REPRESSIT: A novel class of clinical immune checkpoint inhibitors

在肿瘤微环境中，T细胞的持续或“强直”刺激通过抑制性免疫受体（IRs）诱导检查点信号。这种现象抑制了T细胞的功能，导致衰竭表型和它们随后无法消除癌细胞。通过ir靶向抗体（如抗pd -1，抗ctla -4）阻断检查点可以部分逆转这一过程，并彻底改变了癌症免疫治疗。然而，很大一部分患者，例如不表达IR配体的肿瘤，不能从这种治疗中获益。因此，仍有大量未满足的需要有待解决。我们的目标是改变目前以配体为中心的“封锁”范式。本文开发的REPRESSIT平台技术将提供一种全新的方法，通过开发一类新的配体非依赖性检查点疗法。这些受体抑制由磷酸酶募集（RIPR）分子募集酪氨酸磷酸酶到IR并关闭IR信号，从而重新激活耗尽的T或NK细胞以有效清除癌细胞。REPRESSIT联盟联合了IR生物学、肿瘤免疫学、蛋白质工程、生物物理学和蛋白质组学方面独特的互补专业知识和模型，以：1)定义针对多个检查点IR靶点的RIPR分子的设计原则，2)评估信号抑制的IR作用模式，3)使用临床前癌症模型优化RIPR分子的功效，以及4)展示体内概念验证（PoC）)，重点关注高度相关的T和NK细胞IRs已知显示tonic信号。REPRESSIT将提供针对携带磷酸酪氨酸IR的现成RIPR设计的技术平台。该项目将为我们创新免疫检查点疗法的长期愿景提供基础，具有前所未有的疗效，并为许多目前治疗无效的癌症患者提供极大的改善视角。

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.