A Methamphetamine Conjugate Vaccine: From Manufacturing to IND

描述（由申请人提供）：甲基苯丙胺（冰毒）的滥用在美国和世界范围内造成了巨大的医疗和社会成本；然而，目前还没有批准用于治疗冰毒成瘾的药物。使用甲基苯丙胺结合疫苗（MCV）对成瘾患者进行免疫接种是一种很有前途的新策略，它可以刺激患者自身免疫系统产生长效、保护性的抗甲基苯丙胺抗体。这些抗体会阻止或减慢甲基苯丙胺进入大脑的速度，保护使用者免受甲基苯丙胺的有益和毒性作用的影响，从而减少在康复治疗期间再次使用甲基苯丙胺的医疗后果。拟议工作的目的是扩大生产MCV的生产过程，在毒理学研究中测试MCV以证明其安全性，并完成首次人体临床试验的计划。候选MCV是在阿肯色大学医学科学（UAMS）开发和优化的，在那里进行了广泛的临床前动物试验，证明了安全性和有效性。治疗尼古丁和可卡因成瘾的疫苗已经在人类身上进行了测试，对那些产生大量抗药物抗体的患者来说，结果是积极的。这种创新的新型MCV与最先进的佐剂相结合，有望显著提高抗体滴度，并对甲基苯丙胺具有非常高的亲和力。该MCV的重要特征包括经过严格测试和优化的甲基苯丙胺半抗原化学结构，甲基苯丙胺半抗原与免疫刺激载体蛋白结合的精细化学，以及快速产生高滴度抗甲基苯丙胺抗体的下一代佐剂。半抗原、载体蛋白和佐剂是决定疫苗成功与否的基本参数；这个MCV满足了所有的要求。该项目的最终目标是向FDA提交成功的研究性新药申请（IND）。为了实现这一目标，InterveXion Therapeutics和UAMS的团队将与几家高素质的供应商一起完成四个具体目标。首先，将扩大制造平台的规模，并生成数据，以表明生产系统是可靠的，MCV在存储期间是稳定的。一旦得到证实，将生产一批适合人类使用的MCV。其次，大鼠毒理学研究将为预期的MCV佐剂安全给药人类提供支持。第三，将为首次临床试验制定方案和所有支持文件，以显示MCV在人类受试者中的安全性和耐受性。最后，IND包将被编写、组装并提交给FDA。在拟议的工作结束后，该团队将准备启动活性甲基苯丙胺疫苗的首次临床试验。

DESCRIPTION (provided by applicant): Abuse of methamphetamine (METH) exacts significant medical and social costs in the US and worldwide; yet, there are no medications approved for the treatment of METH addiction. Immunization of addicted patients with a METH-conjugate vaccine (MCV) is a promising new strategy that could stimulate a patient's own immune system to generate long acting, protective anti-METH antibodies. These antibodies would block or slow the rate at which METH enters the brain, shield the user from METH's rewarding and toxic effects, and thereby reduce the medical consequences of relapse to METH use during rehabilitation therapy. The purpose of the proposed work is to scale-up the manufacturing process to produce an MCV, test the MCV in toxicology studies to show its safety, and complete plans for a first in human clinical trial. The candidate MCV was developed and optimized at the University of Arkansas for Medical Sciences (UAMS) where extensive preclinical animal testing demonstrated both safety and efficacy. Vaccines for treating nicotine and cocaine addiction have already been tested in humans, with positive outcomes for those patients making large quantities of anti-drug antibodies. This innovative new MCV, in combination with a state of the art adjuvant, is expected to stimulate significantly higher antibody titers with very high affinity for METH. The important characteristics of this MCV include a rigorously tested and optimized METH hapten chemical structure, refined chemistry for the conjugation of METH hapten to an immunostimulatory carrier protein, and a next generation adjuvant that rapidly generates high titers of anti- METH antibodies. Together, the hapten, carrier protein and adjuvant are essential parameters that determine the success of a vaccine; this MCV fulfills them all. The ultimate goal of this project is to submit a successful investigational new drug application (IND) to the FDA. To reach this goal, the team from InterveXion Therapeutics and UAMS, along with several highly qualified vendors, will accomplish four specific aims. First, the manufacturing platform will be scaled-up and data will be generated to show that the production system is reliable and the MCV is stable during storage. Once proven, a batch of MCV suitable for use in humans will be produced. Second, toxicology studies in rats will provide support for the expected safe administration of MCV with adjuvant to humans. Third, a protocol and all supporting documents for the first clinical trial wil be developed to show the safety and tolerability of the MCV in human subjects. Finally, the IND package will be written, assembled, and submitted to the FDA. At the conclusion of the proposed work, this team will be poised to initiate the first clinical trial for an active METH vaccine.