Preclinical Translational Studies with DRHQ

DRHQ 的临床前转化研究

基本信息

批准号：
10454781
负责人：
ARTHUR A. VANDENBARK
金额：
--
依托单位：
PORTLAND VA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10454781
关键词：
Acute Address Affect Antibodies Area B-Lymphocytes Binding Biological Biological Assay Biological Markers Blocking Antibodies Blood CCL2 gene CCL4 gene CNS Demyelinating Autoimmune Diseases Caring Cells Chronic Clinical Clinical Trials Clinical Trials Design Coupled Data Dendritic Cells Development Diagnosis Dose Drug Kinetics Endothelial Cells Excretory function Experimental Autoimmune Encephalomyelitis Extracellular Domain FDA approved Feedback Funding Agency Generations Goals Grant HLA-DR2 Antigen Half-Life Haplotypes Homologous Gene Human Immunoglobulin G Immunoglobulin M Individual Inflammatory Infusion procedures Injections Interleukin-10 Interleukin-2 Interleukin-6 Investigational Drugs Investigational New Drug Application Label Laboratories Legal patent Link MHC Class II Genes Macrophage Activation Methamphetamine dependence Middle Cerebral Artery Occlusion Migration Inhibitory Factor Multiple Sclerosis Mus Neuraxis Neurologic Neurologic Deficit Neutralizing antibody assay Pathogenicity Patients Persons Pharmaceutical Preparations Pharmacodynamics Phase Phase I Clinical Trials Phase II Clinical Trials Phase III Clinical Trials Phosphotransferases Plasma Primary Progressive Multiple Sclerosis Process Relapse Relapsing-Remitting Multiple Sclerosis Research Priority Resources Risk Factors Rodent Model Role Safety Secondary Progressive Multiple Sclerosis Secondary to Serum Severities Signal Transduction Small Business Technology Transfer Research Stroke T-Cell Activation T-Lymphocyte TNF gene Therapeutic Therapeutic Effect Time Tissues Toxicology Translating Traumatic Brain Injury Treatment Efficacy United States United States Department of Veterans Affairs United States National Institutes of Health Veterans antibody detection base chemokine commercialization cytokine design disabling disease experience extracellular first-in-human human study immunoregulation in vivo invention macrophage meetings migration monocyte mouse model multiple sclerosis patient neuroprotection neutralizing antibody novel potential biomarker pre-clinical preclinical study programs receptor research clinical testing stroke model success translational study young adult

项目摘要

Project Summary/Abstract: Multiple Sclerosis (MS) is the most common neurologic disabling disease among young adults, affecting over 400,000 people in the United States, 2.5 million worldwide and 20,000 under the care of the Department of Veterans Affairs. Most MS individuals are initially diagnosed with relapsing-remitting MS (RRMS) and then eventually transition to secondary progressive MS (SPMS). When MS individuals enter SPMS, neurologic deficits progressively worsen over time. Approximately 15% of people with MS are initially diagnosed with primary progressive MS (PPMS) and display increasing neurologic deficits without periods of relapse. Almost all the FDA approved therapeutics for MS are for patients with RRMS and there are very limited therapeutic options for people with progressive MS. A key cytokine/chemokine thought to drive the early inflammatory stage of MS to a chronic progressive phase is macrophage migration inhibitory factor (MIF). We have designed a potent biological construct called RTL1000 and a second-generation derivative, DRhQ, that bind tightly to the MIF receptor, CD74, and competitively inhibit MIF binding and it’s downstream signaling as well as inhibit T cell activation and release of IL-2. RTL/DRhQ treatment was also found to promote neuroprotection and reduce the severity of acute and chronic EAE, a mouse model of MS. RTL1000 was found to be safe and well tolerated at doses 60 mg in a Phase I safety trial in patients with either RRMS or SPMS. However, RTL1000 contains the extracellular domains of the MS risk factor, HLA-DR2 and as such, the FDA limited RTL1000 administration in the clinical trial to HLA-DR2 positive patients (~50% of total MS subjects). Our second generation construct, DRhQ, retains the potent immunomodulatory activity of RTL1000 but is HLA invariant and thus suitable for all patients. In order to treat both DR2 positive and negative individuals with progressive MS, we are proposing crucial preclinical studies of DRhQ and its mouse homologue, DRmQ, which will advance DRhQ towards a First- In-Human (FIH) Phase 1 clinical trial. In this Merit Review application, we will evaluate: 1) multi-compartmental pharmacokinetics; 2) validate relevant biomarkers, including infusion induced cytokine release, inhibition of phosphorylated extracellular-related kinase (pERK1/2) and related cytokines, and inhibition of IL-2 secretion induced by activated T cells; and 3) potential neutralizing activity of anti-drug antibodies against DRhQ. The data collected during this project will be used to support the filing of an Investigational New Drug (IND) application to the FDA for a FIH study. The previous success of RTL1000 in reaching a Phase 1 clinical trial gives us confidence that we will achieve success in Phase 1 as well as Phase 2 and 3 clinical trials with DRhQ.

