A Methamphetamine Conjugate Vaccine: From Manufacturing to IND

描述(申请人提供)：滥用甲基苯丙胺(冰毒)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。用冰毒结合疫苗(MCV)免疫成瘾患者是一种很有前途的新策略，它可以刺激患者自己的免疫系统产生长效、保护性的抗冰毒抗体。这些抗体将阻止或减缓冰毒进入大脑的速度，保护使用者免受冰毒的回报和毒性影响，从而减少康复治疗期间再次使用冰毒的医疗后果。拟议工作的目的是扩大制造工艺以生产MCV，在毒理学研究中测试MCV以证明其安全性，并完成首次人类临床试验的计划。候选MCV是由阿肯色医学大学(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，对于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MCV与一种最先进的佐剂相结合，预计将刺激显著更高的抗体效价，对冰毒具有非常高的亲和力。这种MCV的重要特征包括经过严格测试和优化的甲基半抗原化学结构，用于将甲基半抗原与免疫刺激载体蛋白偶联的精细化学，以及快速产生高滴度抗甲基抗体的下一代佐剂。总而言之，半抗原、载体蛋白和佐剂是决定疫苗成功的基本参数；这种MCV满足了所有这些参数。该项目的最终目标是向FDA提交一份成功的新药研究申请(IND)。为了实现这一目标，InterveXion治疗公司和UAMS的团队以及几家高素质的供应商将实现四个具体目标。首先，将制造平台放大并生成数据，以表明生产系统可靠，MCV在存储期间稳定。一旦证实，将生产一批适合人类使用的MCV。其次，在大鼠身上进行的毒理学研究将为预期的对人类使用带有佐剂的MCV的安全给予提供支持。第三，将制定首次临床试验的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。在拟议的工作结束时，该小组将准备启动活性冰毒疫苗的第一次临床试验。

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.