESSIT: A novel class of clinical immune checkpoint inhibitors

Introduction

In the tumor microenvironment, continuous or “tonic” stimulation of T cells induces checkpoint signaling through inhibitory immune receptors (IRs). This phenomenon suppresses T cell function, contributing to an exhaustion phenotype and their consequent failure to eliminate cancer cells.

Current Treatment Limitations

Checkpoint blockade through IR-targeting antibodies (e.g. anti-PD-1, anti-CTLA-4) can partially reverse this process and has revolutionized cancer immunotherapy. However, a large fraction of patients, e.g. with tumors that do not express IR ligands, do not benefit from this treatment. Thus, a large unmet need remains to be addressed.

Project Aim

We aim to change the current ligand-centric “blockade” paradigm. The REPRESSIT platform technology developed herein will provide a radically new approach through the development of a novel class of ligand-independent checkpoint therapeutics.

Mechanism of Action

These Receptor Inhibition by Phosphatase Recruitment (RIPR) molecules recruit tyrosine phosphatases to the IR and shut down IR signaling, thereby reactivating exhausted T or NK cells to effectively clear cancer cells.

Consortium Expertise

The REPRESSIT consortium unites unique complementary expertise and models in:

1. IR biology
2. Tumor immunology
3. Protein engineering
4. Biophysics
5. Proteomics

Project Objectives

The objectives of the project are to:

1. Define the design principles of RIPR molecules against multiple checkpoint IR targets.
2. Evaluate the IR mode of action of signal inhibition.
3. Optimize RIPR molecules for their efficacy using preclinical cancer models.
4. Demonstrate in vivo proof-of-concept (PoC), focusing on a highly relevant panel of T and NK cell IRs known to display tonic signaling.

Long-term Vision

REPRESSIT will deliver a technology platform for off-the-shelf RIPR designs targeting phosphotyrosine-carrying IR. This project will provide the foundation for our long-term vision of innovative immune checkpoint therapeutics with unprecedented efficacy and provide a greatly improved perspective to the many cancer patients for whom current treatment is ineffective.