Preclinical Translational Studies with DRHQ

DRHQ 的临床前转化研究

• 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
• 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

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.

项目概要/摘要： 多发性硬化症（MS）是年轻人中最常见的神经系统致残性疾病， 在美国有40万人，全世界有250万人，其中2万人在美国卫生部的照顾下， 退伍军人事务部大多数MS患者最初被诊断为复发缓解型MS（RRMS）， 最终转变为继发性进展性MS（SPMS）。当MS个体进入SPMS时，神经功能缺损 随着时间的推移逐渐恶化。大约15%的MS患者最初被诊断为原发性 进行性MS（PPMS），并显示出不断增加的神经功能缺损而无复发期。几乎所有的 FDA批准的MS治疗方法适用于RRMS患者， 一种关键的细胞因子/趋化因子，被认为是驱动MS早期炎症阶段的关键因子， 慢性进展期是巨噬细胞移动抑制因子（MIF）。我们设计了一个强大的 一种名为RTL 1000的生物构建体和一种第二代衍生物DRhQ，它们与MIF紧密结合 受体CD 74，竞争性抑制MIF结合及其下游信号传导，以及抑制T细胞 IL-2的激活和释放。还发现RTL/DRhQ治疗促进神经保护并减少神经元损伤。 在急性和慢性EAE的严重程度方面，发现MS的小鼠模型RTL 1000是安全的并且耐受良好， 在RRMS或SPMS患者中进行的I期安全性试验中，剂量≥ 60 mg。但是，RTL 1000包含 MS风险因子HLA-DR 2的细胞外结构域，因此，FDA限制在MS患者中施用RTL 1000。 HLA-DR 2阳性患者（约占MS受试者总数的50%）的临床试验。我们的第二代结构， DRhQ保留了RTL 1000的有效免疫调节活性，但HLA不变，因此适用于所有 患者为了治疗DR 2阳性和阴性的进行性MS患者，我们建议 DRhQ及其小鼠同源物DRmQ的重要临床前研究，这将使DRhQ向第一个 人体（FIH）1期临床试验。在本Merit Review应用程序中，我们将评价：1）多房室 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， 磷酸化细胞外相关激酶（pERK 1/2）和相关细胞因子，以及抑制IL-2分泌 由活化的T细胞诱导;和3）针对DRhQ的抗药物抗体的潜在中和活性。数据 本项目期间收集的信息将用于支持研究性新药（IND）申请的提交， FDA进行FIH研究。RTL 1000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、2期和3期临床试验中取得成功。