Aurigene Discovery Technologies Limited, Bangalore, India.
BioDrugs. 2018 Oct;32(5):481-497. doi: 10.1007/s40259-018-0303-4.
Advances in harnessing the immune system for cancer treatment have been spectacular in recent years as witnessed by the approval of a number of antibodies targeting the PD-1/PD-L1 immune checkpoint pathway spanning an expanding list of indications. However, it is well recognized that while these antibodies show impressive clinical activity, they suffer from shortcomings including the failure to show response in a majority of patients, their need to be administered by intravenous injection, and immune-related adverse events due to the breaking of immune self-tolerance. Small-molecule-based therapeutic approaches offer the potential to address the shortcomings of these antibody-based checkpoint inhibitors. In the first part of this review, we discuss the rationale for small-molecule-based checkpoint therapy followed by efforts on the discovery of small-molecule-based approaches targeting the PD-1/PD-L1 axis and other immune checkpoint pathways. In the latter part of the article, we describe small-molecule inhibitors simultaneously targeting two non-redundant checkpoint inhibitor pathways as an approach to improve the response rate. A brief review of the progress of an oral small-molecule checkpoint inhibitor currently in clinical development is presented at the end.
近年来，利用免疫系统治疗癌症方面取得了显著进展，已有多种针对 PD-1/PD-L1 免疫检查点通路的抗体获得批准，适应证不断扩大，这足以证明这一点。然而，人们已经充分认识到，尽管这些抗体表现出了令人印象深刻的临床活性，但它们也存在一些缺点，包括大多数患者没有应答、需要静脉注射给药以及由于打破免疫自身耐受而引起的免疫相关不良事件。基于小分子的治疗方法有可能解决这些基于抗体的检查点抑制剂的缺点。在这篇综述的第一部分，我们讨论了基于小分子的检查点治疗的基本原理，然后介绍了针对 PD-1/PD-L1 轴和其他免疫检查点通路的基于小分子的方法的发现工作。在文章的后半部分，我们描述了同时针对两个非冗余检查点抑制剂通路的小分子抑制剂作为提高应答率的一种方法。最后简要介绍了一种正在临床开发中的口服小分子检查点抑制剂的进展。
