Preclinical Translational Studies with DRHQ

DRHQ 的临床前转化研究

基本信息

批准号：
10618863
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 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10618863
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 Central Nervous System 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 Macrophage Activation Methamphetamine dependence Middle Cerebral Artery Occlusion Migration Inhibitory Factor Multiple Sclerosis Mus Neurologic Neurologic Deficit Neutralizing antibody assay Pathogenicity Patients Persons Pharmaceutical Preparations Pharmacodynamics Phase Phase I Clinical Trials Phase II Clinical Trials Phosphorylation Phosphorylation Inhibition 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 chemokine commercialization cytokine design disabling disease experience extracellular first-in-human human study immunoregulation in vivo invention manufacture meetings migration monocyte mouse model multiple sclerosis patient neuroprotection neutralizing antibody novel potential biomarker pre-Investigational New Drug meeting 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性致残性疾病，影响美国有40万人，全球250万人，在部门的照顾下有20,000人退伍军人事务。大多数MS个体最初被诊断出患有复发的MS（RRMS），然后甚至过渡到次级渐进式MS（SPM）。当MS个人进入SPM时，神经系统缺陷大约15％的MS患者最初被诊断出患有主要进行性MS（PPM）并显示出越来越多的神经系统缺陷，而无需缓解时期。几乎全部 FDA批准的MS疗法是针对RRMS患者的，并且治疗方案非常有限患有进步的MS的人。一个关键的细胞因子/趋化因子被认为可以推动MS的早期炎症阶段慢性进行阶段是巨噬细胞迁移抑制因子（MIF）。我们设计了有效的生物构造称为RTL1000和第二代衍生物DRHQ，与MIF紧密结合受体，CD74，竞争性抑制MIF结合，并且是下游信号，并且抑制T细胞 IL-2的激活和释放。还发现RTL/DRHQ治疗可促进神经保护并减少急性和慢性EAE的严重程度，MS的小鼠模型。发现RTL1000是安全且容忍的在I期安全试验中，RRMS或SPMS患者的I期安全试验中的剂量60mg。但是，RTL1000包含 MS风险因素的细胞外域HLA-DR2等，因此，FDA有限的RTL1000给药 HLA-DR2阳性患者的临床试验（约占MS总受试者的50％）。我们的第二代结构， DRHQ保留RTL1000的潜在免疫调节活性，但是HLA不变的，因此适合所有人患者。为了用渐进式MS处理DR2阳性和负面个体，我们正在提议 DRHQ及其小鼠同源物DRMQ的关键临床前研究，该研究将使DRHQ前进人类（FIH）1期临床试验。在此功绩审查申请中，我们将评估：1）多室药代动力学； 2）验证相关的生物标志物，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，并抑制IL-2分泌由活化的T细胞诱导； 3）抗药物抗体对DRHQ的潜在中和活性。数据该项目期间收集的将用于支持调查新药（IND）申请 FDA进行了FIH研究。 RTL1000在达到1期临床试验中的先前成功使我们有信心我们将在第1阶段以及第2阶段和3阶段的临床试验中取得成功。