Liposomal Nicotine Vaccine Development

脂质体尼古丁疫苗开发

• 批准号: 8211742
• 负责人: Gary Fujii
• 金额: $ 34.48万
• 依托单位: MOLECULAR EXPRESS, INC.
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-01 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8211742
• 关键词: Achievement; Adjuvant; Adverse drug effect; Affinity; Agonist; Alkaloids; Animals; Antibodies; Antibody Specificity; Antigen Targeting; Antigens; Binding; Biological; Biological Assay; Blood - brain barrier anatomy; Blood Circulation; Brain; Buffers; Caliber; Carbohydrates; Chemicals; Cigar; Cigarette; Clinical; Complex; Coupled; Development; Disease; Dose; Drug Delivery Systems; Drug Formulations; Engineering; Enzyme-Linked Immunosorbent Assay; Goals; Haptens; Health; Immune response; Immune system; Immunization; Inbred BALB C Mice; Individual; Inflammatory; Laboratories; Lead; Legal; Lipids; Liposomes; Loxoribine; Measures; Methods; Molecular; Monitor; Mus; Neuraxis; Nicotine; Nicotine Dependence; Oligonucleotides; One-Step dentin bonding system; Oral Tobacco; Peptides; Pharmaceutical Preparations; Phase; Precipitation; Production; Radioimmunoassay; Reaction; Regulatory Pathway; Relative (related person); Safety; Sampling; Serum; Signal Transduction; Small Business Technology Transfer Research; Solutions; Specificity; Subcutaneous Injections; Surface; System; TLR4 gene; TLR7 gene; Technology; Testing; Time; Tobacco; Toll-like receptors; United States; Vaccinated; Vaccination; Vaccines; Vesicle; Withdrawal Symptom; aluminum sulfate; base; commercialization; craving; design; engineering design; flexibility; immunogenic; immunogenicity; in vivo; innovation; interest; manufacturing process; meetings; monophosphoryl lipid A; nicotine replacement; phase 1 study; prevent; psychostimulant; receptor; response; success; vaccine development; vaccine efficacy

DESCRIPTION (provided by applicant): In response to RFA-DA-11-004, we propose in this STTR Phase I application to develop and test a nicotine vaccine utilizing a chemical derivative of the drug, or hapten, coupled to an immunostimulatory, adjuvant-containing liposome. The current approach to curbing nicotine addiction is the use of over the counter nicotine replacement products, but this approach has yielded only modest results. A vaccine approach allows the individual to mount an immune response wherein highly specific antibodies sequester the nicotine while it is still in the bloodstream. The antibody-drug complex can then counteract the reinforcing effects of the nicotine by blunting the ability of nicotine to cross the blood-brain barrier, as well as preventing any detrimental side effects of the drug on the central nervous system. In order to optimize the immune response generated, the liposomal formulations will include selected Toll-like receptor (TLR) agonists as adjuvants. TLRs augment the immune response by activating an inflammatory signaling cascade in the host. Our initial formulations will incorporate the following TLR agonists for testing: MPL (TLR4); loxoribine (TLR7/8) and; an oligonucleotide containing a CpG motif (TLR9). The TLR- containing immunogenic liposomes will be conjugated to the lead nicotine hapten, AM1, which was identified by the Janda laboratory. This hapten will be conjugated to the VesiVax(R) conjugatable adjuvant lipid vesicles (CALV) using a one step reaction. Once prepared and characterized, the lipsomes will be tested for immunogenicity in mice. These Phase I studies will allow us to identify one or more VesiVax(R).-nicotine formulations to optimize and develop into a nicotine vaccine for clinical advancement in the STTR Phase II application. PUBLIC HEALTH RELEVANCE: Nicotine is the most widely used, readily available legal psychostimulant in the world and is highly additictive. The delivery of a vaccine based on a nicotine hapten coupled to an immunogenic liposome formulation represents a significant advancement in curbing nicotine addiction. This innovative approach maximizes the immunogenic potential of the nicotine moiety by formulating it with a Toll- like Receptor adjuvant loaded liposome to elicit high specificity antibodies capable of binding to and sequestering nicotine drug present in the bloodstream. This method could decrease the addictive potential of nicotine by preventing free access to receptors in the brain thus, alleviating one of the largest health concerns in the United States.

描述（由申请人提供）：为了响应 RFA-DA-11-004，我们建议在此 STTR 第一阶段申请中利用药物的化学衍生物或半抗原与免疫刺激性含佐剂脂质体偶联来开发和测试尼古丁疫苗。目前抑制尼古丁成瘾的方法是使用非处方尼古丁替代产品，但这种方法收效甚微。疫苗方法允许个体产生免疫反应，其中高度特异性的抗体在尼古丁仍在血液中时隔离尼古丁。然后，抗体-药物复合物可以通过削弱尼古丁穿过血脑屏障的能力来抵消尼古丁的增强作用，并防止药物对中枢神经系统产生任何有害的副作用。 为了优化产生的免疫反应，脂质体制剂将包含选定的 Toll 样受体 (TLR) 激动剂作为佐剂。 TLR 通过激活宿主体内的炎症信号级联反应来增强免疫反应。我们的初始配方将包含以下 TLR 激动剂进行测试：MPL (TLR4)；洛索立宾 (TLR7/8) 和；含有 CpG 基序 (TLR9​​) 的寡核苷酸。含有 TLR 的免疫原性脂质体将与 Janda 实验室鉴定的主要尼古丁半抗原 AM1 缀合。该半抗原将通过一步反应与 VesiVax® 可缀合佐剂脂质囊泡 (CALV) 缀合。一旦制备和表征，脂质体将在小鼠中进行免疫原性测试。这些 I 期研究将使我们能够确定一种或多种 VesiVax(R).-尼古丁配方，以优化并开发成尼古丁疫苗，以促进 STTR II 期应用的临床进展。 公共卫生相关性：尼古丁是世界上使用最广泛、最容易获得的合法精神兴奋剂，并且具有高度成瘾性。基于与免疫原性脂质体制剂偶联的尼古丁半抗原的疫苗的递送代表了抑制尼古丁成瘾方面的显着进步。这种创新方法通过将尼古丁部分与装载有Toll样受体佐剂的脂质体配制在一起，以引发能够结合并隔离血液中存在的尼古丁药物的高特异性抗体，从而最大限度地提高尼古丁部分的免疫原性潜力。这种方法可以通过阻止尼古丁自由进入大脑中的受体来降低尼古丁的成瘾潜力，从而缓解美国最大的健康问题之一。