Antigen delivery using novel Fc receptor ligands

说明(申请人提供)：为了使疫苗有效，疫苗混合物中包含的抗原必须获得并由抗原提呈细胞递呈。以明矾为基础的疫苗通常会导致免疫反应不对称或不完全。此外，针对明矾中的单分子或多肽片段的免疫反应通常很弱。我们开发了一种新的将抗原输送到抗原提呈细胞的策略，初步研究表明，这种策略在增强体内和体外的抗原特异性免疫反应方面非常有效。我们的策略依赖于使用新型的FcGammaR工程配体(FcRls)来靶向抗原提呈细胞上表达的FcGammaR(FcGammaR)，FcGammaR(FcRls)是由Ig G的铰链和CH2(HCH2)区域的线性聚合物组成的。FcRL具有许多有利的特性，这表明它们作为疫苗递送剂的潜力。拟议研究的目的是确定FcRls是否可以作为疫苗递送系统，以肉毒杆菌神经毒素作为模式毒素诱导保护性免疫。为了实现这些目标，我们提出：1)。利用FcRLS作为疫苗递送剂来诱导针对BONT/A的免疫反应。FcRls作为BoNT HC抗原疫苗递送剂的优化。3)。FcRL诱导的针对ONT/A HC抗原的免疫应答的特征。4)。FcRL诱导的抗原提呈细胞功能改变的特征。 我们的初步数据表明，使用FcRls靶向APC抗原是设计新疫苗的一种合理而有效的策略。拟议的研究将包括1)。开发潜在有效的针对BONT的免疫原。2)确定在疫苗开发中使用FcRls的效果。3)建立针对Fc的靶向抗原的效用(R作为一种增强APC提呈抗原的手段和4)提供关于Fc(R介导的内化)中作用的补体的基本信息。在这些研究过程中获得的知识将适用于建立对包括大量NIAID A、B和C类优先病原体及其有毒产物在内的多种病原体的保护性免疫。这些毒素的例子包括炭疽毒素、蓖麻毒素和相关毒素以及肉毒梭菌神经毒素。

DESCRIPTION (provided by applicant): For vaccines to be effective, antigens contained in the vaccine mixture must be acquired and presented by antigen presenting cells. Alum-based vaccines often result in the induction of immune responses that are skewed or incomplete. Additionally, immune responses directed against single molecules or peptide fragments in alum are often weak. We have developed a novel strategy for delivering antigen to antigen presenting cells that preliminary studies have shown to be highly effective at augmenting antigen-specific immune responses in vivo and in vitro. Our strategy relies on targeting antigen to Fcgamma receptors (FcgammaR) expressed on antigen presenting cells using novel engineered ligands for FcgammaR (FcRLs) that are composed of linear polymers of the hinge and CH2 (HCH2) regions of IgG. FcRLs have many advantageous features which suggests their potential as a vaccine delivery agents. The goal of the proposed studies is to determine if FcRLs can function as a vaccine delivery system for the purpose of inducing protective immunity using botulinum neurotoxin as a model toxin. To accomplish these goals we propose the: 1). Utilization of FcRLs as a vaccine delivery agent for the induction of immune responses against BoNT/A. 2). Optimization of FcRLs as vaccine delivery agent for BoNT Hc antigens. 3). Characterization of FcRL-induced immune responses to BoNT/A Hc antigens. 4). Characterization of FcRL-induced alterations in antigen presenting cell function. Our preliminary data are suggestive that using FcRLs to target antigen to APCs represent a sound and effective strategy for the design of new vaccines. The proposed studies will 1). Develop potentially effective immunogens against BoNT. 2) Determine the efficacy of using FcRLs in vaccine development. 3) Establish the utility of targeting antigen to Fc(R as a means of augmenting antigen presentation by APCs and 4) Provide basic information on the role complement in Fc(R mediated internalization The knowledge gained in the course of these studies would have applicability to the establishment of protective immunity against a wide number of pathogens including numerous NIAID Category A, B and C Priority Pathogens and their toxic products. Examples of these include anthrax toxin, ricin and related toxins and the clostridium botulinum neurotoxins.