REPRESSIT: A novel class of clinical immune checkpoint inhibitors

REPRESSIT：一类新型临床免疫检查点抑制剂

• 批准号: 10088081
• 金额: $ 73.36万
• 依托单位: UNIVERSITY OF OXFORD
• 依托单位国家: 英国
• 项目类别: EU-Funded
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=10088081
• 关键词: REPRESSIT; novel; class; clinical; immune

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.

在肿瘤微环境中，T细胞的连续或“强直”刺激通过抑制性免疫受体（IR）诱导检查点信号传导。这种现象抑制T细胞功能，导致耗竭表型及其随后的无法消除癌细胞。通过IR靶向抗体（例如抗PD-1、抗CTLA-4）的检查点阻断可以部分逆转这一过程，并且已经彻底改变了癌症免疫疗法。然而，大部分患者，例如具有不表达IR配体的肿瘤的患者，不受益于这种治疗。因此，仍有大量未满足的需求有待解决。我们的目标是改变目前配体中心的“封锁”模式。本文开发的REPRESSIT平台技术将通过开发一类新的配体非依赖性检查点疗法提供一种全新的方法。这些通过磷酸酶募集的受体抑制（RIPR）分子将酪氨酸磷酸酶募集到IR并关闭IR信号传导，从而重新激活耗尽的T或NK细胞以有效地清除癌细胞。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的独特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分子的设计原理，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）证明体内概念验证（proof-of-concept，PROCESSION），聚焦于已知显示紧张性信号传导的高度相关的T和NK细胞IR组。REPRESSIT将为靶向磷酸酪氨酸载体IR的现成RIPR设计提供技术平台。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大大改善的前景。