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Structural basis of a novel PD-L1 nanobody for immune checkpoint blockade

机译：新型PD-L1纳米抗体用于免疫检查点封锁的结构基础

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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?? 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.
机译：使用抗体靶向免疫检查点，尤其是PD-1 / PD-L1，已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KN035，一种抗PD-L1纳米抗体，可以强烈诱导T细胞反应并抑制肿瘤生长。与PD-L1和游离PD-L1络合的KN035的晶体结构在1.7和2.7？处解析。分辨率分别表明，KN035主要通过21个氨基酸的单个表面环与PD-1（编程的死亡蛋白1）竞争PD-L1上的同一平坦表面。该环形成两个短螺旋，并与PD-L1残基（如Ile54，Tyr56和Arg113）形成关键的疏水和离子相互作用，后者也参与PD-1结合。详尽的诱变研究确定了PD-L1表面的热点残基，并为KN035与PD-L1的结合比PD-1更强（约1.000倍）和其与PD-L2的结合缺乏提供了解释。总体而言，这项研究揭示了单个KN035或PD-1免疫球蛋白可变支架如何通过单表面环或β-折叠链与平坦的蛋白表面结合。并为设计新的免疫检查点阻滞剂和产生用于联合治疗的双特异性抗体提供了基础。

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