Liposomal Nicotine Vaccine Development

描述(由申请人提供)：为了响应RFA-DA-11-004，我们在这项STTR第一阶段申请中建议开发和测试一种尼古丁疫苗，该疫苗使用药物的化学衍生物或半抗原，与免疫刺激、含有佐剂的脂质体偶联。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，但这种方法只产生了不大的效果。疫苗方法允许个体产生免疫反应，当尼古丁仍在血液中时，高度特异的抗体隔离尼古丁。然后，抗体-药物复合体可以通过削弱尼古丁通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的任何有害副作用。为了优化产生的免疫反应，脂质体配方将包括选定的Toll样受体(TLR)激动剂作为佐剂。TLRs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括以下用于测试的TLR激动剂：MPL(TLR4)；洛索里宾(TLR7/8)和含有CpG基序的寡核苷酸(TLR9)。含有TLR的免疫原脂质体将与Janda实验室鉴定的烟碱半抗原AM1偶联。这种半抗原将通过一步反应连接到VesiVax(R)可结合佐剂脂泡(CALV)上。一旦制备和表征，将在小鼠身上测试免疫原性。这些第一阶段的研究将使我们能够确定一种或多种VesiVax(R)。-尼古丁配方，以优化和开发成尼古丁疫苗，在STTR第二阶段的应用中取得临床进展。 与公共健康相关：尼古丁是世界上使用最广泛、最容易获得的合法精神刺激剂，并且具有很强的附加性。基于尼古丁半抗原与免疫原脂质体制剂相结合的疫苗的交付代表着在遏制尼古丁成瘾方面的重大进展。这种创新的方法最大限度地提高了尼古丁部分的免疫原性，方法是将尼古丁部分与Toll样受体佐剂脂质体结合，以诱导能够与存在于血流中的尼古丁药物结合和隔离的高特异性抗体。这种方法可以通过阻止自由接触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担忧之一。

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.