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

调节性T细胞(Tregs)是自身免疫性疾病和炎症性疾病的重要治疗靶点，参与免疫反应的调节。低剂量的白介素2(IL-2，IL-2LD)在体内刺激和扩大Treg。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半衰期和活性的第二代IL-2突变蛋白。我们的目标是通过使用氧化特异性表位(OSE)的抗体(Abs)来开发针对炎症部位的第三代IL-2(IL-2IT)，OSE既是炎症的通用标志，也是炎症的介质。IL-2-OSEAb融合蛋白可能通过抗体中和促炎性OSE和IL-2刺激Treg的双重作用机制来抑制局部炎症。作为概念验证，我们设计了第一个IL-2IT，其中IL-2N88R突变蛋白与来自原型抗OSE抗体的sc Fv融合。这种IL-2IT(I)与IL-2受体和OSE结合，(Ii)具有延长的半衰期，(Iii)与天然IL-2相比在小鼠中具有更好的治疗效果。我们的总体目标是通过测试不同的抗OSE抗体与IL-2和IL-2突变蛋白的组合来设计优化的IL-2IT，并完成其在小鼠和猕猴的临床前开发。我们将验证IL-2IT在心血管疾病(CVD)中的使用，即动脉粥样硬化、脉管炎、心肌梗死和SLE相关性CVD，因为这些条件已被证明通过在小鼠中输注Treg、本地IL-2和OSE-Abs而得到改善。在使用IL-2、OSE-Abs、心血管疾病模型和本地IL-2临床试验方面的领先专家的支持下，IL-2IT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，这些疾病是导致死亡和发病的主要原因。此外，它将验证更广泛的概念，即将任何治疗分子靶向炎症部位。

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.