Liposomal Nicotine Vaccine Development

描述（由申请人提供）：为了响应RFA-DA-11-004，我们建议在STTR I期申请中开发和测试一种尼古丁疫苗，该疫苗利用药物的化学衍生物或半抗原偶联免疫刺激、含佐剂的脂质体。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有限的效果。一种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将其隔离。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强化作用，同时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应答，脂质体制剂将包括选定的toll样受体（TLR）激动剂作为佐剂。tlr通过激活宿主的炎症信号级联来增强免疫反应。我们的初始配方将纳入以下TLR激动剂进行测试：MPL (TLR4)；洛索瑞滨（TLR7/8）；含有CpG基序的寡核苷酸（TLR9）。含TLR的免疫原性脂质体将与Janda实验室鉴定的尼古丁半抗原AM1偶联。该半抗原将通过一步反应与VesiVax(R)共轭佐剂脂质囊泡（CALV）偶联。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)。-尼古丁配方优化并开发成尼古丁疫苗，用于STTR二期临床应用。

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.