Engineering of a Novel CDN Nanoparticle Platform

描述(由申请人提供)：多年来，使用蛋白质和多肽抗原来诱导特定的免疫反应一直是一个激烈的努力领域，目标是开发改进的疫苗。原则上，这种方法是有吸引力的，因为它有可能提供免疫学特异性，更严格地控制制造过程，并消除与免疫原生产相关的大多数二次材料来源或污染物。然而，当蛋白质和多肽作为可溶性抗原使用时，通常不能有效地刺激宿主的免疫反应。免疫刺激佐剂分子(IAM)和免疫刺激佐剂分子(IAM)联合应用可以显著提高机体对蛋白质和多肽抗原的免疫应答，但由于它们的物理化学性质不同，往往导致它们共同传递给免疫系统细胞的效率低下。由于蛋白质和多肽抗原通常需要强佐剂来诱导强大的免疫反应，特别是细胞毒性T细胞反应，如果靶抗原能够与IAM一起包装在颗粒输送载体中，则可以产生更有效的免疫原。为了克服将蛋白质和多肽抗原与有效佐剂分子结合在一起的问题，我们一直在开发一种基于纳米颗粒脂质体的技术，称为VesiVax(R)系统，以促进疫苗开发过程。在这些研究中，我们建议证明VesiVax(R)形式的环二核苷酸(CDN)可以刺激强大的免疫反应。通过这项提议创建的VesiVax(R)CDN配方将被设计成可扩展到商业数量并具有成本效益的制造。在SBIR第一阶段研究中，我们将首先在VesiVax(R)系统中配制不同浓度的CDN类似物。为了评估VesiVax(R)CDN制剂的免疫反应和疗效，我们将用我们基于2型单纯疱疹病毒(HSV2)gD胞外结构域糖蛋白(GD1-306-HD)的特性良好的抗原来配制脂质体。含有GD1-306-HD的VesiVax(R)CDN制剂将被制备，并在雌性小鼠和豚鼠单纯疱疹病毒2型感染模型上进行评估。

DESCRIPTION (provided by applicant): For many years, the use of protein and peptide antigens to induce specific immune responses has been an area of intense effort with the goal of developing improved vaccines. In principle, this approach is attractive because it has the potential to provide immunological specificity, tighter control of manufacturing processes, and elimination of most of the secondary sources of materials or contaminants associated with the production of the immunogen. However, proteins and peptides are typically ineffective at stimulating host immune responses when used as soluble antigens. Co-administration with immunostimulatory adjuvant molecules (IAMs) can significantly improve the immune response against protein and peptide antigens, but differences in their physicochemical properties often makes their delivery together to the cells of the immune system inefficient. Since protein and peptide antigens generally require administration with a strong adjuvant to induce potent immune responses, in particular, cytotoxic T cell responses, if the target antigen can be packaged together with an IAM in a particulate delivery vehicle, a much more effective immunogen could be created. To overcome the problem of combining protein and peptide antigens together with a potent adjuvant molecule, we have been developing a nanoparticulate liposome-based technology, called the VesiVax (r) system, to facilitate the vaccine development process. In these studies, we propose to demonstrate that VesiVax(r) formulations of cyclic dinucleotides (CDNs) can stimulate potent immune responses. The VesiVax(r) CDN formulation to be created through this proposal will be designed to be scalable to commercial quantities and cost effective to manufacture. In the SBIR Phase I studies, we will first formulate different concentration of a CDN analog in the VesiVax(r) system. To evaluate the immune response and efficacy of the VesiVax(r) CDN formulations, the liposomes will be formulated with our well-characterized antigen that is based on the gD ectodomain glycoprotein (gD1-306-HD) of the herpes simplex virus type 2 (HSV2). VesiVax(r) CDN formulations containing gD1-306-HD will be prepared and evaluated in female mouse and guinea pig models of HSV2 infection.