Cátedras Consejo Nacional de Ciencia y Tecnología (CONACYT), Mexico City; Department of Pharmacology, Faculty of Medicine, Universidad Autónoma de México (UNAM), Mexico City; Peripheral Research Unit in Translational Biomedicine, Faculty of Medicine, UNAM, and Centro Médico Nacional 20 de noviembre, Instituto de Seguridad y Servicios Sociales de los Trabajadores del Estado (ISSSTE), Mexico City, Mexico.
Department of Pharmacology, Faculty of Medicine, Universidad Autónoma de México (UNAM), Mexico City; Peripheral Research Unit in Translational Biomedicine, Faculty of Medicine, UNAM, and Centro Médico Nacional 20 de noviembre, Instituto de Seguridad y Servicios Sociales de los Trabajadores del Estado (ISSSTE), Mexico City, Mexico.
Rev Invest Clin. 2020 Oct 20;73(1):008-016. doi: 10.24875/RIC.20000341.
Programmed cell death protein 1 (PD-1) and its ligand, programmed death-ligand-1 (PD-L1), play key roles in the suppression of the cytotoxic activity of T cells. PD-L1 is overexpressed on various types of cancer cells, leading to immune evasion. In the past decade, therapeutic antibodies that target the PD-1/PD-L1 axis have been developed to inhibit the immune suppression triggered by these two proteins. At present, five antibodies (two anti-PD-1 and three anti-PD-L1) have received approval by regulatory agencies in the US and Europe. In this work, we aimed to review their clinical applications and adverse effects. Furthermore, using their reported crystal structures, we discuss the similarities and differences between the PD-1/PD-L1 interface and the epitopes that are recognized by the antibodies. Detailed analyses of the contact residues involved in the ligand-receptor and target-antibody interactions have shown partial overlap. Altogether, the data presented here demonstrate that: (1) in contrast to other therapeutic antibodies, anti-PD-1/PD-L1 has a wide range of clinical applications; (2) these targeted therapies are not exempt from adverse effects; and (3) the characterization of the structural domains that are recognized by the antibodies can guide the development of new PD-1- and PD-L1-blocking agents.
程序性细胞死亡蛋白 1（PD-1）及其配体程序性死亡配体-1（PD-L1）在抑制 T 细胞细胞毒性活性方面发挥着关键作用。PD-L1 在各种类型的癌细胞上过表达，导致免疫逃逸。在过去的十年中，已经开发出针对 PD-1/PD-L1 轴的治疗性抗体，以抑制这两种蛋白引发的免疫抑制。目前，在美国和欧洲的监管机构已经批准了五种抗体（两种抗 PD-1 和三种抗 PD-L1）。在这项工作中，我们旨在综述它们的临床应用和不良反应。此外，我们还利用它们报道的晶体结构，讨论了 PD-1/PD-L1 结合界面与抗体识别的表位之间的相似性和差异性。对配体-受体和靶标-抗体相互作用涉及的结合残基的详细分析表明存在部分重叠。总的来说，这里呈现的数据表明：（1）与其他治疗性抗体相比，抗 PD-1/PD-L1 具有广泛的临床应用；（2）这些靶向治疗并非没有不良反应；（3）对抗体识别的结构域的特性进行分析可以指导新型 PD-1 和 PD-L1 阻断剂的开发。
