Chimeric anti-Methamphetamine Monoclonal Antibody for Treating Stimulant Toxicity

描述（由申请人提供）：过量和滥用甲基苯丙胺（(+)-冰毒），(+)-安非他明（(+)- amp）或(1)-亚甲二氧基甲基苯丙胺（(1)- mdma）在美国和国外确切的重大医疗和社会成本。然而，到目前为止，还没有药物被批准用于治疗这些药物的急性和慢性毒性。还需要一些药物，帮助病人从急诊科过渡到促进健康行为改变的长期治疗项目。拟议研究的目的是生产并完成一种新的嵌合单克隆抗体拮抗剂（指定ch- mAb4G9）的临床前试验，该拮抗剂将结合(+)-甲基安非他明、(+)- amp和(+)- mdma。Ch-mAb4G9选择性地快速结合血液中的这些靶配体，逆转这些药物进入大脑的流动，使它们失去活性，而不改变任何儿茶酚胺受体的功能，从而为治疗药物滥用提供了一种独特的方法。该项目的目标是成功完成一项新药研究申请（IND），适应症是治疗兴奋剂过量。Ch-mAb4G9可以在急诊科使用，通过减少过量的急性反应来启动治疗。然后，它可以作为行为矫正计划的一部分，阻止愉悦，加强刺激作用。与小分子拮抗剂不同，单克隆抗体（mAb）疗法不会影响正常的中枢神经系统活性或系统稳态，也不会与精神活性药物相互作用。此外，他们的静脉（iv）管理将导致迅速的有益作用，过量。因此，Ch-mAb4G9可以产生广泛的影响，而不排除其他治疗方案。在拟议的研究中，mAb4G9是一种高亲和力的抗-(+)-甲基安非他明小鼠单抗，可以降低iv(+)-甲基安非他明对大鼠的影响，将作为人/小鼠嵌合单抗生产，并在大鼠身上进行安全性和临床前有效性测试，为美国食品和药物管理局（FDA）批准的人体试验做准备。一个跨学科的学术/行业团队将完成必要的，综合的特定目标：1)建立一个高产的主细胞库，分泌ch-mAb4G9并生产用于测试的药物；2)广泛测试ch-mAb4G9与小鼠单克隆抗体的生物等效性；3)体外（人和大鼠）和体内（大鼠）毒理学试验；4)成功申请新药所需的文件准备、质量控制和临床方案开发。仅NIDA的资金就支持了这些发现和方法的开发，使我们走到了这一步。然而，如果没有GO的资助，这项工作不能被合理地期望成功进行，因为这些fda要求的研究是昂贵的，而早期药物开发公司为人体试验准备新的药物滥用疗法的资本资金是稀缺的。尽管如此，该项目已准备好在获得资金后立即投入使用，并且该新疗法的成功开发与FDA的验证将利用研究人员之前的工作来开发长期可持续项目所需的资源。

DESCRIPTION (provided by applicant): Overdose and abuse of methamphetamine ((+)-METH), (+)-amphetamine ((+)-AMP), or (1)- methylenedioxymethamphetamine ((1)-MDMA) exact significant medical and social costs in the USA and abroad. However, to date, no medications are approved to treat acute and chronic toxicity from these drugs. Medicines that will help transition patients from the emergency department into longer-term treatment programs that promote healthy behavioral change are also needed. The purpose of the proposed research is to produce and complete pre-clinical tests of a new, chimeric monoclonal antibody antagonist (designated ch- mAb4G9) that will bind (+)-METH, (+)-AMP, and (+)-MDMA. Ch-mAb4G9 selectively and quickly binds these target ligands in the blood, reversing the flux of these drugs into the brain and rendering them inactive without altering the function of any catecholamine receptor, thus providing a unique approach for treating drug abuse. The goal of this project is to successfully complete an investigational new drug application (IND) with the indication being treatment of stimulant overdose. Ch-mAb4G9 could be given in the emergency department to initiate treatment by reducing the acute effects of an overdose. It could then be given as part of a behavioral modification program to block pleasurable, reinforcing stimulant effects. Unlike small molecule antagonists, monoclonal antibody (mAb) therapies should not affect normal CNS activity or systemic homeostasis, and they will not interact with psychoactive medications. Furthermore, their intravenous (iv) administration will result in rapid beneficial effects in an overdose. Ch-mAb4G9 could thus have a broad impact, without excluding other treatment options. In the proposed research, mAb4G9, a high affinity anti-(+)-METH mouse mAb that reduces the effects of iv (+)-METH doses in rats, will be produced as a human/mouse chimeric mAb and tested in rats for safety and pre-clinical efficacy in preparation for Food and Drug Administration (FDA)-approved human trials. A transdisciplinary academic/industry team will accomplish the necessary, integrated Specific Aims: 1) establishing a high-yield master cell bank that secretes ch-mAb4G9 and producing the medication for testing; 2) extensive testing of ch-mAb4G9 for bioequivalence with the mouse form of the mAb; 3) in vitro (human and rat) and in vivo (rat) toxicology testing; and 4) document preparation, quality control, and clinical protocol development necessary for a successful IND application. NIDA funding alone has supported the discoveries and methods development that have brought us to this point. However, this work cannot be reasonably expected to be carried out successfully without GO grant support because these FDA-required studies are expensive, and capital funding for early-stage drug development companies to prepare new drug abuse therapies for human trials is scarce. Nevertheless, this project is ready to be deployed immediately upon funding, and the successful development of this new therapy with FDA validation will leverage the previous work by the investigators to develop the resources needed for a long-term, sustainable program. PUBLIC HEALTH RELEVANCE: We have developed a new medication for treating toxic effects from overdose and long-term use of (+)- methamphetamine, (+)-amphetamine, and (1)methylenedioxymethamphetamine ((1)-MDMA) which has the potential to reduce their devastating behavioral and societal effects, and therefore improve public health. This innovative antibody medication could provide an essential missing component in transitioning the patient from emergency care into long-term programs that promote healthy behavioral changes. This project will produce and perform all testing of a chimeric monoclonal antibody medication necessary to prepare for conducting human clinical trials.