Chimeric anti-Methamphetamine Monoclonal Antibody for Treating Stimulant Toxicity

描述（由申请方提供）：过量和滥用甲基苯丙胺（（+）-METH）、（+）-苯丙胺（（+）-AMP）或（1）-亚甲二氧基甲基苯丙胺（（1）-MDMA）在美国和国外造成了重大的医疗和社会成本。然而，迄今为止，没有药物被批准用于治疗这些药物的急性和慢性毒性。还需要帮助患者从急诊室过渡到促进健康行为改变的长期治疗计划的药物。拟定研究的目的是生产并完成一种新型嵌合单克隆抗体拮抗剂（命名为ch-mAb 4G 9）的临床前试验，该拮抗剂将结合（+）-METH、（+）-AMP和（+）-MDMA。Ch-mAb 4G 9选择性地快速结合血液中的这些靶向配体，逆转这些药物进入大脑的流量，使它们失去活性，而不改变任何儿茶酚胺受体的功能，从而提供了一种治疗药物滥用的独特方法。本项目的目标是成功完成一项研究性新药申请（IND），适应症为治疗兴奋剂过量。Ch-mAb 4G 9可以在急诊科给予，通过减少过量的急性影响来开始治疗。然后，它可以作为行为矫正计划的一部分，以阻止愉快的，加强刺激的效果。与小分子拮抗剂不同，单克隆抗体（mAb）治疗不应影响正常的CNS活动或全身稳态，并且它们不会与精神活性药物相互作用。此外，它们的静脉内（iv）给药将在过量时产生快速的有益作用。因此，Ch-mAb 4G 9可能具有广泛的影响，而不排除其他治疗选择。在拟议的研究中，mAb 4G 9是一种高亲和力抗（+）-METH小鼠mAb，可降低大鼠静脉注射（+）-METH剂量的影响，将作为人/小鼠嵌合mAb生产，并在大鼠中测试安全性和临床前疗效，为食品和药物管理局（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）建立分泌ch-mAb 4G 9的高产主细胞库，并生产用于测试的药物; 2）广泛测试ch-mAb 4G 9与小鼠形式mAb的生物等效性; 3）体外（人和大鼠）和体内（大鼠）毒理学测试;以及4）成功IND申请所需的文件准备、质量控制和临床方案开发。仅NIDA的资金就支持了使我们走到这一步的发现和方法的发展。然而，如果没有GO赠款的支持，这项工作就不能合理地预期成功地进行，因为这些FDA要求的研究是昂贵的，而且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部署，并且这种经过FDA验证的新疗法的成功开发将利用研究人员先前的工作来开发长期可持续计划所需的资源。 公共卫生相关性：我们开发了一种新的药物，用于治疗过量和长期使用（+）-甲基苯丙胺，（+）-苯丙胺和（1）亚甲二氧基甲基苯丙胺（（1）-MDMA）的毒性作用，这有可能减少其破坏性的行为和社会影响，从而改善公众健康。这种创新的抗体药物可以为患者从紧急护理过渡到促进健康行为改变的长期计划提供一个重要的缺失成分。该项目将生产和执行嵌合单克隆抗体药物的所有测试，为进行人体临床试验做准备。

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.