Institute of Immunity & Transplantation, Division of Infection & Immunity, University College London, Royal Free Campus, London, UK.
Early Oncology Discovery, Early Oncology R&D, AstraZeneca, Gaithersburg, MD, USA.
Nat Rev Drug Discov. 2020 Dec;19(12):860-883. doi: 10.1038/s41573-020-0081-9. Epub 2020 Sep 16.
Therapeutic targeting of immune checkpoints has garnered significant attention in the area of cancer immunotherapy, in which efforts have focused in particular on cytotoxic T lymphocyte antigen 4 (CTLA4) and PD1, both of which are members of the CD28 family. In autoimmunity, these same pathways can be targeted to opposite effect: to curb the over-exuberant immune response. The CTLA4 checkpoint serves as an exemplar, whereby CTLA4 activity is blocked by antibodies in cancer immunotherapy and augmented by the provision of soluble CTLA4 in autoimmunity. Here, we review the targeting of co-stimulatory molecules in autoimmune diseases, focusing in particular on agents directed at members of the CD28 or tumour necrosis factor receptor families. We present the state of the art in co-stimulatory blockade approaches, including rational combinations of immune inhibitory agents, and discuss the future opportunities and challenges in this field.
免疫检查点的治疗靶向在癌症免疫治疗领域引起了广泛关注，特别是针对细胞毒性 T 淋巴细胞抗原 4（CTLA4）和 PD1，它们都是 CD28 家族的成员。在自身免疫中，同样的途径可以被靶向以产生相反的效果：抑制过度活跃的免疫反应。CTLA4 检查点就是一个很好的例子，在癌症免疫治疗中，通过抗体阻断 CTLA4 的活性，而在自身免疫中，通过提供可溶性 CTLA4 来增强其活性。在这里，我们综述了自身免疫性疾病中协同刺激分子的靶向治疗，特别关注针对 CD28 或肿瘤坏死因子受体家族成员的药物。我们介绍了协同刺激阻断方法的最新进展，包括免疫抑制药物的合理组合，并讨论了该领域的未来机遇和挑战。
