Optimization of VesiVax® Lipidated Tucaresol Formulations

 描述(由申请人提供)：人们对开发新的免疫刺激佐剂分子有很大的兴趣和需求，这些佐剂分子可以刺激强大的免疫反应。到目前为止，唯一被批准用于人类的免疫刺激佐剂分子是Toll样受体(TLR)4激动剂，单磷酰脂A(MPL)。其他免疫刺激佐剂分子，如Poly I：C，合成双链RNA模拟物(TLR3)，Resiquimod，合成单链RNA模拟物(TLR7/8)或CpG，DNA寡核苷酸(TLR9)，已在一些疾病适应症的临床开发中。一类新的免疫刺激佐剂分子--环二核苷酸(CDN)最近被证明通过激活一种称为干扰素基因刺激物(STINT)的内部受体而发挥出强大的免疫刺激特性。在这个项目中，我们建议优化一种小分子免疫刺激佐剂Tucaresol，我们合成了这种佐剂的“脂尾”，以便于在VesiVax(R)疫苗和佐剂平台技术中进行配方。我们将合成脂化的对甲酚(LT)衍生物，并用一种模型重组蛋白抗原(即gD3PEPcD-HD)制备VesiVax(R)LT制剂，我们已经证明，这种重组蛋白抗原在我们特征良好的小鼠阴道内HSV2攻击模型中提供保护性免疫反应。

 DESCRIPTION (provided by applicant): There is a significant interest and need for developing new immunostimulatory adjuvant molecules that stimulate potent immune responses. To date, the only immunostimulatory adjuvant molecule that has been approved for human use is the Toll-like Receptor (TLR) 4 agonist, monophosphoryl lipid A (MPL). Other immunostimulatory adjuvant molecules such as poly I:C, a synthetic double stranded RNA mimic (TLR3), resiquimod, a synthetic single stranded RNA mimic (TLR7/8) or CpG, a DNA oligonucleotide (TLR9), have been in clinical development for a number of disease indications. A new class of immunostimulatory adjuvant molecules, cyclic dinucleotides (CDNs), have recently been shown to exert potent immunostimulatory properties through activation of an internal receptor called the STimulator of INterferon Genes (STING). In this project, we propose to optimize a small molecule immunostimulatory adjuvant, tucaresol, which we have synthesized with a "lipid tail" to facilitate formulation in the VesiVax(r) vaccine and adjuvant platform technology. We will synthesize lipidated tucaresol (LT) derivatives and prepare VesiVax(r) LT formulations with a model recombinant protein antigen (i.e., gD3PEPcD-HD) which we have shown to provide protective immune responses in our well-characterized mouse model of intravaginal HSV2 challenge.