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.

全身性红斑狼疮（SLE）是一种原型自身免疫性疾病，至少影响1.5 百万美国人。当前的免疫抑制治疗是有效的，但可以伴随感染和毒性，尤其是在较长时间内应用时。因此，仍然存在对安全，更有效的治疗的重要需求。众所周知，SLE患者的标志性由调节性T细胞降低并获得白介素2（IL-2）的缺陷。低剂量重组IL-2的瞬时处理增加在阻断T卵泡辅助细胞的同时，调节性T细胞数。因此，治疗减少了自身抗体形成和免疫复合物沉积，而无需诱导全身免疫抑制。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治疗在一项小型临床试验中，安全达到了显着的功效。但是，当前的低剂量RIL-2 治疗的半衰期很短，在注射部位引起局部反应，有不必要的增加了几种先天免疫细胞类型，例如天然杀伤细胞和嗜酸性粒细胞。到在患者中获得理想的结果，我们设计了一个长效的IL-2类似物APT602，该模拟有望产生与IL-2相关的激动剂的低和稳定循环水平。创新的药物候选者将有选择性刺激调节性T细胞，同时最大程度地减少阴性临床效果。重要的是，已经证明了更好的功效和安全性多种动物模型。该阶段I SBIR提案的具体目的是确定是否每周两次治疗 MAPT602持续8周将更有效地停止疾病进展100天的随访，与低剂量的RMIL-2（重组鼠IL2）相比疾病发作。