Evaluation of P2X7 as a therapeutic target in autoimmune encephalomyelitis and in tumor immunity

P2X7 作为自身免疫性脑脊髓炎和肿瘤免疫治疗靶点的评估

• 批准号: 406945353
• 负责人: Professor Dr. Friedrich Koch-Nolte
• 金额: --
• 依托单位: Institut für Immunologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2019
• 资助国家: 德国
• 起止时间: 2018-12-31 至 2023-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/406945353?language=en
• 关键词: Evaluation; P2X7; therapeutic; target; autoimmune

P2X7, a ligand-gated ion channel, and ARTC2, a toxin-related ecto-enzyme, are immune cell surface proteins that sense ATP and NAD+ released from cells as endogenous danger signals during sterile inflammation. On myeloid cells, P2X7 is a key mediator of inflammation. On T cells, ARTC2 and P2X7 regulate Treg function and survival. We have discovered in a previous collaborative study, that depletion of regulatory T cells by activation the ARTC2/P2X7 axis can be used to promote anti-tumor immune responses. Recently, we have developed P2X7-blocking and P2X7-potentiating nanobodies (Nbs) and Nb based biologics. We found that blocking P2X7 function with these biologics in vivo represents a promising novel therapeutic strategy to ameliorate inflammation. These biologics can be administered either by repeated systemic injections or via continued endogenous synthesis after transduction of cells in vivo with adeno-associated viral (AAV) vectors coding for these Nb. So far, little is known about the in vivo pharmacodynamics of these biologics, and about their capacity to reach and block their targets on immune cells in lymphatic organs, inflamed tissues or tumors. The blood-brain barrier (BBB) in particular poses a natural obstacle for protein-based biologics to reach their targets in the central nervous system (CNS). Moreover, the role of P2X7 in autoimmune inflammatory diseases and in the tumor microenvironment still need to be precisely delineated. The central goal of this study is to evaluate P2X7 as a therapeutic target in models of experimental autoimmune encephalomyelitis (EAE) and in anti-tumor response. A second goal of this study is to optimize the in vivo targeting of P2X7 in the CNS and in the tumor microenvironment using Nb-based biologics. In both models, we will exploit systemic injections as well as AAV-mediated long-term endogenous production of the Nb-based biologics to better understand the role P2X7 and to evaluate the therapeutic benefits associated with its short and long-term functional modulation. Moreover, we will explore the potential of Fc-engineering and of bispecific-targeting to enhance the effector functions of Nb based biologics. We expect the results of this project to provide valuable new insights into the pathophysiological roles of P2X7 in inflammation and immunity and to validate its relevance as a therapeutic target.

P2X7是一种配体门控离子通道，ARTC2是一种毒素相关的外酶，它们是免疫细胞表面的蛋白，在无菌炎症过程中，它们能感知细胞释放的ATP和NAD+作为内源性危险信号。在髓样细胞中，P2X7是炎症的关键介质。在T细胞上，ARTC2和P2X7调节Treg的功能和存活。我们在之前的一项合作研究中发现，通过激活ARTC2/P2X7轴来消耗调节性T细胞可以用来促进抗肿瘤免疫反应。最近，我们开发了p2x7阻断和p2x7增强纳米体（Nbs）和基于Nb的生物制剂。我们发现，在体内用这些生物制剂阻断P2X7的功能是一种有希望的改善炎症的新治疗策略。这些生物制剂既可以通过反复全身注射给药，也可以通过编码这些Nb的腺相关病毒（AAV）载体在体内转导细胞后继续内源性合成给药。到目前为止，对这些生物制剂的体内药效学，以及它们到达和阻断淋巴器官、炎症组织或肿瘤免疫细胞靶点的能力知之甚少。特别是血脑屏障（BBB）对蛋白质生物制剂到达中枢神经系统（CNS）的靶点构成了天然障碍。此外，P2X7在自身免疫性炎症疾病和肿瘤微环境中的作用仍需要精确描述。本研究的中心目标是评估P2X7作为实验性自身免疫性脑脊髓炎（EAE）模型的治疗靶点和抗肿瘤反应。本研究的第二个目标是使用基于nb的生物制剂优化P2X7在中枢神经系统和肿瘤微环境中的体内靶向性。在这两种模型中，我们将利用全身注射和aav介导的长期内源性nb基生物制剂的生产，以更好地了解P2X7的作用，并评估其短期和长期功能调节相关的治疗益处。此外，我们将探索fc工程和双特异性靶向的潜力，以增强Nb基生物制剂的效应功能。我们期望这个项目的结果能够为P2X7在炎症和免疫中的病理生理作用提供有价值的新见解，并验证其作为治疗靶点的相关性。