IL2-based Immunotherapy for Lupus

基于 IL2 的狼疮免疫疗法

• 批准号: 9253700
• 负责人: RIDONG CHEN
• 金额: $ 22.5万
• 依托单位: APT THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-14 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9253700
• 关键词: Adverse effects; Affect; Affinity; Agonist; Aldesleukin; American; Animal Model; Antigen-Antibody Complex; Applications Grants; Autoantibodies; Autoantigens; Autoimmune Diseases; Autoimmune Process; B-Lymphocytes; Binding; Binding Sites; Blood Vessels; CD3 Antigens; CD4 Positive T Lymphocytes; CD8B1 gene; Cell Count; Cell Line; Cell physiology; Cells; Chimeric Proteins; Chinese Hamster Ovary Cell; Clinical Trials; Data; Deposition; Development; Diabetes Mellitus; Disease; Disease Progression; Disease remission; Dose; Engineering; Equilibrium; Eragrostis; Escherichia coli; Female; Generations; Half-Life; Helper-Inducer T-Lymphocyte; Human; IL17 gene; IL2 gene; IL2RA gene; Immune; Immune system; Immunosuppression; Immunosuppressive Agents; Immunotherapy; In Vitro; Infection; Inflammation; Injection of therapeutic agent; Insulin; Insulin-Dependent Diabetes Mellitus; Interleukin-2; Kidney; Lupus; Maintenance; Mammalian Cell; Mediating; Memory; Modeling; Mus; Mutation; NK Cell Activation; Natural Killer Cells; Nephritis; Non obese; Nuclear; Onset of illness; Organ; Outcome; Pancreas; Patients; Pharmaceutical Preparations; Phase; Phenotype; Plasma; Production; Proteinuria; Reaction; Recombinant Interleukin-2; Recombinant Proteins; Recombinants; Refractory; Regulatory T-Lymphocyte; Relapse; Renal carcinoma; Safety; Self Tolerance; Serum Albumin; Signal Transduction; Site; Small Business Innovation Research Grant; Syndrome; System; Systemic Lupus Erythematosus; T-Lymphocyte; Therapeutic; Therapeutic Effect; Thymus Gland; Time; Toxic effect; Work; analog; base; cell type; clinical effect; cytokine; design; drug candidate; effective therapy; eosinophil; follow-up; immunogenic; improved; innovation; melanoma; molecular size; mortality; mouse model; novel; prevent; receptor; response

Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease that affects at least 1.5 million Americans. Current immunosuppressive treatments are effective but can be accompanied by infections and toxicity, especially when applied over a longer period of time. Hence, there remains a significant unmet need for safe and more effective treatments. It is well established that patients with SLE are marked by reduced regulatory T cells and acquired deficiency of interleukin-2 (IL-2). Transient treatment with low-dose recombinant IL-2 increases regulatory T cell number while blocking T follicular helper cells. Hence, the treatment reduced autoantibody formation and immune complex deposition without inducing systemic immune suppression. These data strongly support development of IL-2 based therapy. Importantly, low-dose rIL-2 therapy safely achieved significant efficacy in a small clinical trial. However, current low-dose rIL-2 therapy has a very short half-life and causes local reaction at injection sites, with an unwanted increase in several innate immune cell types such as natural killer cells and eosinophils. To obtain ideal outcomes in patients, we have designed a long-acting IL-2 analog, APT602, that promises to generate low and stable circulating levels of IL-2 related agonist. The innovative drug candidate will enable selective stimulation of regulatory T cells while minimizing negative clinical effects. Importantly, a better efficacy and safety profile has been demonstrated in multiple animal models. The specific aim of this Phase I SBIR proposal is to determine whether twice weekly treatment with mAPT602 for 8 weeks will more effectively halt the disease progression for 100 days of follow-up, compared with low-dose rmIL-2 (recombinant murine IL2) in the mouse model of SLE at the time of disease onset.

系统性红斑狼疮(SLE)是一种典型的自身免疫性疾病，影响至少1.5 百万美国人。目前的免疫抑制治疗是有效的，但可能伴随着 感染和毒性，尤其是在较长时间使用时。因此，有遗迹 对安全和更有效的治疗的重大未得到满足的需求。 众所周知，SLE患者以调节性T细胞减少和后天获得性T细胞为标志 白介素2(IL-2)缺乏。小剂量重组IL-2可增加短暂性治疗 调节T细胞数量，同时阻断T滤泡辅助细胞。因此，治疗减少了 自身抗体的形成和免疫复合体的沉积，而不会引起全身免疫抑制。 这些数据有力地支持了基于IL-2的治疗的发展。重要的是，小剂量rIL-2治疗 在一项小型临床试验中安全地取得了显著的疗效。然而，目前低剂量的rIL-2 治疗的半衰期很短，并在注射部位引起局部反应，有不必要的 几种先天免疫细胞类型的增加，如自然杀伤细胞和嗜酸性粒细胞。至 为了在患者中获得理想的结果，我们设计了一种长效IL-2类似物APT602，它 有望产生低水平和稳定的IL-2相关激动剂。创新药物 候选者将实现对调节性T细胞的选择性刺激，同时将负面影响降至最低 临床效果。重要的是，更好的有效性和安全性已在 多种动物模型。 这项第一阶段SBIR建议的具体目标是确定是否每周两次使用 MAPT602持续8周将更有效地阻止疾病进展100天的随访， 与小剂量rmIL-2(重组小鼠IL-2)在系统性红斑狼疮小鼠模型中的比较 疾病发作。