项目摘要/摘要：多发性硬化症 (MS) 是年轻人中最常见的神经功能障碍疾病，影响超过美国有 400,000 人，全世界有 250 万人，其中 20,000 人受到卫生部的照顾退伍军人事务部。大多数多发性硬化症患者最初被诊断为复发缓解型多发性硬化症 (RRMS)，然后被诊断为患有复发缓解型多发性硬化症 (RRMS)。最终转变为继发性进行性多发性硬化症 (SPMS) 当多发性硬化症个体进入 SPMS 时，会出现神经功能缺损。随着时间的推移，病情逐渐恶化。大约 15% 的多发性硬化症患者最初被诊断为原发性多发性硬化症。进行性多发性硬化症 (PPMS) 并表现出不断增加的神经功能缺损，但几乎没有复发期。 FDA 批准的多发性硬化症治疗方法适用于 RRMS 患者，而针对多发性硬化症的治疗选择非常有限患有进行性多发性硬化症的人。被认为是导致多发性硬化症早期炎症阶段发展的关键细胞因子/趋化因子。慢性进行性阶段是巨噬细胞迁移抑制因子（MIF）。称为 RTL1000 的生物构建体和第二代衍生物 DRhQ，与 MIF 紧密结合受体 CD74 并竞争性抑制 MIF 结合及其下游信号传导以及抑制 T 细胞还发现 RTL/DRhQ 治疗的激活和释放可以促进神经保护并减少急性和慢性 EAE 的严重程度，MS 小鼠模型被发现是安全且耐受性良好的。在 RRMS 或 SPMS 患者的 I 期安全性试验中，剂量≤60 mg 然而，RTL1000 包含 MS 危险因子 HLA-DR2 的细胞外结构域，因此 FDA 限制 RTL1000 的给药针对 HLA-DR2 阳性患者（约占 MS 受试者总数的 50%）的临床试验， DRhQ，保留了 RTL1000 的强大免疫调节活性，但 HLA 不变，因此适合所有人群为了治疗患有进行性多发性硬化症的 DR2 阳性和阴性患者，我们建议。 DRhQ 及其小鼠同源物 DRmQ 的重要临床前研究，这将推动 DRhQ 迈向首个人体 (FIH) 1 期临床试验在此优点审查申请中，我们将评估：1) 多室。 2) 验证相关生物标志物，包括输注诱导的细胞因子释放、抑制磷酸化细胞外相关激酶 (pERK1/2) 和相关细胞因子，以及抑制 IL-2 分泌由活化的 T 细胞诱导；3) 抗 DRhQ 药物抗体的潜在中和活性。该项目期间收集的资金将用于支持提交新药研究 (IND) 申请 FDA 进行 FIH 研究，RTL1000 之前在 1 期临床试验中的成功给了我们信心。我们将在 DRhQ 的 1 期以及 2 期和 3 期临床试验中取得成功。