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

用于治疗甲基苯丙胺使用障碍的长效抗甲基苯丙胺单克隆抗体的 IND 项目

• 批准号: 10706499
• 负责人: Misty Ward Stevens
• 金额: $ 433.63万
• 依托单位: INTERVEXION THERAPEUTICS, LLC
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-30 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10706499
• 关键词: Adherence; Affinity; Amendment; Animals; Antibodies; Behavior Therapy; Behavioral; Binding; Biological Assay; Brain; Cell Line; Chronic; Clinical; Clinical Protocols; Clinical Research; Clinical Trials; Cognitive; Data; Development; Diagnosis; Dose; Drug Kinetics; FDA approved; Fab Immunoglobulins; Frequencies; Goals; Grant; Half-Life; Health; Health Care Costs; Healthcare; Home; Human; Immunoglobulin G; In Vitro; Infusion procedures; Length; Methamphetamine; Methamphetamine overdose; Methamphetamine use disorder; Modeling; Modification; Monoclonal Antibodies; Motor Activity; Mutation; Outcome; Participant; Patient Care; Patient-Focused Outcomes; Patients; Persons; Pharmaceutical Preparations; Population; Preclinical Testing; Preparation; Production; Rattus; Recovery; Relapse; Research; Research Design; Risk; Rodent; Running; Safety; Step Tests; Stimulant; Testing; Time; Toxicokinetics; Toxicology; Treatment Cost; Vaccines; Visit; Work; Writing; antagonist; candidate selection; cell bank; clinic ready; clinical development; compliance behavior; contingency management; cost; design; disability; efficacy study; first-in-human; healthy volunteer; humanized monoclonal antibodies; immunogenicity; improved; lead candidate; manufacture; manufacturing process; medication compliance; meetings; methamphetamine effect; methamphetamine use; nonhuman primate; phase 1 study; pre-Investigational New Drug meeting; programs; response; stable cell line

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.

项目摘要 2017年，美国有近100万人被诊断出患有甲基苯丙胺（甲基苯丙胺）使用障碍（MUD）。 一旦建立，泥可能会持续很长时间，并且很难治疗。但是仍然没有FDA批准 专为泥浆指示的药物。抗METH抗体已在有效方面进行了测试 模型并表现出减少甲基霉菌在啮齿动物中的刺激作用的能力。在人类中，这些一样 抗体通过减少分布量并可能减少对大脑的分布来改变METH PK。 当前的抗体将每月涂一次；由于更少 经常给药。该应用的目的是确定具有的后续抗METH单克隆抗体 扩展半衰期并进行指导发展和毒理学研究，以便在项目结束时 它已经准备好进行首次人类临床试验。除了提高合规性外，长效的好处 治疗泥浆的抗体可能包括较低的治疗成本和总体更好的临床结果。确定的 抗体也将被充分人性化，这可能会降低慢性服用时抗原性的风险。 该项目将通过四个特定目标完成。 AIM 1是选择最终铅候选人长期 作用抗体。一个以前七个以前人性化的甲基结合区域的面板将作为晶圆厂生产 在大鼠中的甲基刺激的运动模型中测试。最好的将与两个IgG常数域配对 选择了突变以延长其半衰期。将在同一效率模型中比较两个IgG 具有体外表征，并选择了最终候选者。 在AIM 2中，将为最终候选IgG开发克隆细胞系和可扩展的制造过程。一个 主细胞库将从细胞系生成，并用于制造临床批次。 50升跑步 生产用于开发工作和测试的材料，然后将制造250L批次以提供抗体 AIM 3中的毒理学测试。最后，将制造500升GMP批次用于人类的首次临床研究。 将在AIM 3下进行大鼠的毒理学研究。单剂量研究将测试IV剂量 至1.5 g/kg。多剂量研究将每隔一周一次测试每隔1 g/kg的剂量，持续六个月。抗体 将确定有毒动力学和免疫原性以及典型的毒理学结果。 AIM 4包括开发监管提交和其他制剂以进行初始临床试验。 AIM 1完成后，将与FDA举行预先开会，然后临床方案完全 根据讨论开发。随着计划的发展，整个IND包括质量，非临床和 FDA特定的模块将在最后编写和提交。 该项目的预期结果是一种诊所就绪的人源化单克隆抗体，用于治疗泥浆 必须每2-3个月服用一次。这样的候选人将提供改善的患者预后 治疗燃烧和更高的依从性。