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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/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药物的能力 (p)MHC 构建体 DRα1-hMOG-35-55，用于治疗急性和慢性 EAE，其效力与母体相当匹配的 DR2-Tg 小鼠和 DR2 阴性不匹配小鼠中的 RTL1000 分子 (pDR2-MOG-35-55)。在达到第一阶段里程碑后，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 举行的 IND 前会议，其中关键输入获得这些数据是为了提交人类第一阶段安全性和耐受性研究。包括药代动力学 (PK)、毒代动力学 (TK) 和潜在下游效应的表征此外，本研究将评估作为体内生物标志物的内在生物标志物。 DRα1-hMOG-35-55 抑制外周血单核细胞 (PBMC) CD74 表达的活性，巨噬细胞迁移抑制因子 (MIF) 的主要细胞受体，与多发性硬化症有关无论是在文献中还是在多发性硬化症受试者的样本进展中，我们提出的研究都是以这种方式进行的。临床前开发计划使 RTL1000 人体临床试验成为可能，旨在分阶段 DRα1- hMOG-35-55 用于 cGMP 生产和人体 1 期临床试验所需的正式临床前研究这些临床前研究支持的临床方案通常遵循用于受试者的临床方案。 RTL1000（单剂量安全性的双盲、安慰剂对照、第一阶段、剂量递增研究） RTL1000 用于复发缓解型或继发性进行性多发性硬化症受试者）证明 RTL1000 在 DRα1-hMOG-剂量<60mg（1,000μg/kg）时是安全的且耐受性良好。 35-55 将在人体 1 期试验中输注，将以与 FDA 的 IND 前讨论为指导，并将取决于确定两者的最小有效剂量（MED）以及最大耐受剂量（MTD）我们第一阶段 STTR 的数据表明，DRα1-hMOG-35-55 的剂量更高。是抑制体外 T 细胞活化以及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 申请，以启动 DRα1- 的治疗试验 MS 受试者中的 hMOG-35-55。