Preclinical Translational Studies 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系统致残性疾病，影响超过 美国有40万人，全世界有250万人，有2万人由卫生部照顾 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)，然后 最终转变为继发性进行性多发性硬化症(SPMS)。当MS患者进入SPMS时，神经功能障碍 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 进行性多发性硬化症(PPMS)，表现为神经功能缺失增加，无复发期。几乎所有的 FDA批准的治疗多发性硬化症的药物是针对RRMS患者的，治疗选择非常有限 进行性多发性硬化症患者A关键细胞因子/趋化因子被认为推动多发性硬化症早期炎症阶段 巨噬细胞移动抑制因子(MIF)是一个慢性进展期。我们设计了一种强有力的 名为RTL1000的生物结构和与MIF紧密结合的第二代衍生物DRhQ 受体CD74和竞争性抑制MIF结合及其下游信号转导和抑制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和减少 急性和慢性EAE的严重性，RTL1000女士的小鼠模型被发现是安全的，并且耐受性良好 对患有RRMS或SPMS的患者进行I期安全性试验，剂量为60 mg的。但是，RTL1000包含 多发性硬化症危险因子的胞外结构域，人类白细胞抗原-DR2，因此，FDA限制RTL1000在 对人类白细胞抗原DR2阳性患者(约占MS患者总数的50%)的临床试验。我们的第二代结构， DRhQ，保留了RTL1000强大的免疫调节活性，但具有HLA不变性，因此适用于ALL 病人。为了同时治疗DR2阳性和阴性的进行性多发性硬化症患者，我们建议 DRhQ及其小鼠同源物DRmQ的关键临床前研究将推动DRhQ走向第一个- 人内(FIH)1期临床试验。在此Merit Review应用程序中，我们将评估：1)多分区 药代动力学；2)验证相关生物标志物，包括输液诱导的细胞因子释放，抑制 PERK1/2及其相关细胞因子与IL-2分泌的抑制 由活化的T细胞诱导；3)抗DRhQ的抗药物抗体的潜在中和活性。数据 在本项目期间收集的资金将用于支持提交研究新药(IND)申请，以 美国食品和药物管理局进行了一项FIH研究。RTL1000之前在一期临床试验中的成功给了我们信心 我们将在DRhQ的第一阶段以及第二阶段和第三阶段临床试验中取得成功。

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.