Department of Chemistry, Chemistry Building, Room 426, 578 South Shaw Lane, Michigan State University , East Lansing, Michigan 48824, United States.
ACS Chem Biol. 2013;8(6):1253-62. doi: 10.1021/cb400060x. Epub 2013 Mar 29.
The development of an effective immunotherapy is an attractive strategy toward cancer treatment. Tumor associated carbohydrate antigens (TACAs) are overexpressed on a variety of cancer cell surfaces, which present tempting targets for anticancer vaccine development. However, such carbohydrates are often poorly immunogenic. To overcome this challenge, we show here that the display of a very weak TACA, the monomeric Tn antigen, on bacteriophage Qβ virus-like particles elicits powerful humoral responses to the carbohydrate. The effects of adjuvants, antigen display pattern, and vaccine dose on the strength and subclasses of antibody responses were established. The local density of antigen rather than the total amount of antigen administered was found to be crucial for induction of high Tn-specific IgG titers. The ability to display antigens in an organized and high density manner is a key advantage of virus-like particles such as Qβ as vaccine carriers. Glycan microarray analysis showed that the antibodies generated were highly selective toward Tn antigens. Furthermore, Qβ elicited much higher levels of IgG antibodies than other types of virus-like particles, and the IgG antibodies produced reacted strongly with the native Tn antigens on human leukemia cells. Thus, Qβ presents a highly attractive platform for the development of carbohydrate-based anticancer vaccines.
开发有效的免疫疗法是癌症治疗的一种有吸引力的策略。肿瘤相关碳水化合物抗原(TACA)在多种癌细胞表面过度表达,这为抗癌疫苗的开发提供了诱人的目标。然而,这些碳水化合物通常免疫原性较差。为了克服这一挑战,我们在这里表明,在噬菌体 Qβ病毒样颗粒上展示非常弱的 Tn 抗原单体可引发针对碳水化合物的强大体液反应。确定了佐剂、抗原展示模式和疫苗剂量对抗体反应的强度和亚类的影响。发现抗原的局部密度而不是给予的抗原总量对于诱导高 Tn 特异性 IgG 滴度至关重要。以有组织和高密度方式展示抗原的能力是 Qβ等病毒样颗粒作为疫苗载体的关键优势。糖基微阵列分析表明,产生的抗体对 Tn 抗原具有高度选择性。此外,Qβ 引发的 IgG 抗体水平远高于其他类型的病毒样颗粒,并且产生的 IgG 抗体与人白血病细胞上的天然 Tn 抗原强烈反应。因此,Qβ为开发基于碳水化合物的抗癌疫苗提供了一个极具吸引力的平台。
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