State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai, China.
MAbs. 2023 Jan-Dec;15(1):2236740. doi: 10.1080/19420862.2023.2236740.
Antibody-based immune checkpoint blockade (ICB)-based therapeutics have become effective clinical applications for cancers. Applications of monoclonal antibodies (mAbs) to de-activate the PD-1-PD-L1 pathway could effectively reverse the phenotype of depleted activated thymocytes (T cells) to recover their anti-tumoral activities. High-resolution structures of the complexes of the therapeutic monoclonal antibodies with PD-1 or PD-L1 have revealed the key inter-molecular interactions and provided valuable insights into the fundamental mechanisms by which these antibodies inhibit PD-L1-PD-1 binding. Each anti-PD-1 mAb exhibits a unique blockade mechanism, such as interference with large PD-1-PD-L1 contacting interfaces, steric hindrance by overlapping a small area of this site, or binding to an -glycosylated site. In contrast, all therapeutic anti-PD-L1 mAbs bind to a similar area of PD-L1. Here, we summarized advances in the structural characterization of the complexes of commercial mAbs that target PD-1 or PD-L1. In particular, we focus on the unique characteristics of those mAb structures, epitopes, and blockade mechanisms. It is well known that the use of antibodies as anti-tumor drugs has increased recently and both PD-1 and PD-L1 have attracted substantial attention as target for antibodies derived from new technologies. By focusing on structural characterization, this review aims to aid the development of novel antibodies targeting PD-1 or PD-L1 in the future.
基于抗体的免疫检查点阻断（ICB）治疗已成为癌症的有效临床应用。单克隆抗体（mAbs）的应用可用于激活 PD-1-PD-L1 通路，有效逆转耗竭激活的胸腺细胞（T 细胞）的表型，恢复其抗肿瘤活性。治疗性单克隆抗体与 PD-1 或 PD-L1 复合物的高分辨率结构揭示了关键的分子间相互作用，并为这些抗体抑制 PD-L1-PD-1 结合的基本机制提供了有价值的见解。每种抗 PD-1 mAb 都表现出独特的阻断机制，例如干扰 PD-1-PD-L1 相互作用的大界面、通过重叠该位点的一小部分来产生空间位阻，或与 -糖基化位点结合。相比之下，所有治疗性抗 PD-L1 mAb 都结合 PD-L1 的相似区域。在这里，我们总结了靶向 PD-1 或 PD-L1 的商业 mAb 复合物结构特征的进展。特别是，我们专注于这些 mAb 结构、表位和阻断机制的独特特征。众所周知，抗体作为抗肿瘤药物的使用最近有所增加，PD-1 和 PD-L1 都作为抗体的靶点吸引了人们的极大关注，这些抗体来自新技术。通过关注结构特征，本综述旨在为未来靶向 PD-1 或 PD-L1 的新型抗体的开发提供帮助。
