Department of Chemistry, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul, 05029, Republic of Korea.
Department of Bio Engineering, Hanyang University, 222 Wangsimni-ro, Seongdong-gu, Seoul, 04763, Republic of Korea.
Sci Rep. 2017 Jul 17;7(1):5532. doi: 10.1038/s41598-017-06002-8.
In 2016 and 2017, monoclonal antibodies targeting PD-L1, including atezolizumab, durvalumab, and avelumab, were approved by the FDA for the treatment of multiple advanced cancers. And many other anti-PD-L1 antibodies are under clinical trials. Recently, the crystal structures of PD-L1 in complex with BMS-936559 and avelumab have been determined, revealing details of the antigen-antibody interactions. However, it is still unknown how atezolizumab and durvalumab specifically recognize PD-L1, although this is important for investigating novel binding sites on PD-L1 targeted by other therapeutic antibodies for the design and improvement of anti-PD-L1 agents. Here, we report the crystal structures of PD-L1 in complex with atezolizumab and durvalumab to elucidate the precise epitopes involved and the structural basis for PD-1/PD-L1 blockade by these antibodies. A comprehensive comparison of PD-L1 interactions with anti-PD-L1 antibodies provides a better understanding of the mechanism of PD-L1 blockade as well as new insights into the rational design of improved anti-PD-L1 therapeutics.
在 2016 年和 2017 年，靶向 PD-L1 的单克隆抗体，包括阿特珠单抗、度伐鲁单抗和avelumab，被 FDA 批准用于治疗多种晚期癌症。还有许多其他抗 PD-L1 抗体正在临床试验中。最近，PD-L1 与 BMS-936559 和avelumab 复合物的晶体结构已经被确定，揭示了抗原-抗体相互作用的细节。然而，尽管这对于研究其他治疗性抗体针对 PD-L1 的新型结合位点，从而设计和改进抗 PD-L1 药物非常重要，但 atezolizumab 和 durvalumab 如何特异性识别 PD-L1 仍然未知。在这里，我们报告了 PD-L1 与 atezolizumab 和 durvalumab 复合物的晶体结构，以阐明涉及的精确表位以及这些抗体阻断 PD-1/PD-L1 的结构基础。对 PD-L1 与抗 PD-L1 抗体相互作用的全面比较，提供了对 PD-L1 阻断机制的更好理解，以及对改进的抗 PD-L1 治疗药物的合理设计的新见解。
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