Targeted Therapy for Myasthenia Gravis

重症肌无力的靶向治疗

• 批准号: 10004729
• 负责人: HENRY J KAMINSKI
• 金额: $ 23.28万
• 依托单位: ARC BIOTECHNOLOGY, LLC
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10004729
• 关键词: Address; Adrenal Cortex Hormones; Adverse effects; Affinity; Animal Model; Antibodies; Autoantibodies; Autoimmune Diseases; Autoimmune Process; Baculoviruses; Binding; Binding Proteins; Biological Assay; Biotechnology; CD55 Antigens; Cessation of life; Cholinergic Receptors; Chronic; Clinical; Communication; Complement; Complement Activation; Complement Inactivators; Cytolysis; Development; Doctor of Philosophy; Dose; Enzyme-Linked Immunosorbent Assay; Erythrocytes; Generalized Myasthenia Gravis; Generations; Goals; Hospitalization; Human; Immunization; Injury; Insecta; Investigation; Larva; Lead; Legal patent; Letters; Life; Link; Measures; Mediating; Minority; Muscle; Muscle Cells; Muscle Weakness; Myasthenia Gravis; Myoblasts; Nerve; Neuromuscular Diseases; Neuromuscular Junction; Pathogenesis; Pathology; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacodynamics; Phase; Production; Proteins; Quality of life; Rare Diseases; Rattus; Recombinants; Rodent Model; Series; Serum; Severities; Severity of illness; Sheep; Site; Skeletal Muscle; Small Business Technology Transfer Research; Specificity; Synaptic Membranes; System; Technology; Therapeutic; Time; Toxic effect; Treatment Efficacy; Weight; Work; base; comparative efficacy; complement system; cost; design; disabling disease; drug candidate; early phase trial; expectation; human disease; improved; in vitro Assay; neuromuscular; neuromuscular transmission; novel; oral infection; pre-clinical; research clinical testing; success; systemic toxicity; targeted treatment; therapeutic development; therapeutic target

Myasthenia gravis is a severe neuromuscular disease primarily caused by complement activating autoantibodies directed towards the skeletal muscle acetylcholine receptor. Present treatments are ineffectiveand uniformly have adverse effects, which negatively impact quality of life. Despite being a rare disease, myasthenia gravis is a costly one with a hospitalization expense of half a billion dollars in 2013. The investigative team through extensive basic and preclinical assessment have demonstrated the complement system as a valid therapeutic target, which has been further confirmed by the recent FDA approval of a first generation complement inhibitor as treatment for generalized myasthenia gravis. We have shown in proof- of-concept investigations the ability to target a complement inhibitor to the neuromuscular junction and moderate disease severity in rodent models of myasthenia gravis. The work led to issuance of U.S. Patent No. 8,961,981 for targeting a therapeutic to the neuromuscular junction and our establishment of ARC BioTechnology, LLC to develop the technology for human use. If we are successful in fulfilling the expectations of our candidate drug profile, we will produce a drug with limited toxicity associated with systemic complement inhibition, prolonged duration of action, and enhanced efficacy compared with presently available drugs and those in development. In Phase 1 of the STTR we propose three mile-stone driven specific aims in order to develop a lead compound for phase 2 development. Aim 1 will achieve small batch synthesis of a series of constructs with a complement inhibitor domain and a domain targeting the compound to proteins concentrated at the neuromuscular junction. Aim 2 will identify lead compound (s) through validated in vitro assays of complement inhibitory activity and affinity for target proteins. Aim 3 assesses lead compound(s) for moderation of severity in validated animal models of myasthenia gravis produced by administration of antibody directed against the acetylcholine receptor or immunization with purified acetylcholine receptor. Successful completion of the milestones will trigger progression to Phase 2 to assess efficacy and pharmacodynamics of the lead compound.

重症肌无力是一种严重的神经肌肉疾病，主要由补体引起。 激活针对骨骼肌乙酰胆碱受体的自身抗体。现在时 治疗无效，且均有不良影响，对产品质量产生负面影响。 生活。尽管重症肌无力是一种罕见的疾病，但住院费用很高。 2013年的支出为5亿美元。调查小组通过广泛的基础和 临床前评估表明补体系统是一种有效的治疗方法。 Target，这一点得到了FDA最近批准的第一代 补体抑制剂治疗全身性重症肌无力。我们已经在证据中证明了- Of-Concept研究针对神经肌肉的补体抑制剂的能力 重症肌无力啮齿动物模型中的交界处和中等疾病严重程度。这项工作导致了 针对神经肌肉接头的治疗药物颁发美国专利8,961,981号 我们成立了ARC生物技术有限责任公司，以开发人类使用的技术。如果 我们成功地实现了候选药物配置文件的期望，我们将生产一种 与全身补体抑制相关的毒性有限的药物，延长 作用持续时间，与目前可用的药物和 那些正在发展中的人。在STTR的第一阶段，我们建议用三英里长的石块驱动特定的 旨在开发一种用于第二阶段开发的先导化合物。目标1将实现小目标 批量合成一系列含有补体抑制因子结构域和结构域的结构物 将该化合物定位于集中在神经肌肉连接处的蛋白质。目标2将 通过体外补体抑制活性验证鉴定先导化合物(S) 以及对目标蛋白的亲和力。目的3评估铅化合物(S)对严重程度的缓和 抗体导向注射法建立重症肌无力动物模型的验证 抗乙酰胆碱受体或用纯化的乙酰胆碱受体免疫。 成功完成里程碑将触发进入第二阶段以评估疗效 以及先导化合物的药效学。