Peterson Eric C, Gentry W Brooks, Owens S Michael
Department of Pharmacology and Toxicology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.
Department of Pharmacology and Toxicology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA; Department of Anesthesiology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.
Adv Pharmacol. 2014;69:107-27. doi: 10.1016/B978-0-12-420118-7.00003-2.
Monoclonal antibody-based medications designed to bind (+)-methamphetamine (METH) with high affinity are among the newest approaches to the treatment of METH abuse and the associated medical complications. The potential clinical indications for these medications include treatment of overdose, reduction of drug dependence, and protection of vulnerable populations from METH-related complications. Research designed to discover and conduct preclinical and clinical testing of these antibodies suggests a scientific vision for how intact monoclonal antibody (mAb) (singular and plural) or small antigen-binding fragments of mAb could be engineered to optimize the proteins for specific therapeutic applications. In this review, we discuss keys to success in this development process including choosing predictors of specificity, efficacy, duration of action, and safety of the medications in disease models of acute and chronic drug abuse. We consider important aspects of METH-like hapten design and how hapten structural features influence specificity and affinity, with an example of a high-resolution X-ray crystal structure of a high-affinity antibody to demonstrate this structural relationship. Additionally, several prototype anti-METH mAb forms such as antigen-binding fragments and single-chain variable fragments are under development. Unique, customizable aspects of these fragments are presented with specific possible clinical indications. Finally, we discuss clinical trial progress of the first in kind anti-METH mAb, for which METH is the disease target instead of vulnerable central nervous system networks of receptors, binding sites, and neuronal connections.
旨在与（+）-甲基苯丙胺（METH）高亲和力结合的单克隆抗体类药物是治疗甲基苯丙胺滥用及相关医学并发症的最新方法之一。这些药物的潜在临床适应症包括治疗过量用药、减轻药物依赖以及保护易感人群免受与甲基苯丙胺相关的并发症影响。旨在发现并进行这些抗体的临床前和临床试验的研究提出了一种科学设想，即如何对完整的单克隆抗体（mAb，单数和复数）或mAb的小抗原结合片段进行工程改造，以优化这些蛋白质用于特定的治疗应用。在本综述中，我们讨论了这一研发过程中的成功关键，包括在急性和慢性药物滥用疾病模型中选择药物特异性、疗效、作用持续时间和安全性的预测指标。我们考虑了类甲基苯丙胺半抗原设计的重要方面以及半抗原结构特征如何影响特异性和亲和力，并以一种高亲和力抗体的高分辨率X射线晶体结构为例来说明这种结构关系。此外，几种原型抗甲基苯丙胺单克隆抗体形式，如抗原结合片段和单链可变片段正在研发中。这些片段独特的、可定制的方面以及具体可能的临床适应症也进行了介绍。最后，我们讨论了首个以甲基苯丙胺为疾病靶点而非脆弱的中枢神经系统受体、结合位点和神经元连接网络的抗甲基苯丙胺单克隆抗体的临床试验进展。
