REPRESSIT: A novel class of clinical immune checkpoint inhibitors

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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. 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. We aim to change the current ligandcentric “blockade” paradigm. The REPRESSIT platform technology developed herein will provide a radically new approach, through development of a novel class of ligand-independent checkpoint therapeutics. 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. The REPRESSIT consortium unites unique complementary expertise and models in IR biology, tumor immunology, protein engineering, biophysics and proteomics, to: 1) define the design principles of RIPR molecules against multiple checkpoint IR targets, 2) evaluate the IR mode of action ofsignal inhibition, 3) optimize RIPR molecule for their efficacy using preclinical cancer models, and 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. REPRESSIT will deliver a technology platform for off-the-shelf RIPR designs targeting phosphotyrosinecarrying 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 which current treatment is ineffective.