Identification and Characterization of an Agonistic Aptamer Against the T Cell Costimulatory Receptor, OX40
Identification and Characterization of an Agonistic Aptamer Against the T Cell Costimulatory Receptor, OX40
复制标题
DOI：
10.1089/nat.2012.0388
复制
发表时间：
2013-02-01
影响因子：
4
通讯作者：
Nair, Smita K.
中科院分区：
文献类型：
--
作者：
Pratico, Elizabeth D.;Sullenger, Bruce A.;Nair, Smita K.
可以靶向并消除恶性细胞或病毒感染细胞的有效免疫应答的诱导需要抗原特异性效应T细胞的刺激。一个富有成效的和持久的记忆反应需要2个信号：通过T细胞受体的接合抗原识别提供的特异性信号和通过这些新激活的T细胞上的共刺激分子（如OX 40）的接合的次级信号。0X 40 - 0X 40-配体相互作用对于产生生产性效应和记忆T细胞功能是关键的。因此，刺激活化T细胞上的0X 40的激动性抗体已被用作佐剂以增强免疫应答。我们先前证明了经修饰以刺激鼠OX 40的适体在鼠黑素瘤模型中增强了疫苗介导的免疫应答。在这项研究中，我们描述了一个激动性的适体，靶向人类OX 40（hOX 40）的发展。使用配体的系统进化通过指数富集分离该h 0X 40适体，并以高亲和力[解离常数（K-d）< 10 nM]结合靶纯化蛋白。此外，如通过流式细胞术测定的，h 0X 40适体-链霉亲和素复合物对活化的T细胞上的h 0X 40具有类似于50 nM的表观结合亲和力，并且特异性结合活化的人T细胞。适体的多价形式，但不是适体的突变形式，能够刺激T细胞上的OX 40并增强细胞增殖和干扰素-γ产生。未来的研究将评估hOX 40适体与基于树突状细胞的疫苗联合用于过继性细胞治疗的抗原特异性T细胞的离体刺激的治疗潜力。
Induction of an effective immune response that can target and eliminate malignant cells or virus-infected cells requires the stimulation of antigen-specific effector T cells. A productive and long-lasting memory response requires 2 signals: a specific signal provided by antigen recognition through engagement of the T cell receptor and a secondary signal via engagement of costimulatory molecules (such as OX40) on these newly activated T cells. The OX40-OX40-ligand interaction is critical for the generation of productive effector and memory T cell functions. Thus agonistic antibodies that stimulate OX40 on activated T cells have been used as adjuvants to augment immune responses. We previously demonstrated that an aptamer modified to stimulate murine OX40 enhanced vaccine-mediated immune responses in a murine melanoma model. In this study, we describe the development of an agonistic aptamer that targets human OX40 (hOX40). This hOX40 aptamer was isolated using systematic evolution of ligands by exponential enrichment and binds the target purified protein with high affinity [dissociation constants (K-d) < 10 nM]. Moreover, the hOX40 aptamer-streptavidin complex has an apparent binding affinity of similar to 50nM for hOX40 on activated T cells as determined by flow cytometry and specifically binds activated human T cells. A multivalent version of the aptamer, but not a mutant version of the aptamer, was able to stimulate OX40 on T cells and enhance cell proliferation and interferon-gamma production. Future studies will assess the therapeutic potential of hOX40 aptamers for ex vivo stimulation of antigen specific T cells in conjunction with dendritic cell-based vaccines for adoptive cellular therapy.