Laboratory of Immunology and Inflammation, School of Life Sciences and Biopharmaceutics, Guangdong Pharmaceutical University, Guangzhou 510006, China.
Department of Biology, School of Life Sciences and Biopharmaceutics, Guangdong Pharmaceutical University, Guangzhou 510006, China.
Cancer Biol Med. 2024 May 24;21(6):451-72. doi: 10.20892/j.issn.2095-3941.2024.0055.
Over the past two decades, immunotherapies have increasingly been considered as first-line treatments for most cancers. One such treatment is immune checkpoint blockade (ICB), which has demonstrated promising results against various solid tumors in clinical trials. Monoclonal antibodies (mAbs) are currently available as immune checkpoint inhibitors (ICIs). These ICIs target specific immune checkpoints, including cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) and programmed cell death protein 1 (PD-1). Clinical trial results strongly support the feasibility of this immunotherapeutic approach. However, a substantial proportion of patients with cancer develop resistance or tolerance to treatment, owing to tumor immune evasion mechanisms that counteract the host immune response. Consequently, substantial research focus has been aimed at identifying additional ICIs or synergistic inhibitory receptors to enhance the effectiveness of anti-PD-1, anti-programmed cell death ligand 1 (anti-PD-L1), and anti-CTLA-4 treatments. Recently, several immune checkpoint molecular targets have been identified, such as T cell immunoreceptor with Ig and ITIM domains (TIGIT), mucin domain containing-3 (TIM-3), lymphocyte activation gene-3 (LAG-3), V-domain immunoglobulin suppressor of T cell activation (VISTA), B and T lymphocyte attenuator (BTLA), and signal-regulatory protein α (SIRPα). Functional mAbs targeting these molecules are under development. CTLA-4, PD-1/PD-L1, and other recently discovered immune checkpoint proteins with distinct structures are at the forefront of research. This review discusses these structures, as well as clinical progress in mAbs targeting these immune checkpoint molecules and their potential applications.
在过去的二十年中，免疫疗法越来越被认为是大多数癌症的一线治疗方法。其中一种治疗方法是免疫检查点阻断（ICB），它在临床试验中对各种实体瘤显示出了有希望的结果。单克隆抗体（mAbs）目前可作为免疫检查点抑制剂（ICIs）。这些 ICIs 针对特定的免疫检查点，包括细胞毒性 T 淋巴细胞相关抗原-4（CTLA-4）和程序性细胞死亡蛋白 1（PD-1）。临床试验结果强烈支持这种免疫治疗方法的可行性。然而，相当一部分癌症患者由于肿瘤免疫逃逸机制抵消了宿主免疫反应，对治疗产生了耐药性或耐受性。因此，大量研究集中在寻找额外的 ICIs 或协同抑制性受体上，以提高抗 PD-1、抗程序性细胞死亡配体 1（抗 PD-L1）和抗 CTLA-4 治疗的效果。最近，已经鉴定出了几种免疫检查点分子靶标，例如 T 细胞免疫受体含有 Ig 和 ITIM 结构域（TIGIT）、粘蛋白结构域包含-3（TIM-3）、淋巴细胞激活基因-3（LAG-3）、V 结构域免疫球蛋白抑制 T 细胞活化（VISTA）、B 和 T 淋巴细胞衰减器（BTLA）和信号调节蛋白α（SIRPα）。针对这些分子的功能性 mAbs 正在开发中。CTLA-4、PD-1/PD-L1 和其他最近发现的具有不同结构的免疫检查点蛋白处于研究的前沿。本文讨论了这些结构，以及针对这些免疫检查点分子的 mAbs 的临床进展及其潜在应用。
