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）：对甲基苯丙胺（MA）的免疫接种在帮助患者停止滥用方面具有潜在的价值。针对尼古丁和可卡因的疫苗在动物和人体研究中都很有希望。免疫治疗MA成瘾的方法似乎也很有希望，但需要做很多工作来设计一种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和先天免疫系统toll受体信号的发现为调节对外来抗原的免疫反应打开了新的途径。我们将利用这些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。我们的初步结果表明，一种新的MA疫苗显示出大量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在功效上产生关键差异。我们将使用不同的结合物和不同的免疫载体合成一组MA结合疫苗。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和一种新的基于脂肽的自佐剂疫苗载体。此外，将检查一组佐剂，仔细选择以补充所选载体的生物活性。这些佐剂包括CpG寡核苷酸、MPL和角鲨烯基佐剂；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。基于这些数据，将选择一种临床候选药物和2种备用药物，并在准备IND申请时更详细地描述其特征。将评估疫苗改变MA药代动力学和代谢的能力，以及对恢复MA自我给药的抑制作用。最后，将生产适合I期临床试验的材料，并完成正式的毒理学测试。在筹资期结束后，我们预计将提交IND并开始MA疫苗的临床测试。在过去的两年里，贝勒大学的主要研究人员已经成功地进行了合作。Thomas Kosten博士与我们的顾问Fox博士一起工作了10多年，从临床前概念到成功的临床试验，开发了一种可卡因疫苗。therese Kosten博士是兴奋剂滥用动物模型的权威专家。Drs。罗森、鲍恩和奥森在免疫学方面有着丰富的经验。奥森和金赛一直致力于DMA疫苗的开发。我们团队的综合经验为疫苗快速进入人体第一阶段研究奠定了理想的基础。