Developing Immunotherapeutics for Methamphetamine Abuse

开发针对甲基苯丙胺滥用的免疫疗法

• 批准号: 7340807
• 负责人: THOMAS Richard KOSTEN
• 金额: $ 69.69万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7340807
• 关键词: Adjuvant; Adjuvant Study; Affinity; Aluminum Hydroxide; Amphetamines; Animal Model; Animals; Antibodies; Antibody Formation; Antigens; Australia; Back; Behavior; Behavioral; Benzene; Biological; CD4 Positive T Lymphocytes; Carrier Proteins; Cholera Toxin; Chronic; Clinical; Clinical Research; Clinical Trials; Cocaine; Collaborations; Complement; Conjugate Vaccines; Conjugated Carrier; DNA Vaccines; Data; Development; Dose; Drug Kinetics; Epitopes; Foxes; Funding; Haptens; Helper-Inducer T-Lymphocyte; Human; Hydroxide Ion; Hydroxides; Immune response; Immune system; Immunization; Immunologic Adjuvants; Immunology; Immunotherapeutic agent; Injection of therapeutic agent; Kentucky; Laboratories; Membrane Proteins; Meningitis; Metabolism; Methamphetamine; Methods; Modeling; Motor Activity; Mus; Neisseria; Neisseria meningitidis; Neurotransmitters; Nicotine; Oligonucleotides; Outcome; Patients; Peptide Vaccines; Phase; Phase I Clinical Trials; Positioning Attribute; Preparation; Rattus; Receptor Signaling; Relapse; Research; Research Personnel; Rodent Model; Route; Safety; Self Administration; Squalene; Structure; Testing; Tetanus Toxoid; TiterMax; Toxicology; Universities; Vaccines; Work; addiction; aluminum sulfate; attenuation; base; chemokine; cytokine; design; ecstasy; experience; immunogenic; methamphetamine abuse; monophosphoryl lipid A; novel; pre-clinical; programs; receptor; research clinical testing; response; stimulant abuse; tool; vaccine candidate; vaccine development

DESCRIPTION (provided by applicant): Immunization against methamphetamine (MA) is potentially valuable in assisting patients in stopping their abuse. Vaccines against both nicotine and cocaine have been promising in both animal and human studies. Immunotherapeutic approaches to MA addiction also appear promising, but much work is needed to design a MA vaccine that induces high levels of specific antibody. Recent discoveries about regulatory cytokine and chemokine networks and innate immune system toll receptor signaling has opened the door to new ways to regulate immune responses to foreign antigens. We will use these advances in immunological adjuvants and carrier proteins to make a safe and effective MA vaccine. Our Preliminary Results with a new MA vaccine show substantial antibody levels and effects on locomotor activity, but indicate that the carrier protein and adjuvant will make a critical difference in efficacy. We will synthesize a panel of conjugate MA vaccines using different conjugates and different immunological carriers. Four carriers will be compared: Tetanus toxoid, neisseria meningitidis outer membrane protein (OMPC), cholera toxin B and a new lipopeptide based, self-adjuvanting vaccine carrier. In addition, a panel of adjuvants will be examined, carefully selected to complement the biological activity of the selected carrier. These adjuvants include CpG oligonucleotides, MPL, and a squalene-based adjuvant; CFA and alum will be included as controls. Outcomes will be the quantity, quality, and persistence of the antibody response in rodent models as well as inhibition of MA-induced locomotor activity. Based on these data, a clinical candidate and 2 back-ups will be selected and characterized in more detail in preparation for an IND filing. The ability of the vaccine to alter MA pharmacokinetics and metabolism will be assessed, as well as inhibition of reinstatement of MA self-administration. Finally, material suitable for use in a Phase I clinical trial will be manufactured and formal toxicology testing will be completed. At the completion of the funding period, we anticipate filing an IND and commencing clinical testing of a MA vaccine. The key investigators in this application have been successfully collaborating at Baylor for the last two years. Dr. Thomas Kosten has worked with our consultant Dr. Fox for over 10 years developing a cocaine vaccine from pre-clinical concept to successful clinical trials. Dr.Therese Kosten is a leading expert in animal models of stimulant abuse. Drs. Rossen, Baughn and Orson have extensive experience in immunology, and Drs. Orson and Kinsey have been working on the development of DMA vaccines. Our group's combined experience is ideally positioned to get a vaccine quickly into phase 1 human studies.

描述（由申请人提供）：针对甲基苯丙胺 (MA) 的免疫对于帮助患者停止滥用具有潜在价值。针对尼古丁和可卡因的疫苗在动物和人类研究中都表现出良好的前景。针对 MA 成瘾的免疫治疗方法似乎也很有前景，但需要做大量工作来设计诱导高水平特异性抗体的 MA 疫苗。最近关于调节细胞因子和趋化因子网络以及先天免疫系统收费受体信号传导的发现为调节对外来抗原免疫反应的新方法打开了大门。我们将利用这些在免疫佐剂和载体蛋白方面的进展来制造安全有效的 MA 疫苗。我们对新型 MA 疫苗的初步结果显示出显着的抗体水平和对运动活动的影响，但表明载体蛋白和佐剂将对功效产生关键影响。我们将使用不同的缀合物和不同的免疫载体合成一组 MA 缀合物疫苗。将比较四种载体：破伤风类毒素、脑膜炎奈瑟菌外膜蛋白 (OMPC)、霍乱毒素 B 和一种基于脂肽的新型自我辅助疫苗载体。此外，还将检查和仔细选择一组佐剂，以补充所选载体的生物活性。这些佐剂包括 CpG 寡核苷酸、MPL 和基于角鲨烯的佐剂； CFA 和明矾将作为对照。结果将是啮齿动物模型中抗体反应的数量、质量和持久性以及对 MA 诱导的运动活动的抑制。根据这些数据，将选择一名临床候选药物和 2 名备用药物，并对其进行更详细的描述，以准备 IND 申请。将评估疫苗改变 MA 药代动力学和代谢的能力，以及对 MA 自我给药恢复的抑制作用。最后，将制造出适合用于第一阶段临床试验的材料，并完成正式的毒理学测试。资助期结束后，我们预计将提交 IND 申请并开始 MA 疫苗的临床测试。过去两年，该申请的主要研究人员一直在贝勒大学成功合作。 Thomas Kosten 博士与我们的顾问 Fox 博士合作了 10 多年，开发可卡因疫苗，从临床前概念到成功的临床试验。 Therese Kosten 博士是兴奋剂滥用动物模型方面的领先专家。博士。罗森（Rossen）、鲍恩（Baughn）和奥森（Orson）在免疫学方面拥有丰富的经验，博士。 Orson 和 Kinsey 一直致力于 DMA 疫苗的开发。我们团队的综合经验非常适合将疫苗快速进入第一阶段人体研究。