IND-enabling program for a long-acting anti-methamphetamine monoclonal antibody for treating methamphetamine use disorder

项目摘要 2017年，美国近100万人被诊断出患有甲基苯丙胺(冰毒)使用障碍(MUD)。 一旦确定，泥浆可以持续很长时间，非常难以治疗。然而，仍然没有FDA批准的 专门针对泥浆的药物。抗冰毒抗体已经在临床前进行了有效性测试 模型，并已显示出有能力减少冰毒对啮齿动物的刺激作用。在人类身上，这些相同的 抗体通过减少分布体积和可能减少分布到大脑来改变冰毒蛋白。 目前的抗体将每月给药一次；作用时间更长的药物将增加依从性，因为 频繁服药。这项应用的目标是用一种新的抗冰毒单抗 延长半衰期，并进行支持印度的开发和毒理学研究，以便在项目结束时 它已经准备好进行首例人类临床试验。除了提高合规性外，长期有效的 用于治疗MUD的抗体可能包括更低的治疗成本和总体上更好的临床结果。被识别的人 抗体也将完全人源化，这可能会降低长期服用时的抗原性风险。 该项目将通过四个具体目标来完成。目标1是选出最终的领先者候选人Long- 作用抗体。一个由七个以前人化的冰毒结合区域组成的小组将作为Fabs和 在冰毒刺激的大鼠运动模型中进行了测试。最好的将与两个免疫球蛋白恒定结构域配对， 选择了突变来延长他们的半衰期。这两种免疫球蛋白将在相同的疗效模型中进行比较， 与体外表征，并最终选出候选。 在目标2中，将为最终候选抗体开发克隆细胞系和可扩展的制造工艺。一个 母细胞库将从细胞系中生成，并用于临床批次的生产。一次50L的跑步将会 生产用于开发工作和测试的材料，然后将生产250L批次，以提供抗体 AIM 3的毒理学测试。最后，将生产一批500L的GMP，用于首次人类临床研究。 对大鼠的IND毒理学研究将在目标3下进行。一项单剂量研究将测试IV剂量 降至1.5g/kg。一项多剂量研究将在六个月内每隔一周测试最高1克/公斤的剂量。抗体 毒代动力学和免疫原性将与典型的毒理学结果一起确定。 AIM 4包括制定监管提交文件和初步临床试验的其他准备工作。 在AIM 1完成后，将与FDA举行IND前会议，然后将全面制定临床方案 在讨论的基础上开发的。随着计划的发展，整个IND包括质量的、非临床的和 FDA特定的模块将在最后编写和提交。 该项目的预期结果是临床上可用于治疗MUD的人源化单抗。 必须每2-3个月服用一次。这样的候选者将以更低的成本提供更好的患者结果 治疗负担和更高的依从性。

PROJECT ABSTRACT Nearly 1 million people in the US were diagnosed with a methamphetamine (METH) use disorder (MUD) in 2017. Once established, MUD can last a long time and is very difficult to treat. Yet there are still no FDA-approved medications indicated specifically for MUD. Anti-METH antibodies have been tested preclinically in efficacy models and have shown the ability to reduce METH’s stimulant effects in rodents. In humans, these same antibodies alter METH PK by reducing volume of distribution and likely decreasing distribution to the brain. Current antibodies would be dosed once a month; longer-acting agents would increase compliance due to less frequent dosing. The goal of this application is to identify a follow-on anti-METH monoclonal antibody with an extended half-life and conduct IND-enabling development and toxicology studies so that at the end of the project it is ready for a first-in-human clinical trial. In addition to increased compliance, the benefits of a long-acting antibody for treating MUD may include lower cost of treatment and overall better clinical outcomes. The identified antibody will also be fully humanized, which may lower the risk of antigenicity upon chronic dosing. The project will be accomplished through four Specific Aims. Aim 1 is to select the final lead candidate long- acting antibody. A panel of seven previously humanized METH-binding regions will be produced as Fabs and tested in a METH-stimulated locomotor model in rats. The best will be paired with two IgG constant domains that have selected mutations to extend their half-life. The two IgG will be compared in the same efficacy model, along with in vitro characterization, and the final candidate selected. In Aim 2, a clonal cell line and scalable manufacturing process will be developed for the final candidate IgG. A Master Cell Bank will be generated from the cell line and used for manufacture of clinical batches. A 50L run will produce material for development work and testing, then a 250L batch will be made to provide antibody for toxicology testing in Aim 3. Finally, a 500L GMP batch will be manufactured for first-in-human clinical studies. IND-enabling toxicology studies in rats will be conducted under Aim 3. A single-dose study will test IV doses up to 1.5 g/kg. A multiple-dose study will test doses up to 1 g/kg given every other week for six months. Antibody toxicokinetics and immunogenicity will be determined along with typical toxicology outcomes. Aim 4 consists of the development of the regulatory submissions and other preparations for initial clinical trials. A pre-IND meeting will be held with FDA following the completion of Aim 1, then a clinical protocol will be fully developed based on the discussion. As the program develops, the entire IND including quality, nonclinical, and FDA-specific modules will be written and submitted at the end. The expected outcome of this project is a clinic-ready humanized monoclonal antibody to treat MUD that only has to be dosed once every 2-3 months. Such a candidate would deliver improved patient outcomes with lower treatment burden and higher adherence.