Multivalent 4-1BB binding aptamers costimulate CD8+ T cells and inhibit tumor growth in mice
Multivalent 4-1BB binding aptamers costimulate CD8+ T cells and inhibit tumor growth in mice
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DOI：
10.1172/jci33365
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发表时间：
2008-01-01
影响因子：
15.9
通讯作者：
Gilboa, Eli
中科院分区：
文献类型：
--
作者：
McNamara, James O., II;Kolonias, Despina;Gilboa, Eli
4-1BB是促进活化T细胞存活和扩增的主要共刺激受体。先前已显示施用激动性抗4-1BB Ab增强小鼠中的肿瘤免疫。抗体是基于细胞的产品，带来了巨大的成本、制造和监管挑战。适体是基于寡核苷酸的配体，其表现出与Ab相当或超过Ab的特异性和亲合力。迄今为止，各种适体已显示出抑制其同源靶标的功能。在这里，我们已经描述了开发的适体，结合4-1BB活化的小鼠T细胞的表面上表达的，并显示，多价配置的适体共刺激T细胞在体外活化和介导的肿瘤排斥小鼠。因为适体可以化学合成，所以制造和监管批准过程应该比Ab简单得多并且成本更低。因此，激动性适体可以代表用于免疫系统的治疗操作的Ab的上级替代方案。
4-1BB is a major costimulatory receptor that promotes the survival and expansion of activated T cells. Administration of agonistic anti-4-1BB Abs has been previously shown to enhance tumor immunity in mice. Abs are cell-based products posing significant cost, manufacturing and regulatory challenges. Aptamers are oligo-nucleotide-based ligands that exhibit specificity and avidity comparable to, or exceeding, that of Abs. To date, various aptamers have been shown to inhibit the function of their cognate target. Here, we have described the development of an aptamer that binds 4-1BB expressed on the surface of activated mouse T cells and shown that multivalent configurations of the aptamer costimulated T cell activation in vitro and mediated tumor rejection in mice. Because aptamers can be chemically synthesized, manufacturing and the regulatory approval process should be substantially simpler and less costly than for Abs Agonistic aptamers could therefore represent a superior alternative to Abs for the therapeutic manipulation of the immune system.