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

开发 DRα1-MOG-35-55 用于治疗 DR2 阴性多发性硬化症受试者

• 批准号: 9345703
• 负责人: ARTHUR A. VANDENBARK
• 金额: $ 70.27万
• 依托单位: VIROGENOMICS BIODEVELOPMENT, INC.
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-02-01 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9345703
• 关键词: Acute; Address; Animals; Antibodies; Antibody Formation; Binding; Biochemical; Biological; Biological Markers; Biological Pharmacology; Brain; Buffers; C57BL/6 Mouse; CD3 Antigens; Cell Proliferation; Chronic; Clinical; Clinical Data; Clinical Protocols; Clinical Trials Design; Complement; Cyclic GMP; Data; Development; Development Plans; Disease Progression; Dose; Double-Blind Method; Down-Regulation; Drug Kinetics; Evaluation; Experimental Autoimmune Encephalomyelitis; Female; Generations; Goals; Half-Life; Histocompatibility Antigens Class II; Histologic; Human; Immunologics; In Vitro; Investigational Drugs; Investigational New Drug Application; Label; Lipopolysaccharides; Literature; Lymphocyte antigen; Magnetic Resonance Imaging; Major Histocompatibility Complex; Maximum Tolerated Dose; Migration Inhibitory Factor; Multiple Sclerosis; Mus; No-Observed-Adverse-Effect Level; Parents; Patients; Pattern; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Placebo Control; Placebos; Plasma; Positioning Attribute; Production; Proteins; Relapse; Safety; Sampling; Secondary Progressive Multiple Sclerosis; Signal Transduction; Small Business Technology Transfer Research; Solubility; Spinal Cord; System; T-Cell Activation; Testing; Therapeutic Trials; Time; Tissues; Toxic effect; Toxicokinetics; clinical investigation; cohort; fast protein liquid chromatography; human subject; immunogenic; in vivo; macrophage migration inhibitory factor receptor; male; manufacturing process; meetings; neutralizing antibody; novel; pre-clinical; preclinical development; preclinical study; response; safety study; sex

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.

项目摘要/摘要 我们最近完成的第一阶段动物研究证明了我们新型第二代部分的能力 （p）MHC构造，DRα1-HMOG-35-55，以与父的效力治疗急性和慢性EAE 匹配的DR2-TG小鼠和DR2负不匹配的小鼠中的RTL1000分子（PDR2-MOG-35-55）。 达到了我们的1阶段里程碑后，我们的II期应用将产生完全人性化的DRα1-HMOG-35-55 分子并组装支持与FDA预先交往的必要的临床前数据，其中关键输入 为了使人类的1阶段安全性和耐受性研究能够获得。这些数据将 包括药代动力学（PK），有毒动力学（TK）的表征和潜力的下游效应 抗药物抗体（ADA）生产。此外，这项研究将评估为体内生物标志物固有的 DRα1-HMOG-35-55的活性抑制CD74的外周血单核细胞（PBMC）的活性 巨噬细胞迁移抑制因子（MIF）的主要细胞受体已在MS疾病中暗示 文献和来自MS受试者的样本中的进展。我们提出的研究是在图案的 临床前开发计划启用了RTL1000人类临床试验，旨在进行DRα1-阶段 HMOG-35-55用于CGMP制造和正式临床前研究，用于人类1期临床试验所必需的 主题。这些临床前研究需要支持的临床方案通常会遵循 RTL1000（双盲，安慰剂对照，第1阶段，剂量降低研究 RTL1000在复发恢复或次要进行性多发性硬化症的受试者中） 证明RTL1000的安全性和耐受性良好，剂量<60mg（1,000µg/kg）。剂量的drα1-hmog- 35-55在人类1期试验中被感染将由与FDA进行预先讨论的指导，并将取决于 在最小有效剂量（MED）以及最大耐受剂量（MTD）上 性别中的性别。我们1阶段STTR的数据确定，较高剂量的DRα1-HMOG-35-55 在体外抑制T细胞激活和治疗女性与雄性的慢性EA所必需 需要建立单独的药物和重叠效率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IDS，以启动DRα1-的治疗试验 MS受试者的HMOG-35-55。