Dept. of Medicinal and Biological Chemistry , University of Toledo , Toledo , Ohio 43606 , United States.
Dept. of Chemistry and Biochemistry , University of Toledo , Toledo , Ohio 43606 , United States.
ACS Chem Biol. 2018 Aug 17;13(8):2130-2142. doi: 10.1021/acschembio.8b00312. Epub 2018 Jul 2.
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 PamCysSK, 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.
利用天然抗体来增强疫苗的免疫原性是癌症免疫治疗的一种很有前途的方法。抗岩藻糖（anti-Rha）抗体是存在于人类血清中的一些最常见的天然抗碳水化合物抗体。因此，岩藻糖可用作含有岩藻糖的疫苗的靶向部分，以制备有效的疫苗制剂。先前已经表明，在小鼠中产生的抗-Rha 抗体可有效地与岩藻糖偶联疫苗结合，并通过刺激性 Fc 受体被抗原呈递细胞 (APC) 摄取。这导致抗原的有效摄取和加工，最终由主要组织相容性复合物 (MHC) 分子呈递。在本文中，我们表明天然人抗-Rha 抗体也可以以类似的机制使用，并且可以通过靶向岩藻糖偶联抗原来增强免疫原性。为此，我们使用岩藻糖亲和柱从人血清中纯化了人抗-Rha 抗体。在体外，人抗-Rha 抗体被证明可增强 APC 对模型抗原岩藻糖-卵清蛋白（Rha-Ova）的摄取。在体内，与非抗-Rha 人抗体相比，它们可改善对 Rha-Ova 的 CD4+T 细胞的启动。此外，在接受岩藻糖修饰的 MUC1-Tn 癌症疫苗接种之前接受人抗-Rha 抗体的小鼠中，观察到对癌症抗原 MUC1-Tn 的 CD4+和 CD8+T 细胞的启动均增加。疫苗缀合物包含 PamCysSK，一种 Toll 样受体 (TLR) 激动剂，通过铜自由基加成化学与源自肿瘤标志物 MUC-1 的 20 个氨基酸糖肽连接，该糖肽含有肿瘤相关碳水化合物抗原α-N-乙酰半乳糖胺（GalNAc）。被激活的 CD8+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造有效疫苗的靶向部分。
