Structural basis of checkpoint blockade by monoclonal antibodies in cancer immunotherapy.
Structural basis of checkpoint blockade by monoclonal antibodies in cancer immunotherapy.
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DOI：
10.1038/ncomms13354
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发表时间：
2016-10-31
影响因子：
16.6
通讯作者：
Heo, Yong-Seok
中科院分区：
文献类型：
--
作者：
Lee, Ju Yeon;Lee, Hyun Tae;Shin, Woori;Chae, Jongseok;Choi, Jaemo;Kim, Sung Hyun;Lim, Heejin;Heo, Tae Won;Park, Kyeong Young;Ryu, Seong Eon;Son, Ji Young;Lee, Jee Un;Heo, Yong-Seok
癌细胞表达通过遗传和表观遗传改变衍生的肿瘤特异性抗原，这些抗原可能是 T 细胞介导的免疫反应的目标。然而，癌细胞可以通过激活特定的抑制信号通路（称为免疫检查点）来抑制免疫，从而避免免疫监视。近年来，单克隆抗体对PD-1、PD-L1和CTLA-4等检查点分子的阻断使得肿瘤学突破性疗法的发展成为可能，针对这些检查点分子的四种治疗性抗体已被FDA批准用于治疗多种类型的癌症。在这里，我们报告了与治疗性抗体的 Fab 片段复合的检查点分子的晶体结构，包括 PD-1/pembrolizumab、PD-1/nivolumab、PD-L1/BMS-936559 和 CTLA-4/tremelimumab。这些复杂的结构阐明了抗体的精确表位和检查点阻断的分子机制，为改进能够减弱检查点信号传导以治疗癌症的单克隆抗体提供了有用的信息。 免疫疗法为癌症患者提供了新的治疗选择。在这里，作者报告了其中一些与其靶点结合的疗法的晶体结构。
Cancer cells express tumour-specific antigens derived via genetic and epigenetic alterations, which may be targeted by T-cell-mediated immune responses. However, cancer cells can avoid immune surveillance by suppressing immunity through activation of specific inhibitory signalling pathways, referred to as immune checkpoints. In recent years, the blockade of checkpoint molecules such as PD-1, PD-L1 and CTLA-4, with monoclonal antibodies has enabled the development of breakthrough therapies in oncology, and four therapeutic antibodies targeting these checkpoint molecules have been approved by the FDA for the treatment of several types of cancer. Here, we report the crystal structures of checkpoint molecules in complex with the Fab fragments of therapeutic antibodies, including PD-1/pembrolizumab, PD-1/nivolumab, PD-L1/BMS-936559 and CTLA-4/tremelimumab. These complex structures elucidate the precise epitopes of the antibodies and the molecular mechanisms underlying checkpoint blockade, providing useful information for the improvement of monoclonal antibodies capable of attenuating checkpoint signalling for the treatment of cancer. Immunotherapy is offering patients with cancer new therapy options. Here, the authors report on the crystal structures of some of these therapies bound to their targets.
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DOI：
10.1056/nejmoa1003466
发表时间：
2010-08-19
期刊：
The New England journal of medicine
影响因子：
--
作者：
Hodi FS;O'Day SJ;McDermott DF;Weber RW;Sosman JA;Haanen JB;Gonzalez R;Robert C;Schadendorf D;Hassel JC;Akerley W;van den Eertwegh AJ;Lutzky J;Lorigan P;Vaubel JM;Linette GP;Hogg D;Ottensmeier CH;Lebbé C;Peschel C;Quirt I;Clark JI;Wolchok JD;Weber JS;Tian J;Yellin MJ;Nichol GM;Hoos A;Urba WJ
通讯作者：
Urba WJ
T细胞共刺激和共抑制的分子机制。
DOI：
10.1038/nri3405
发表时间：
2013-04
期刊：
Nature reviews. Immunology
影响因子：
--
作者：
通讯作者：
--
DOI：
10.1038/nrc3239
发表时间：
2012-03-22
期刊：
Nature reviews. Cancer
影响因子：
--
作者：
Pardoll DM
通讯作者：
Pardoll DM
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
影响因子：
30.5
作者：
Latchman, Y;Wood, CR;Freeman, GJ
通讯作者：
Freeman, GJ