Development of DRα1-MOG-35-55 for treatment of DR2 negative MS subjects

项目总结/摘要 我们最近完成的1期动物研究证明了我们的新的第二代部分的能力， （p）MHC构建体，DRα1-hMOG-35-55，以与亲本相当的效力治疗急性和慢性EAE RTL 1000分子（pDR 2-MOG-35-55）在匹配的DR 2-Tg小鼠和DR 2阴性错配小鼠中的表达。 在达到我们的第一阶段里程碑后，我们的第二阶段应用将产生完全人源化的DRα1-hMOG-35-55 分子和组装必要的临床前数据，以支持与FDA的IND前会议， 将获得，以便能够提交人体I期安全性和耐受性研究。这些数据将 包括药代动力学（PK）、毒代动力学（TK）和潜在的下游效应的表征 抗药物抗体（ADA）的产生。此外，本研究将评估作为体内生物标志物的内在 DRα1-hMOG-35-55抑制外周血单个核细胞（PBMC）CD 74表达的活性， 巨噬细胞移动抑制因子（MIF）的主要细胞受体，与MS疾病有关 在文献和MS受试者的样本中均存在进展。我们提出的研究是按照 临床前开发计划，使RTL 1000人体临床试验，并设计阶段DRα1- hMOG-35-55用于cGMP生产和人体I期临床试验所需的正式临床前研究 科目这些临床前研究支持的临床方案通常遵循 RTL 1000（评价单次给药的安全性的双盲、安慰剂对照、I期、剂量递增研究） RTL 1000在复发缓解型或继发性进行性多发性硬化症受试者中的应用）， 结果表明，RTL 1,000在剂量<60 mg（1，000 µg/kg）时安全且耐受性良好。DRα1-hMOG的剂量- 在人类I期试验中输注的35-55将由与FDA的IND前讨论指导，并将取决于 最小有效剂量（MED）以及最大耐受剂量（MTD）， 在这个提案中的性别。来自我们的I期STTR的数据已经确定，较高剂量的DRα1-hMOG-35-55 是体外抑制T细胞活化和治疗女性与男性慢性EAE所必需的，因此 需要建立单独的MED和重叠的功效曲线以产生共同的剂量范围。 预计这些研究将有助于成功提交IND，以启动DRα1- MS受试者中的hMOG-35-55。

PROJECT SUMMARY/ABSTRACT Our recently completed Phase 1 animal studies demonstrated the ability of our novel second generation partial (p)MHC construct, DRα1-hMOG-35-55, to treat acute and chronic EAE with potency comparable to the parent RTL1000 molecule (pDR2-MOG-35-55) in matched DR2-Tg mice and in DR2 negative mismatched mice. Having met our Phase 1 milestones, our Phase II application will produce a fully humanized DRα1-hMOG-35-55 molecule and assemble preclinical data necessary to support a pre-IND meeting with FDA, at which critical input will be obtained in order to enable the filing of a Phase 1 safety and tolerability study in humans. These data will include characterization of the pharmacokinetics (PK), toxicokinetics (TK) and downstream effects of potential anti-drug antibody (ADA) production. Additionally, this study will assess as an in vivo biomarker the intrinsic activity of DRα1-hMOG-35-55 to inhibit peripheral blood mononuclear cell (PBMC) expression of CD74, the major cellular receptor for macrophage migration inhibitory factor (MIF) that has been implicated in MS disease progression both in the literature and in samples from MS subjects. Our proposed studies are patterned after the preclinical development plan that enabled RTL1000 human clinical trials and are designed to stage DRα1- hMOG-35-55 for cGMP manufacture and formal preclinical studies necessary for a Phase 1 clinical trial in human subjects. The clinical protocol to be supported by these preclinical studies will generally follow that used for RTL1000 (Double-Blind, Placebo-Controlled, Phase 1, Dose-Escalation Study of the Safety of a Single Dose of RTL1000 in Subjects with Relapsing Remitting or Secondary Progressive Multiple Sclerosis) which demonstrated that RTL1000 was safe and well tolerated at doses <60mg (1,000µg/kg). Doses of DRα1-hMOG- 35-55 to be infused in the human Phase 1 trial will be guided by pre-IND discussions with FDA and will depend on the minimal effective dose (MED) as well as the maximum tolerated dose (MTD) to be determined for both sexes in this proposal. Data from our Phase 1 STTR has established that a higher dose of DRα1-hMOG-35-55 is required for inhibiting T cell activation in vitro and for treatment of chronic EAE in females vs. males, thus necessitating establishment of separate MEDs and overlapping efficacy curves to yield a common dose range. It is anticipated that these studies will facilitate filing of a successful IND for initiating therapeutic trials with DRα1- hMOG-35-55 in subjects with MS.