Antibody-based Therapy for Methamphetamine Abuse

描述(申请人提供)：该项目的长期目标是开发基于抗体的药物，用于治疗因滥用甲基苯丙胺((+)冰毒)、苯丙胺和摇头丸而引起的医疗问题。滥用这些化学物质可能会导致家庭破裂、精神病、心血管问题和死亡。据设想，这些新药可以用于治疗与合成兴奋剂滥用有关的一系列医疗问题(例如，药物过量、成瘾)。尽管迫切需要药物，但这些药物及其活性代谢物对有效药物的开发提出了一个具有挑战性的问题。这项提议中的实验旨在通过发现识别和中和这些危险化学物质的体内影响的抗药单抗(mAb，包括小鼠和人)来解决这些问题。单抗药物的选择标准将包括高亲和力药物结合，冰毒类药物和代谢物的精确特异性，以及体内测试它们防止这些化学物质通过大脑的能力。在互补性研究中，最好的mAb原型将通过间隔基将重链可变区序列和轻链可变区序列连接起来，从而产生单链抗体(ScFv)。对这些较小结合蛋白的研究将包括两个不同的领域。首先，将使用体外蛋白质翻译技术来筛选具有更高亲和力和特异性的单链抗体。其次，单链抗体将用聚乙二醇进行化学修饰，以控制药代动力学性质。由于scFv比完整的mAb小得多，并被设计成单基因产品，它们最终可能导致更便宜的药物。通过精心设计类似冰毒的半抗原，制备鼠和人的单抗，以及先进的分子工程技术，这项研究计划将生产出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效果，它们为治疗兴奋剂滥用引起的医疗问题提供了一种创新和独特的方法。

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.