Antibody-based Therapy for Methamphetamine Abuse

描述（由申请人提供）：该项目的长期目标是开发基于抗体的药物，用于治疗甲基苯丙胺（（+）METH））、苯丙胺和摇头丸滥用引起的医疗问题。滥用这些化学物质会导致家庭破裂、精神病、心血管问题和死亡。据设想，这些新药物可用于治疗与合成兴奋剂滥用相关的一系列医学问题（例如，药物过量，成瘾）。虽然药物是迫切需要的，这些药物及其活性代谢物提出了一个具有挑战性的问题，有效的药物的发展。本提案中的实验旨在通过发现抗药物单克隆抗体（mAb，小鼠和人类）来解决这些问题，这些抗体可以识别并中和这些危险化学品的体内效应。mAb药物的选择标准将包括高亲和力药物结合，对METH样药物和代谢物的精确特异性，以及体内测试其防止这些化学物质脑渗透的能力。在互补研究中，最好的mAb原型将用于通过间隔基团连接重链和轻链可变区序列来产生单链抗体（scFv）。这些较小的结合蛋白的研究将包括两个独立的领域。首先，将使用体外蛋白翻译技术来筛选具有改善的亲和力和特异性的scFv。其次，scFv将用聚（乙二醇）化学修饰以允许控制药代动力学性质。 由于scFv比完整的mAb小得多，并且被设计为单一基因产物，它们最终可能导致更便宜的药物。通过精心设计METH样半抗原，产生小鼠和人单克隆抗体，以及先进的分子工程技术，该研究计划将产生具有最佳免疫学和药理学特性的新型蛋白质药物。由于所有这些药物都可以在不进入大脑的情况下中和药物作用，因此它们提供了一种创新和独特的方法来治疗兴奋剂滥用引起的医疗问题。

DESCRIPTION (provided by applicant): The long-term objective of this project is to develop antibody-based medications for the treatment of medical problems caused by abuse of methamphetamine ((+)METH)), amphetamine and ecstasy. Abuse of these chemicals can lead to disruption of families, psychosis, cardiovascular problems, and death. It is envisioned that these new medications could be used for treating a range of medical problems associated with synthetic stimulant abuse (e.g., drug overdose, addiction). Although medicines are sorely needed, these drugs and their active metabolites present a challenging problem for the development of effective medications. The experiments in this proposal are designed to address these problems by discovering anti-drug monoclonal antibodies (mAb, both mouse and human) that recognize and neutralize the in vivo effects of these dangerous chemicals. The selection criteria for the mAb medications will include high affinity drug binding, refined specificity for METH-like drugs and metabolites, and in vivo testing for their ability to prevent brain penetration of these chemicals. In complementary studies, the best mAb prototypes will be used to generate single chain antibodies (scFv) by linking the heavy and light chain variable region sequences through a spacer group. Research with these smaller binding proteins will include two separate areas. First, in vitro protein translation techniques will be used to screen for scFv with improved affinity and specificity. Second, the scFv will be chemically modified with poly(ethylene glycol) to allow control of the pharmacokinetic properties. Since scFv are much smaller than intact mAb and are engineered as a single gene product, they could eventually lead to less expensive medications. Through careful design of METH-like haptens, generation of mouse and human mAb, and advanced molecular engineering technology, this research program will produce novel protein-based medications with optimal immunological and pharmacological properties. Because all of these medications can neutralize drug effects without entering the brain, they offer an innovative and unique approach to treating medical problems resulting from stimulant abuse.