Developing Immunotherapeutics for Methamphetamine Abuse

开发针对甲基苯丙胺滥用的免疫疗法

• 批准号: 7894904
• 负责人: FRANK M ORSON
• 金额: $ 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 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7894904
• 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; Methamphetamine dependence; 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; 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)：甲基苯丙胺(MA)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。治疗MA成瘾的免疫治疗方法似乎也很有希望，但要设计一种诱导高水平特异性抗体的MA疫苗，还需要做很多工作。最近关于调节性细胞因子和趋化因子网络以及天然免疫系统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研制安全有效的MA疫苗。我们对一种新的MA疫苗的初步结果显示了大量的抗体水平和对运动活性的影响，但表明载体蛋白和佐剂将在疗效上产生关键的差异。我们将使用不同的结合物和不同的免疫载体合成一组结合物MA疫苗。将对四种载体进行比较：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我调节疫苗载体。此外，还将检查一组佐剂，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和角鲨烯类佐剂；CFA和明矾将作为对照。结果将是在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人和两名备份，并更详细地描述，为IND申报做准备。将评估疫苗改变MA药代动力学和新陈代谢的能力，以及抑制MA自我给药的恢复。最后，将制造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。在资助期结束时，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，这一应用程序的主要研究人员一直在贝勒成功地合作。托马斯·科斯滕博士与我们的顾问福克斯博士合作了10多年，开发出从临床前概念到成功的临床试验的可卡因疫苗。Therese Kosten博士是兴奋剂滥用动物模型方面的领先专家。Rossen博士、Baughn博士和Orson博士在免疫学方面拥有丰富的经验，Orson博士和Kinsey博士一直致力于DMA疫苗的开发。我们小组的联合经验非常适合将疫苗迅速进入第一阶段人体研究。

项目成果

Hapten optimization for cocaine vaccine with improved cocaine recognition.

优化可卡因疫苗的合粒，提高可卡因识别率。

• DOI: 10.1111/cbdd.12326
• 发表时间: 2014-09
• 期刊: Chemical biology & drug design
• 影响因子: 3
• 作者: Ramakrishnan M;Kinsey BM;Singh RA;Kosten TR;Orson FM
• 通讯作者: Orson FM

A vaccine against methamphetamine attenuates its behavioral effects in mice.

• DOI: 10.1016/j.drugalcdep.2012.09.007
• 发表时间: 2013-04-01
• 期刊: DRUG AND ALCOHOL DEPENDENCE
• 影响因子: 4.2
• 作者: Shen, Xiaoyun Y.;Kosten, Therese A.;Lopez, Angel Y.;Kinsey, Berma M.;Kosten, Thomas R.;Orson, Frank M.
• 通讯作者: Orson, Frank M.