Antigen delivery using novel Fc receptor ligands

说明（由申请人提供）：为了使疫苗有效，疫苗混合物中含有的抗原必须由抗原提呈细胞获得并呈递。铝基疫苗往往导致免疫反应的诱导是扭曲的或不完整的。此外，针对明矾中的单分子或肽片段的免疫反应往往很弱。我们已经开发了一种将抗原递送到抗原呈递细胞的新策略，初步研究表明，该策略在体内和体外增强抗原特异性免疫反应方面非常有效。我们的策略依赖于将抗原靶向到抗原呈递细胞上表达的Fcgamma受体（Fcgamma），使用新型工程Fcgamma配体（fcrl），该配体由IgG的铰链和CH2 （HCH2）区域的线性聚合物组成。fcrl具有许多有利的特征，这表明它们具有作为疫苗递送剂的潜力。拟议研究的目的是确定fcrl是否可以作为疫苗递送系统，以肉毒杆菌神经毒素作为模型毒素诱导保护性免疫。为了实现这些目标，我们提出：1)。利用fcrl作为疫苗递送剂诱导针对BoNT/ a的免疫应答。2）. fcrl作为BoNT Hc抗原疫苗递送剂的优化3）. fcrl诱导的BoNT/A Hc抗原免疫反应的表征。4）. fcrl诱导抗原呈递细胞功能改变的表征。

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.