易普利姆玛
CTLA-4号机组
阻断抗体
生物
免疫疗法
免疫检查点
封锁
癌症研究
抗体
癌症免疫疗法
T细胞
细胞毒性T细胞
无容量
医学
免疫系统
癌症
抗原
肿瘤微环境
免疫学
受体
体外
生物化学
作者
Xuexiang Du,Fei Tang,Mingyue Liu,Juanjuan Su,Yan Zhang,Wei Wu,Martin Devenport,Christopher A. Lazarski,Peng Zhang,Xu Wang,Peiying Ye,Changyu Wang,Eugene Hwang,Tinghui Zhu,Ting Xu,Yang Liu
出处
期刊:Cell Research
[Springer Nature]
日期:2018-02-22
卷期号:28 (4): 416-432
被引量:148
标识
DOI:10.1038/s41422-018-0011-0
摘要
It is assumed that anti-CTLA-4 antibodies cause tumor rejection by blocking negative signaling from B7-CTLA-4 interactions. Surprisingly, at concentrations considerably higher than plasma levels achieved by clinically effective dosing, the anti-CTLA-4 antibody Ipilimumab blocks neither B7 trans-endocytosis by CTLA-4 nor CTLA-4 binding to immobilized or cell-associated B7. Consequently, Ipilimumab does not increase B7 on dendritic cells (DCs) from either CTLA4 gene humanized (Ctla4 h/h ) or human CD34+ stem cell-reconstituted NSG™ mice. In Ctla4 h/m mice expressing both human and mouse CTLA4 genes, anti-CTLA-4 antibodies that bind to human but not mouse CTLA-4 efficiently induce Treg depletion and Fc receptor-dependent tumor rejection. The blocking antibody L3D10 is comparable to the non-blocking Ipilimumab in causing tumor rejection. Remarkably, L3D10 progenies that lose blocking activity during humanization remain fully competent in inducing Treg depletion and tumor rejection. Anti-B7 antibodies that effectively block CD4 T cell activation and de novo CD8 T cell priming in lymphoid organs do not negatively affect the immunotherapeutic effect of Ipilimumab. Thus, clinically effective anti-CTLA-4 mAb causes tumor rejection by mechanisms that are independent of checkpoint blockade but dependent on the host Fc receptor. Our data call for a reappraisal of the CTLA-4 checkpoint blockade hypothesis and provide new insights for the next generation of safe and effective anti-CTLA-4 mAbs.
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