IL2-based Immunotherapy for Lupus

基于 IL2 的狼疮免疫疗法

基本信息

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
项目类别：
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

项目摘要

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，但可能伴随感染和毒性，特别是在较长时间使用时。因此，还剩下对安全和更有效的治疗的巨大需求尚未得到满足。众所周知，SLE 患者的特点是调节性 T 细胞减少，并且获得性白细胞介素-2 (IL-2) 缺乏。低剂量重组 IL-2 瞬时治疗可增加调节 T 细胞数量，同时阻断滤泡辅助 T 细胞。因此治疗量减少了自身抗体形成和免疫复合物沉积，而不引起全身免疫抑制。这些数据有力地支持了基于 IL-2 的疗法的开发。重要的是，低剂量 rIL-2 治疗在一项小型临床试验中安全地取得了显着疗效。然而，目前的低剂量rIL-2 疗法的半衰期非常短，会在注射部位引起局部反应，从而产生不必要的副作用几种先天免疫细胞类型的增加，例如自然杀伤细胞和嗜酸性粒细胞。到为了让患者获得理想的治疗效果，我们设计了一种长效 IL-2 类似物 APT602，有望产生低且稳定的循环水平的 IL-2 相关激动剂。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面影响临床效果。重要的是，更好的功效和安全性已在多种动物模型。该 I 期 SBIR 提案的具体目的是确定是否每周两次使用 mAPT602 8周将更有效地阻止100天随访中的疾病进展，在 SLE 小鼠模型中与低剂量 rmIL-2（重组鼠 IL2）进行比较疾病发作。