设为首页收藏本站
开启辅助访问
切换到窄版

 找回密码
 注册

QQ登录

只需一步,快速开始

搜索
查看: 293|回复: 0

ScFv为基础的嵌合抗原受体诱导T细胞攻击IL13Rα2阳性神经胶质瘤的特征和功能分析

[复制链接]
发表于 2015-12-10 22:22:15 | 显示全部楼层 |阅读模式
Characterization and Functional Analysis of scFv-based Chimeric Antigen Receptors to Redirect T Cells to IL13Rα2-positive Glioma
Abstract
Immunotherapy with T cells expressing chimeric antigen receptors (CARs) is an attractive approach to improve outcomes for patients with glioblastoma (GBM). IL13Rα2 is expressed at a high frequency in GBM but not in normal brain, making it a promising CAR T-cell therapy target. IL13Rα2-specific CARs generated up to date contain mutated forms of IL13 as an antigen-binding domain. While these CARs target IL13Rα2, they also recognize IL13Rα1, which is broadly expressed. To overcome this limitation, we constructed a panel of IL13Rα2-specific CARs that contain the IL13Rα2-specific single-chain variable fragment (scFv) 47 as an antigen binding domain, short or long spacer regions, a transmembrane domain, and endodomains derived from costimulatory molecules and CD3.ζ (IL13Rα2-CARs). IL13Rα2-CAR T cells recognized IL13Rα2-positive target cells in coculture and cytotoxicity assays with no cross-reactivity to IL13Rα1. However, only IL13Rα2-CAR T cells with a short spacer region produced IL2 in an antigen-dependent fashion. In vivo, T cells expressing IL13Rα2-CARs with short spacer regions and CD28.ζ, 41BB.ζ, and CD28.OX40.ζ endodomains had potent anti-glioma activity conferring a significant survival advantage in comparison to mice that received control T cells. Thus, IL13Rα2-CAR T cells hold the promise to improve current IL13Rα2-targeted immunotherapy approaches for GBM and other IL13Rα2-positive malignancies. Molecular Therapy (2015);
ScFv为基础的嵌合抗原受体诱导T细胞攻击IL13Rα2阳性神经胶质瘤的特征和功能分析
摘要:
嵌合抗原受体修饰的T细胞免疫治疗对于神经胶质母细胞瘤病人而言,是一个非常吸引人的治疗途径。IL13Rα2分子在胶质母细胞瘤细胞表面高度表达,但是在正常脑细胞表面不怎么表达,从而成为一个理想的CAR-T细胞针对的靶点。IL13Rα2修饰的CARs到目前为止的设计包含变异形式的IL13作为一个抗原结合区域。当这些CARs靶向IL13Rα2时,它们同样靶向广泛表达的IL13Rα1分子。为了克服这样的限制,我们设计了一个特异性的IL13Rα2 CARs,它包含了IL13Rα2特异性的单链可变区域(scFv)47作为一个抗原结合区域,或长或短的间隔区、一个跨膜结构域、来自共刺激分子和CD3的内部区域。在共培养和细胞毒性试验中,IL13Rα2 CAR-T细胞识别IL13Rα2阳性细胞,与IL13Rα1没有交叉反应。然而,只有IL13Rα2-CAR 短间隔区的T细胞产生抗原依赖性。在体内,具有更短间隔区和CD28.ζ、41BB.ζ、CD28、OX40.ζ内域的IL13Rα2-CARsT细胞具有很强的抗胶质瘤活性。因此,IL13Rα2-CAR T细胞有希望改进目前IL13Rα2靶向免疫治疗神经胶质目细胞瘤和其他IL13Rα2阳性肿瘤。
出自爱康得

Charachterization and functional analysis of scFvbased 2015.12.10.pdf

183.51 KB, 下载次数: 162

您需要登录后才可以回帖 登录 | 注册

本版积分规则

QQ|申请友链|小黑屋|手机版|Archiver|生物信息学论坛 ( 蜀ICP备09031721号  

GMT+8, 2017-1-23 12:22 , Processed in 0.118469 second(s), 23 queries .

Powered by Discuz! X3

© 2001-2013 Comsenz Inc.

快速回复 返回顶部 返回列表