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((+)-甲基)、(+)-苯丙胺((+)-AMP)或(1)-亚甲基二氧基甲基苯丙胺((1)-MDMA)在美国和国外都造成了巨大的医疗和社会成本。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。还需要帮助患者从急诊科过渡到长期治疗计划的药物，以促进健康行为的改变。拟议研究的目的是生产和完成一种新的嵌合单抗拮抗剂(命名为ch-mAb4G9)的临床前测试，它将结合(+)-METH、(+)-AMP和(+)-MDMA。CH-mAb4G9选择性地和血液中的这些靶配体结合，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以兴奋剂过量治疗为适应症的研究性新药应用(IND)。可以在急诊科给予CH-mAb4G9，通过减少过量服药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，以阻止愉悦的、强化刺激的效果。与小分子拮抗剂不同，单抗治疗不应影响正常的中枢神经系统活动或全身动态平衡，也不会与精神活性药物相互作用。此外，他们的静脉注射会在过量的情况下产生快速的益处。因此，在不排除其他治疗选择的情况下，CH-mAb4G9可以产生广泛的影响。在拟议的研究中，mAb4G9是一种高亲和力的抗(+)-冰毒小鼠单抗，可以减少静脉注射(+)-冰毒剂量对大鼠的影响，将作为人/鼠嵌合单抗生产，并在大鼠身上进行安全性和临床前疗效测试，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/行业团队将实现必要的、综合的具体目标：1)建立一个分泌ch-mAb4G9的高产主细胞库，并生产用于测试的药物；2)广泛测试ch-mAb4G9与小鼠形式的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)成功应用IND所必需的文件准备、质量控制和临床方案开发。仅NIDA的资金就支持了将我们带到这一点的发现和方法开发。然而，如果没有GO赠款的支持，这项工作就不能被合理地期望成功进行，因为这些FDA要求的研究费用高昂，而为早期药物开发公司准备用于人体试验的新药物滥用疗法的资本资金稀缺。然而，一旦获得资金，该项目就可以立即部署，这种经过FDA验证的新疗法的成功开发将利用研究人员之前的工作来开发长期、可持续计划所需的资源。 与公共卫生相关：我们已经开发出一种新的药物，用于治疗过量和长期使用(+)-甲基苯丙胺、(+)-苯丙胺和(1)亚甲基二氧基甲基苯丙胺((1)-MDMA)的毒性效应，它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提供一个必要的缺失部分，将患者从紧急护理过渡到促进健康行为改变的长期计划。该项目将生产并进行嵌合单抗药物的所有测试，为进行人类临床试验做准备。

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.