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的第二代部分 (P)MHC构建物，Drα1-hmog-35-55，用于治疗急性和慢性EAE，其效力与母体相当 RTL1000分子(pDR2-MOG-35-55)在配对的DR2-TG小鼠和DR2阴性的失配小鼠中表达。 在达到我们的第一阶段里程碑之后，我们的第二阶段应用程序将产生一个完全人性化的DRα1-hmog-35-55 分子和收集必要的临床前数据，以支持与FDA的IND前会议，在该会议上，关键输入 将获得，以便能够在人体上进行第一阶段安全性和耐受性研究。这些数据将 包括表征药物动力学(PK)、毒代动力学(TK)和潜在的下游效应 抗药物抗体(ADA)生产。此外，这项研究将评估作为体内生物标记物的内在 DR-α1-hMOG-35-55抑制外周血单个核细胞CD74CD74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病的关系 在文献和MS受试者的样本中都取得了进展。我们建议的研究是仿效的 启用RTL1000人体临床试验的临床前开发计划，旨在将DRα1- 用于生产cGMP的hMOG-35-55和人体一期临床试验所需的正式临床前研究 研究对象。这些临床前研究支持的临床方案通常将遵循用于 RTL1000(双盲，安慰剂对照，第1阶段，单剂量安全性的剂量-递增研究 复发缓解期或继发性进展性多发性硬化症患者的RTL1000) 证明RTL1000在60毫克(1,000微克/公斤)剂量下是安全和耐受性良好的。DRα1-hmog的剂量- 将在人类第一阶段试验中输注的35-55将由IND前与FDA的讨论指导，并将取决于 关于确定两者的最小有效剂量(MED)和最大耐受剂量(MTD) 这项提案中的性别。来自我们第一阶段研究的数据已经证实，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男性慢性EAE所需的，因此 有必要建立单独的药物和重叠的疗效曲线，以产生共同的剂量范围。 预计这些研究将有助于申请成功的IND，以启动DRα1- HMOG-35-55在MS受试者中的表达