Antibody-nanoparticle conjugates for the treatment of methamphetamine abuse

描述(申请人提供)：甲基苯丙胺(冰毒)是美国和世界范围内的主要毒品威胁，目前还没有FDA批准的药物来治疗冰毒引起的医疗问题。治疗冰毒滥用的一种令人兴奋的潜在药物是抗体疗法。临床前研究表明，抗冰毒的高亲和力单抗(MAb)可以迅速减少大脑中冰毒的数量，并减少冰毒诱导的行为效应。目前在临床前试验中有两种形式的抗甲基苯丙氨酸单抗：长效完整的Ig G形式和极短作用的单链可变片段(ScFv)。更小的单链抗体可以比完整单抗更经济地生产，提供相同数量的甲基结合片段所需的蛋白质剂量仅为完整单抗剂量的三分之一；然而，单链抗体在体内的半衰期太短，无法提供更长期的保护，免受冰毒效应的影响。由于药物的药代动力学性质对药物的有效性和效力有很大的影响，创造性地将分子工程和纳米技术应用于这些药物的合理设计，可以改善抗冰毒抗体拮抗剂的性能。纳米技术的进步为定制蛋白质和抗体疗法带来了令人兴奋的新可能性。这些创新之一是一种名为树状大分子的新型分子，它是通过将分子聚合成重复的支链来合成的。该项目的假设是，通过将抗冰毒抗体片段连接到树枝状大分子递送系统，可以定制和优化控制抗冰毒抗体片段的效力和作用时间。本项目的目标是：1-利用分子工程技术生产高亲和力的抗冰毒抗体片段。2-制备和鉴定抗冰毒单链抗体树状大分子递送系统(树状小体)，用于体内药理试验。3-在大鼠的临床前研究中检查新型抗冰毒单链抗体和树突体药物的安全性和药理学特性。这些拟议的研究将整合分子生物学、纳米技术、药代动力学和治疗学领域，并将它们应用于药物滥用的药物开发。如果成功，这些研究将开发新的抗体药物，用于治疗与冰毒滥用有关的一系列临床问题，并可能创建一种定制抗体药代动力学拮抗剂的新范式。公共卫生相关性：这些研究与公共健康直接相关，因为它们将创造新的药物来治疗与甲基苯丙胺滥用相关的医疗问题，甲基苯丙胺滥用是美国和世界的主要毒品威胁。通过分子生物学和纳米技术的结合，我们将创造具有定制特性的抗体拮抗剂，直接应用于与甲基苯丙胺相关的医疗需求，如药物过量和成瘾。

DESCRIPTION (provided by applicant): Methamphetamine (METH) is a principal drug threat in the US and worldwide and there are no FDA approved medications to treat the medical problems caused by METH. One exciting potential medication for the treatment of METH abuse is antibody therapy. Preclinical studies have shown that high affinity monoclonal antibodies (mAb) against METH can quickly reduce the amount of METH in the brain, and reduce METH-induced behavioral effects. There are currently two forms of anti-METH mAbs in preclinical testing: a long-acting intact IgG form and the extremely short-acting single chain variable fragment (scFv). The smaller scFv can be produced more economically than intact mAbs and the protein dose required to deliver the same number of METH-binding fragments is only one-third the intact mAb dose; however, the in vivo half-life of scFv is currently too short to offer longer-term protection from the effects of METH effects. Since the pharmacokinetic properties of a medication have dramatic influences on the effectiveness and potency, an anti-METH antibody antagonist could be improved by creatively applying molecular engineering and nanotechnology to the rational design of these medications. Advances in nanotechnology have introduced exciting new possibilities for customizing protein and antibody therapies. One of these innovations is the new class of molecule called dendrimers, which are synthesized by polymerizing molecules into repeating branched chains. The hypothesis for this project is that the efficacy and duration of action of an anti-METH antibody fragment can be customized and optimally controlled by conjugating it to a dendrimer delivery system. The aims of this project are: 1- Use molecular engineering techniques to produce high affinity anti-METH antibody fragments. 2- Generate and characterize anti-METH scFv dendrimer delivery systems (dendribodies) for in vivo pharmacological testing. 3- Examine the safety and pharmacological properties of the novel anti-METH scFv and dendribody medications in preclinical studies in rats. These proposed studies will integrate the fields of molecular biology, nanotechnology, pharmacokinetics, and therapeutics and apply them to medications development for drug abuse. If successful, these studies will develop new antibody medications for treating a range of clinical problems related to METH abuse, and could possibly create a new paradigm for customizing antibody pharmacokinetic antagonists. PUBLIC HEALTH RELEVANCE: These studies have immediate relevance to public health because they will create new medications to treat medical problems associated with methamphetamine abuse, a principal drug threat in the US and the world. Through the combination of molecular biology and nanotechnology, we will create antibody antagonists with customized properties for direct application to methamphetamine-related medical needs like drug overdose and addiction.