Structural basis of a novel PD-L1 nanobody for immune checkpoint blockade.
Structural basis of a novel PD-L1 nanobody for immune checkpoint blockade.
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用于免疫检查点阻断的新型 PD-L1 纳米抗体的结构基础
DOI：
10.1038/celldisc.2017.4
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发表时间：
2017
期刊：
影响因子：
33.5
通讯作者：
Zhou A
中科院分区：
文献类型：
--
作者：
Zhang F;Wei H;Wang X;Bai Y;Wang P;Wu J;Jiang X;Wang Y;Cai H;Xu T;Zhou A
使用抗体靶向免疫检查点，特别是PD-1/PD-L1，在癌症免疫治疗领域产生了深远的影响。在这里，我们确定了KN 035，一种抗PD-L1纳米抗体，可以强烈诱导T细胞反应并抑制肿瘤生长。KN 035与PD-L1复合物和游离PD-L1的晶体结构分别在1.7和2.7 μ m分辨率下解析，表明KN 035与PD-1（程序性死亡蛋白1）竞争PD-L1上相同的平坦表面，主要通过21个氨基酸的单一表面环。该环形成两个短螺旋，并与PD-L1残基（如Ile 54、Tyr 56和Arg 113）形成关键的疏水和离子相互作用，这些残基也参与PD-1结合。详细的诱变研究确定了PD-L1表面的热点残基，并解释了KN 035与PD-L1的结合比PD-1更强（约1000倍），但与PD-L2缺乏结合。总体而言，这项研究揭示了KN 035或PD-1的单个免疫球蛋白可变支架如何通过单个表面环或β折叠链与平坦的蛋白质表面结合;并为设计新的免疫检查点阻断剂和产生用于联合治疗的双特异性抗体提供了基础。
The use of antibodies to target immune checkpoints, particularly PD-1/PD-L1, has made a profound impact in the field of cancer immunotherapy. Here, we identified KN035, an anti-PD-L1 nanobody that can strongly induce T-cell responses and inhibit tumor growth. The crystal structures of KN035 complexed with PD-L1 and free PD-L1, solved here at 1.7 and 2.7 Å resolution, respectively, show that KN035 competes with PD-1 (programmed death protein 1) for the same flat surface on PD-L1, mainly through a single surface loop of 21 amino acids. This loop forms two short helices and develops key hydrophobic and ionic interactions with PD-L1 residues, such as Ile54, Tyr56 and Arg113, which are also involved in PD-1 binding. The detailed mutagenesis study identified the hotspot residues of the PD-L1 surface and provides an explanation for the stronger (~ 1 000-fold) binding of KN035 to PD-L1 than PD-1 and its lack of binding to PD-L2. Overall, this study reveals how a single immunoglobulin-variable scaffold of KN035 or PD-1 can bind to a flat protein surface through either a single surface loop or beta-sheet strands; and provides a basis for designing new immune checkpoint blockers and generating bi-specific antibodies for combination therapy.