Liposomal Nicotine Vaccine Development

描述（由申请方提供）：作为对RFA-DA-11-004的回应，我们在本STTR I期申请中提议开发和检测一种尼古丁疫苗，该疫苗利用药物的化学衍生物或半抗原，与免疫刺激性、含澄清剂的脂质体偶联。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有限的效果。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流中时将其隔离。然后，抗体-药物复合物可以通过减弱尼古丁穿过血脑屏障的能力来抵消尼古丁的增强作用，以及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择的Toll样受体（TLR）激动剂作为佐剂。TLR通过激活宿主中的炎症信号级联来增强免疫应答。我们的初始制剂将包含以下TLR激动剂用于测试：MPL（TLR 4）;洛索立宾（TLR 7/8）和;含有CpG基序的寡核苷酸（TLR 9）。含有TLR的免疫原性脂质体将与由Janda实验室鉴定的尼古丁半抗原AM 1结合。该半抗原将使用一步反应与VesiVax（R）可缀合的佐剂脂质囊泡（CALV）缀合。制备和表征后，将在小鼠中检测脂质体的免疫原性。这些I期研究将使我们能够识别一种或多种VesiVax（R）。尼古丁制剂，以优化和开发成尼古丁疫苗，用于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、最容易获得的法律的精神兴奋剂，具有高度的添加性。基于偶联至免疫原性脂质体制剂的尼古丁半抗原的疫苗的递送代表了抑制尼古丁成瘾的显著进步。这种创新方法通过将尼古丁部分与负载Toll样受体佐剂的脂质体一起配制，以引发能够结合并螯合血流中存在的尼古丁药物的高特异性抗体，从而使尼古丁部分的免疫原性潜力最大化。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，从而减轻美国最大的健康问题之一。

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.