TiilT - Preclinical development of a 3rd-generation interleukin-2 targeted to inflammatory sites

TiilT - 针对炎症部位的第三代白细胞介素 2 的临床前开发

• 批准号: 10081719
• 金额: $ 43.17万
• 依托单位: KING'S COLLEGE LONDON
• 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=10081719
• 关键词: TiilT; Preclinical; development; 3rd; generation

As major players in the regulation of immune responses, regulatory T cells (Tregs) are important therapeutic targets for autoimmune and inflammatory diseases. Interleukin-2 (IL-2) used at low doses (IL-2LD) stimulate and expand Tregs in vivo. While 1st-generation native IL-2LD are currently under extensive clinical evaluation, pharmaceutical companies are developing 2nd-generation IL-2 muteins with improved half-life and activity. We aim to develop 3rd-generation IL-2 specifically targeting inflammatory sites (IL-2IT) by using antibodies (Abs) against oxidation specific epitopes (OSE) that are both universal markers and mediators of inflammation. IL-2-OSEAb fusion proteins should allow dampening of local inflammation by a double-hit mechanism involving Ab neutralization of proinflammatory OSE and IL-2 stimulation of Tregs. As a proof of concept, we designed a first IL-2IT in which an IL-2N88R mutein is fused to an sc Fv from a prototypic anti-OSE Ab. This IL-2IT (i) binds to IL-2 receptors and OSE, (ii) has an extended half-life and (iii) superior therapeutic efficacy compared to native IL-2 in mice. Our general objectives are to design an optimized IL-2IT by testing combinations of different anti-OSE Ab with IL-2 and IL-2 muteins, and to complete its preclinical development in mice and macaques. We will validate the use of IL-2IT in cardiovascular diseases (CVD), i.e. atherosclerosis, vasculitis, myocardial infarction and SLE associated CVD, as these conditions have been shown to be improved by Treg infusions, native IL-2 and OSE-Abs in mice. Carried by leading experts in the use IL-2, OSE-Abs, models of CVD, and clinical trials with native IL-2, the successful validation of an IL-2IT will open a new era for highly selective and effective immunotherapies based on Treg stimulation for diseases that represent a leading cause of death and morbidity. Furthermore, it will validate the broader concept of targeting any therapeutic molecule to inflammatory sites.

调节性T细胞（Regulatory T cells，Tcells）是免疫应答调节的主要参与者，是自身免疫性疾病和炎症性疾病的重要治疗靶点。低剂量使用的白细胞介素-2（IL-2 LD）在体内刺激和扩增TcB。虽然第一代天然IL-2LD目前正在进行广泛的临床评估，但制药公司正在开发具有改善的半衰期和活性的第二代IL-2突变蛋白。我们的目标是开发第三代IL-2特异性靶向炎症部位（IL-2 IT），通过使用抗氧化特异性表位（OSE）的抗体（Ab），这是通用的标志物和炎症介质。IL-2-OSEAb融合蛋白应允许通过涉及Ab中和促炎性OSE和IL-2刺激TGFAP的双重作用机制来抑制局部炎症。作为概念证明，我们设计了第一种IL-2 IT，其中IL-2N 88 R突变蛋白与来自原型抗OSE Ab的sc Fv融合。该IL-2 IT（i）结合IL-2受体和OSE，（ii）具有延长的半衰期，和（iii）与小鼠中的天然IL-2相比具有上级治疗功效。我们的总体目标是通过测试不同抗OSE Ab与IL-2和IL-2突变蛋白的组合来设计优化的IL-2 IT，并在小鼠和猕猴中完成其临床前开发。我们将验证IL-2 IT在心血管疾病（CVD）（即动脉粥样硬化、血管炎、心肌梗死和SLE相关CVD）中的用途，因为这些病症已显示通过Treg输注、天然IL-2和OSE-Ab在小鼠中得到改善。在使用IL-2、OSE-Abs、CVD模型和天然IL-2临床试验的领先专家的带领下，IL-2 IT的成功验证将为基于Treg刺激的高度选择性和有效的免疫疗法开辟一个新时代，用于代表死亡和发病主要原因的疾病。此外，它将验证将任何治疗分子靶向炎症部位的更广泛的概念。