Using hapten design to discover therapeutic monoclonal antibodies for treating methamphetamine abuse
Using hapten design to discover therapeutic monoclonal antibodies for treating methamphetamine abuse
复制标题
DOI：
10.1124/jpet.106.117150
复制
发表时间：
2007-07-01
影响因子：
3.5
通讯作者：
Owens, S. Michael
中科院分区：
文献类型：
--
作者：
Peterson, Eric C.;Gunnell, Melinda;Owens, S. Michael
当产生针对小分子的单克隆抗体（mAb）时，抗原上的药物样半抗原的化学组成和分子取向是至关重要的决定因素。当试图发现针对滥用药物（+）-甲基苯丙胺[（+）- METH]、（+）-苯丙胺[（+）- AMP]和相关化合物（+）-3，4-亚甲二氧基甲基苯丙胺[（+）- MDMA，外消旋混合物中的正异构体，称为MDMA或摇头丸]的治疗性mAb时，这一点尤其重要。这些研究的目的是设计和合成具有结构属性的（+）- METH样半抗原，所述结构属性可以使它们有效地产生用于治疗与这些滥用的兴奋剂药物相关的医学问题的单克隆抗体。合成模拟这些药物的结构方面的五种原型（+）- METH样半抗原并用于产生mAb。在超过25，000个潜在的小鼠杂交瘤细胞系中筛选抗（+）- METH IgG抗体后，从五种半抗原中选择一种原型mAb，并详细研究其分子特性和临床前疗效。然后使用IgG可变区的氨基酸序列、结构模型、亲和力和每种mAb的配体特异性来帮助阐明重要的治疗特征。这些抗体中有四种对（+）- METH和（+）MDMA表现出高亲和力和特异性;而一种抗体（命名为mAb 4G 9）对（+）- METH、（+）- MDMA和（+）- AMP表现出高亲和力和特异性，对其它METH样配体、非处方药或内源性神经递质没有显著的交叉反应性.综合考虑，本报告中mAb 4G 9和其他抗体的发现代表了理解用于治疗药物成瘾的药物类别特异性治疗性抗体的定制设计过程的重要步骤。
When generating monoclonal antibodies ( mAb) against small molecules, the chemical composition and molecular orientation of the drug- like hapten on the antigen is a crucial determinant. This is especially important when attempting to discover therapeutic mAb against the drugs of abuse ( +)- methamphetamine [( +)- METH], ( +)- amphetamine [( +)- AMP], and the related compound ( +)- 3,4- methylenedioxymethamphetamine [( +)- MDMA, the plus isomer in the racemic mixture known as MDMA or ecstasy]. The goal of these studies was to design and synthesize ( +)- METH- like haptens with structural attributes that could make them effective for generating monoclonal antibodies for treating medical problems associated with these stimulant drugs of abuse. Five prototype ( +)- METH- like haptens, which mimic structural aspects of these drugs, were synthesized and used to generate mAb. After screening for anti-( +)- METH IgG antibodies in more than 25,000 potential mouse hybridoma cell lines, one prototype mAb from each of the five haptens was selected and studied in detail for molecular properties and preclinical efficacy. The amino acid sequences of the IgGvariable regions, structural models, affinity, and ligand specificity of each mAb were then used to help elucidate important therapeutic characteristics. Four of these antibodies exhibited high affinity and specificity to ( +)- METH and ( +)MDMA; whereas one antibody ( designated mAb4G9) exhibited high affinity and specificity to ( +)- METH, ( +)- MDMA, and ( +)- AMP, without significant cross- reactivity against other METH- like ligands, over- the- counter medications, or endogenous neurotransmitters. Considered together, discovery of mAb4G9 and the other antibodies in this report represent an important step in understanding the process for custom design of drug class- specific therapeutic antibodies for the treatment of drug addiction.