Increasing vaccine potency through exosome antigen targeting.
Increasing vaccine potency through exosome antigen targeting.
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DOI：
10.1016/j.vaccine.2011.09.133
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发表时间：
2011-11-21
期刊：
影响因子：
5.5
通讯作者：
Lyerly, Herbert K.
中科院分区：
文献类型：
--
作者：
Hartman, Zachary C.;Wei, Junping;Glass, Oliver K.;Guo, Hongtao;Lei, Gangjun;Yang, Xiao-Yi;Osada, Takuya;Hobeika, Amy;Delcayre, Alain;Le Pecq, Jean-Bernard;Morse, Michael A.;Clay, Timothy M.;Lyerly, Herbert K.
虽然已经在人类癌症中鉴定了许多肿瘤相关抗原（TAA），但是使用经典疫苗方法开发有效的TAA“癌症疫苗”的努力在很大程度上是无效的。最近，已经建立了一种将蛋白质特异性靶向外泌体的方法，该方法利用了乳凝集素的因子V样C1C2结构域将蛋白质特异性靶向外泌体的能力。使用这种方法，我们假设TAA可以靶向外泌体以潜在地增加其免疫原性，因为外泌体已被证明可以运输至抗原呈递细胞（APC）。为了研究这种可能性，我们创建了腺病毒载体，表达两种非突变TAA的细胞外结构域（ECD），这两种TAA通常在癌症患者的肿瘤中发现，癌胚抗原（CEA）和HER2，并将它们偶联到乳凝集素的C1C2结构域。我们发现这些C1C2融合蛋白在体外外泌体中具有增强的表达。我们在未处理和耐受转基因动物模型中观察到对这些抗原中的每一种的抗原特异性免疫应答的显著改善，并且可以进一步证明在人HER2+转基因动物模型中显著增强的治疗性抗肿瘤作用。这些发现表明分泌和运输的模式可以影响不同人TAA的免疫原性，并且可以解释在癌症患者中发现的非突变TAA缺乏免疫原性。他们认为外泌体靶向可以增强未来的抗肿瘤疫苗接种方案。这种靶向外泌体的过程也可以适用于开发一些病毒和寄生虫疾病的更有效疫苗，其中经典疫苗方法已证明存在局限性。
While many tumor associated antigens (TAAs) have been identified in human cancers, efforts to develop efficient TAA “cancer vaccines” using classical vaccine approaches have been largely ineffective. Recently, a process to specifically target proteins to exosomes has been established which takes advantage of the ability of the Factor V like C1C2 domain of lactadherin to specifically address proteins to exosomes. Using this approach, we hypothesized that TAAs could be targeted to exosomes to potentially increase their immunogenicity, as exosomes have been demonstrated to traffic to antigen presenting cells (APC). To investigate this possibility, we created adenoviral vectors expressing the extracellular domain (ECD) of two non-mutated TAAs often found in tumors of cancer patients, carcinoembryonic antigen (CEA) and HER2, and coupled them to the C1C2 domain of lactadherin. We found that these C1C2 fusion proteins had enhanced expression in exosomes in vitro. We saw significant improvement in antigen specific immune responses to each of these antigens in naïve and tolerant transgenic animal models and could further demonstrate significantly enhanced therapeutic anti-tumor effects in a human HER2+ transgenic animal model. These findings demonstrate that the mode of secretion and trafficking can influence the immunogenicity of different human TAAs, and may explain the lack of immunogenicity of non-mutated TAAs found in cancer patients. They suggest that exosomal targeting could enhance future anti-tumor vaccination protocols. This targeting exosome process could also be adapted for the development of more potent vaccines in some viral and parasitic diseases where the classical vaccine approach has demonstrated limitations.
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DOI：
10.1007/978-1-61779-068-3_15
发表时间：
2011-01-01
期刊：
SERUM/PLASMA PROTEOMICS: METHODS AND PROTOCOLS
影响因子：
--
作者：
Taylor, Douglas D.;Zacharias, Wolfgang;Gercel-Taylor, Cicek
通讯作者：
Gercel-Taylor, Cicek
影响因子：
2.2
作者：
Lamparski, HG;Metha-Damani, A;Le Pecq, JB
通讯作者：
Le Pecq, JB
影响因子：
5.6
作者：
Lin, Lin;Huai, Oing;Furie, Barbara C.
通讯作者：
Furie, Barbara C.
影响因子：
11.2
作者：
Rountree, Ryan B.;Mandl, Stefanie J.;Delcayre, Alain
通讯作者：
Delcayre, Alain
影响因子：
2.3
作者：
Clayton, A;Tabi, Z
通讯作者：
Tabi, Z