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， 数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，特别是在较长时间内使用时。因此， 对安全和更有效的治疗的显著未满足的需求。 众所周知，SLE患者的标志是调节性T细胞减少， 白细胞介素-2（IL-2）缺乏。低剂量重组IL-2的短暂治疗增加了 调节T细胞数量，同时阻断T滤泡辅助细胞。因此，治疗减少 自身抗体形成和免疫复合物沉积而不诱导全身免疫抑制。 这些数据强烈支持基于IL-2的治疗的发展。重要的是，低剂量rIL-2治疗 在小型临床试验中安全地取得了显著疗效。然而，目前的低剂量rIL-2 治疗具有非常短的半衰期，并在注射部位引起局部反应， 几种先天免疫细胞类型增加，如自然杀伤细胞和嗜酸性粒细胞。到 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，APT 602， 有望产生低且稳定的IL-2相关激动剂循环水平。创新药 候选者将能够选择性刺激调节性T细胞，同时最大限度地减少负性T细胞。 临床效果重要的是，已证明在以下方面具有更好的疗效和安全性特征： 多种动物模型。 这一I期SBIR提案的具体目的是确定每周两次使用 mAPT 602治疗8周将更有效地阻止疾病进展100天的随访， 与SLE小鼠模型中低剂量rmIL-2（重组鼠IL-2）相比， 发病