Clinical Translation of a Neuron Protective Recombinant Human Antibody

神经元保护性重组人抗体的临床转化

• 批准号: 8090560
• 负责人: MOSES RODRIGUEZ
• 金额: $ 23.66万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8090560
• 关键词: Acute; Address; Adverse effects; Aftercare; Animal Model; Animals; Antibodies; Antigens; Autoimmune Process; Autoimmunity; Axon; Binding; Biological Assay; Biological Preservation; Blood - brain barrier anatomy; Brain; Brain Stem; Cell Death; Cell Line; Cells; Cessation of life; Cholesterol; Chronic; Clinical; Clinical Research; Clinical Trials; Commit; Cultured Cells; Data; Demyelinating Diseases; Disease; Disease model; Dose; Drug Delivery Systems; Experimental Autoimmune Encephalomyelitis; Funding; Ganglioside GM1; Gangliosides; Grant; Health; Human; Immune Targeting; Immune system; Immunoglobulin M; Individual; Integrins; Lesion; Life; Magnetic Resonance Spectroscopy; Measures; Mediating; Membrane; Membrane Microdomains; Minor; Modeling; Monitor; Multiple Sclerosis; Mus; Myelin; N-acetylaspartate; Nervous System Physiology; Nervous system structure; Neurites; Neurologic Deficit; Neurons; Oryctolagus cuniculus; Peripheral; Pharmaceutical Preparations; Primates; Procedures; Process; Production; Property; Proteins; Reading; Receptor Signaling; Recombinant Antibody; Recombinants; Research; Research Proposals; Safety; Serum; Signal Transduction; Signaling Molecule; Spinal Cord; Spinal Cord Lesions; Staging; Surface; Surrogate Markers; TMEV; Testing; Therapeutic; Therapeutic antibodies; Time; Tissues; Titrations; Toxic effect; Translations; Tubulin; Vendor; Virus; base; clinical trials in animals; design; drug development; effective therapy; established cell line; functional improvement; human data; improved; in vivo; mouse model; neurofilament; neuron apoptosis; neuroprotection; prevent; programs; repaired; response; safety study; safety testing; therapy design

DESCRIPTION (provided by applicant): There are currently no effective treatments to prevent or reverse neurologic deficits in MS. All available drugs target the immune system. Long term CNS repair may require a paradigm shift to focus on drugs that target the nervous system. We have identified a human monoclonal IgM that binds to the surface of living neurons, including those of human origin. The IgM promotes neurite extension even in the presence of normally inhibitory CNS myelin and protects neurons in culture from cell death. The IgM was isolated from the serum of an individual who carried it at high levels for many years without adverse effects and has shown no signs of toxicity to cells or animals. In vivo the IgM improves spinal cord axon health in a virus (Theiler's murine encephalomyelitis virus, TMEV) mediated mouse model of chronic progressive MS. A recombinant form of the IgM, called rHIgM12, was constructed, a research production cell line established, certified for GMP production and banked at a vendor. We have manufactured and purified over 200 mg of rHIgM12 using a procedure appropriate for GLP and GMP production. The efficacy of a single i.v. dose of rHIgM12 (25 mg/kg) has been demonstrated to protect axons and preserve neurologic deficits in the TMEV model of MS. Over the time frame of functional improvement, the number of myelinated axons in the spinal cord are preserved, and N-acetyl aspartate (NAA) concentrations in the brain stem increase, as measured by magnetic resonance spectroscopy (MRS). We have validated the use of NAA in the brain stem as a surrogate marker of axon preservation throughout the spinal cord (37). This MRS based assay is easily applicable to human studies and may become a valid clinical trial endpoint. After peripheral administration rHIgM12 accumulates within spinal cord lesions, co-localized with the axon marker, neurofilament. Our data supports a mechanism of action in which the IgM clusters neuron membrane domains by binding to gangliosides, activating tubulin and initiating signals that result in axon protection and process extension. This project is designed to generate sufficient safety and dose response data for rHIgM12 to support a larger translational program. 1) Efficacy and safety studies in an autoimmune mediated model of MS (EAE) will address concerns that administering a CNS binding Ab in the face of active autoimmunity may exacerbate disease. 2) There is clear efficacy in protecting axons in the TMEV model. A rigorous dose response study in this model will further define the minimum effective dose and guide safety studies. 3) Studies to measure the ability of rHIgM12 to cross the blood brain barrier will strengthen the data supporting direct signaling within the CNS and tissue binding studies across species using rHIgM12 will justify species selection in safety studies.

描述（由申请人提供）：目前没有有效的治疗方法来预防或逆转MS的神经功能缺损。所有可用的药物都靶向免疫系统。长期的中枢神经系统修复可能需要一个范式的转变，重点是针对神经系统的药物。我们已经确定了一种人单克隆IgM，它与活神经元（包括人类起源的神经元）的表面结合。即使在正常抑制性CNS髓鞘存在下，IgM也促进神经突延伸，并保护培养中的神经元免于细胞死亡。IgM是从一个人的血清中分离出来的，这个人多年来一直携带高水平的IgM，没有不良反应，也没有显示出对细胞或动物有毒性的迹象。在体内，IgM在病毒（Theiler鼠脑脊髓炎病毒，TMEV）介导的慢性进行性MS的小鼠模型中改善脊髓轴突健康。构建了重组形式的IgM，称为rHIgM 12，建立了研究生产细胞系，经GMP生产认证并在供应商处储存。我们已使用适用于GLP和GMP生产的程序生产并纯化了超过200 mg的rHIgM 12。已经证明了单次静脉注射剂量的rHIgM 12（25 mg/kg）在MS的TMEV模型中保护轴突并保留神经缺陷的功效。在功能改善的时间范围内，脊髓中有髓鞘轴突的数量得到保留，并且脑干中N-乙酰天冬氨酸（NAA）浓度增加，如通过磁共振波谱（MRS）测量的。我们已经验证了在脑干中使用NAA作为整个脊髓轴突保存的替代标记物（37）。这种基于MRS的测定很容易适用于人体研究，并可能成为有效的临床试验终点。外周给药后，rHIgM 12在脊髓病变内蓄积，与轴突标记物神经丝共定位。我们的数据支持一种作用机制，其中IgM通过与神经节苷脂结合，激活微管蛋白并启动导致轴突保护和过程延伸的信号来聚集神经元膜结构域。本项目旨在为rHIgM 12生成足够的安全性和剂量反应数据，以支持更大的转化项目。1)在自身免疫介导的MS（EAE）模型中进行的有效性和安全性研究将解决以下问题：在面临活动性自身免疫时给予CNS结合Ab可能会加重疾病。2)在TMEV模型中，在保护轴突方面有明显的功效。该模型中严格的剂量反应研究将进一步确定最低有效剂量并指导安全性研究。3)测量rHIgM 12穿过血脑屏障能力的研究将加强支持CNS内直接信号传导的数据，使用rHIgM 12进行的跨种属组织结合研究将证明安全性研究中的种属选择是合理的。