Targeted Therapy for Myasthenia Gravis

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。本 治疗是无效的，并统一有不利影响，这对质量产生负面影响， 生活尽管是一种罕见的疾病，重症肌无力是一个昂贵的住院治疗 2013年的5亿美元。调查小组通过广泛的基本和 临床前评估已经证明补体系统是一种有效的治疗方法 目标，这已进一步证实了最近FDA批准的第一代 补体抑制剂治疗全身性重症肌无力。我们已经证明了- 概念研究将补体抑制剂靶向神经肌肉的能力 在啮齿动物重症肌无力模型中，这项工作导致 美国专利号8，961，981的发布，用于将治疗剂靶向神经肌肉接头 我们成立了ARC BioTechnology，LLC来开发人类使用的技术。如果 如果我们成功地实现了我们候选药物概况的期望，我们将生产一种 与全身补体抑制相关的有限毒性药物，长期 作用持续时间，与现有药物相比， 发展中的人。在STTR的第一阶段，我们提出了三个里程碑驱动的具体 目的是开发用于第二阶段开发的先导化合物。目标1将实现小 具有补体抑制剂结构域和结构域的一系列构建体的分批合成 使化合物靶向集中在神经肌肉接头处的蛋白质。目标2将 通过经验证的补体抑制活性的体外测定来鉴定先导化合物 和对靶蛋白的亲和力。目标3评估了铅化合物在以下疾病中的严重程度 通过施用抗体导向的抗体产生的经验证的重症肌无力动物模型 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展至II期，以评估疗效 以及先导化合物的药效学

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.