Antibodies targeting Clec9A promote strong humoral immunity without adjuvant in mice and non-human primates
Antibodies targeting Clec9A promote strong humoral immunity without adjuvant in mice and non-human primates
复制标题
DOI：
10.1002/eji.201445127
复制
发表时间：
2015-03-01
影响因子：
5.4
通讯作者：
Caminschi, Irina
中科院分区：
文献类型：
--
作者：
Li, Jessica;Ahmet, Fatma;Caminschi, Irina
使用抗体将抗原靶向树突状细胞（DC）表面受体已成功用于产生强烈的免疫应答，目前正处于癌症免疫治疗的临床试验中。虽然癌症免疫疗法集中于诱导CD 8（+）T细胞应答，但许多针对病原体或其毒素的成功疫苗利用体液免疫作为主要效应机制。普遍地，这些方法使用了增强体液应答的佐剂或病原体材料。然而，佐剂与安全性问题相关。在小鼠中成功使用的一种在没有佐剂的情况下产生强体液应答的方法是将抗原靶向Clec 9A，也称为DNGR-1，CD 8（+）DC上的受体。在这里，我们要解决两个与临床应用有关的问题。首先，我们解决了针对靶向小鼠Clec 9A的不同抗体的可变的澄清剂依赖性的问题。我们表明，可以成功靶向Clec 9A上的多个位点，但体内强结合和提供合适的辅助T细胞决定簇对疗效至关重要。第二，我们表明，诱导体液免疫CLEC 9A靶向抗原是非常有效的非人灵长类动物，在一个无毒素的设置。我们的研究结果支持将这种疫苗接种方法扩展到人类，并为靶向设计提供了重要见解。
Targeting antigens to dendritic cell (DC) surface receptors using antibodies has been successfully used to generate strong immune responses and is currently in clinical trials for cancer immunotherapy. Whilst cancer immunotherapy focuses on the induction of CD8(+) T-cell responses, many successful vaccines to pathogens or their toxins utilize humoral immunity as the primary effector mechanism. Universally, these approaches have used adjuvants or pathogen material that augment humoral responses. However, adjuvants are associated with safety issues. One approach, successfully used in the mouse, to generate strong humoral responses in the absence of adjuvant is to target antigen to Clec9A, also known as DNGR-1, a receptor on CD8(+) DCs. Here, we address two issues relating to clinical application. First, we address the issue of variable adjuvant-dependence for different antibodies targeting mouse Clec9A. We show that multiple sites on Clec9A can be successfully targeted, but that strong in vivo binding and provision of suitable helper T cell determinants was essential for efficacy. Second, we show that induction of humoral immunity to CLEC9A-targeted antigens is extremely effective in nonhuman primates, in an adjuvant-free setting. Our findings support extending this vaccination approach to humans and offer important insights into targeting design.