Augmenting Vaccine Immunogenicity through the Use of Natural Human Anti-rhamnose Antibodies.
Augmenting Vaccine Immunogenicity through the Use of Natural Human Anti-rhamnose Antibodies.
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DOI：
10.1021/acschembio.8b00312
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发表时间：
2018-08-17
影响因子：
4
通讯作者：
Wall KA
中科院分区：
文献类型：
--
作者：
Hossain MK;Vartak A;Karmakar P;Sucheck SJ;Wall KA
利用天然抗体增强疫苗的免疫原性是一种很有前途的癌症免疫治疗方法。抗鼠李糖（抗Rha）抗体是存在于人血清中的一些最常见的天然抗碳水化合物抗体。因此，鼠李糖可用作含鼠李糖疫苗的靶向部分以制备有效的疫苗制剂。先前显示，在小鼠中产生的抗Rha抗体与Rha缀合的疫苗有效结合，并通过刺激性Fc受体被抗原呈递细胞（APC）拾取。这导致抗原的有效摄取和加工，并最终通过主要组织相容性复合体（MHC）分子呈递。在这篇文章中，我们表明，天然的人抗Rha抗体也可以用于类似的机制和免疫原性可以通过靶向Rha结合抗原增强。在这样做时，我们已经使用鼠李糖亲和柱从人血清中纯化了人抗Rha抗体。在体外，人抗Rha抗体显示出增强APC对模型抗原Rha-卵清蛋白（Rha-Ova）的摄取。在体内，与非抗Rha人抗体相比，他们改善了CD 4 + T细胞对Rha-Ova的引发。此外，在接种鼠李糖修饰的MUC 1-Tn癌症疫苗之前接受人抗Rha抗体的小鼠中观察到CD 4+和CD 8 + T细胞对癌症抗原MUC 1-Tn的引发增加。疫苗偶联物含有Pam 3CysSK 4，Pam 3CysSK 4是一种Toll样受体（TLR）激动剂，通过无铜环加成化学反应与源自肿瘤标志物MUC-1的20个氨基酸糖肽连接，MUC-1含有肿瘤相关碳水化合物抗原α-N-乙酰半乳糖胺（GalNAc）。致敏的CD 8 + T细胞释放IFN-γ并杀死肿瘤细胞。因此，我们已经证实，人抗Rha抗体可以有效地用作制备有效疫苗的靶向部分。
Utilizing natural antibodies to augment vaccine immunogenicity is a promising approach toward cancer immunotherapy. Anti-rhamnose (anti-Rha) antibodies are some of the most common natural anti-carbohydrate antibodies present in human serum. Therefore, rhamnose can be utilized as a targeting moiety for a rhamnose-containing vaccine to prepare an effective vaccine formulation. It was shown previously that anti-Rha antibody generated in mice binds effectively with Rha-conjugated vaccine and is picked up by antigen presenting cells (APCs) through stimulatory Fc receptors. This leads to the effective uptake and processing of antigen and eventually presentation by major histocompatibility complex (MHC) molecules. In this article, we show that natural human anti-Rha antibodies can also be used in a similar mechanism and immunogenicity can be enhanced by targeting Rha-conjugated antigens. In doing so, we have purified human anti-Rha antibodies from human serum using a rhamnose affinity column. In vitro, human anti-Rha antibodies are shown to enhance the uptake of a model antigen, Rha-ovalbumin (Rha-Ova), by APCs. In vivo, they improved the priming of CD4+ T cells to Rha-Ova in comparison to non-anti-Rha human antibodies. Additionally, increased priming of both CD4+ and CD8+ T cells toward the cancer antigen MUC1-Tn was observed in mice that received human anti-Rha antibodies prior to vaccination with a rhamnose-modified MUC1-Tn cancer vaccine. The vaccine conjugate contained Pam3CysSK4, a Toll-like receptor (TLR) agonist linked via copper-free cycloaddition chemistry to a 20-amino-acid glycopeptide derived from the tumor marker MUC-1 containing the tumor-associated carbohydrate antigen α-N-acetyl galactosamine (GalNAc). The primed CD8+ T cells released IFN-γ and killed tumor cells. Therefore, we have confirmed that human anti-Rha antibodies can be effectively utilized as a targeting moiety for making an effective vaccine.
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使用鼠李糖功能化脂质体通过天然抗碳水化合物抗体靶向肿瘤细胞
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