Preclinical Translational Studies with DRHQ

DRHQ 的临床前转化研究

• 批准号: 10015855
• 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/10015855
• 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; Detection; 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; Pathogenicity; Patients; 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 National Institutes of Health; Veterans; 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 最终转变为继发进展型多发性硬化症（SPMS）。当 MS 个体进入 SPMS 时，神经功能缺陷 随着时间的推移逐渐恶化。大约 15% 的多发性硬化症患者最初被诊断为原发性 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，且无复发期。几乎所有的 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。一种关键的细胞因子/趋化因子被认为可驱动 MS 的早期炎症阶段 慢性进展期是巨噬细胞迁移抑制因子（MIF）。我们设计了一个强大的 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 IL-2的激活和释放。 RTL/DRhQ 治疗也被发现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。 RTL1000被发现是安全的并且耐受性良好 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。我们的第二代结构， 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 患者。为了治疗患有进行性多发性硬化症的 DR2 阳性和阴性个体，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）多隔室 药代动力学； 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)针对DRhQ的抗药物抗体的潜在中和活性。数据 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之前成功进入一期临床试验给了我们信心 我们将在 DRhQ 的 1 期以及 2 期和 3 期临床试验中取得成功。