4-1BB (CD137, tumor necrosis factor receptor superfamily 9) is an inducible costimulatory receptor expressed on activated T and natural killer (NK) cells. 4-1BB ligation on T cells triggers a signaling cascade that results in upregulation of antiapoptotic molecules, cytokine secretion, and enhanced effector function. In dysfunctional T cells that have a decreased cytotoxic capacity, 4-1BB ligation demonstrates a potent ability to restore effector functions. On NK cells, 4-1BB signaling can increase antibody-dependent cell-mediated cytotoxicity. Agonistic monoclonal antibodies targeting 4-1BB have been developed to harness 4-1BB signaling for cancer immunotherapy. Preclinical results in a variety of induced and spontaneous tumor models suggest that targeting 4-1BB with agonist antibodies can lead to tumor clearance and durable antitumor immunity. Clinical trials of 2 agonist antibodies, urelumab and utomilumab, are ongoing. Despite initial signs of efficacy, clinical development of urelumab has been hampered by inflammatory liver toxicity at doses >1 mg/kg. Utomilumab has a superior safety profile, but is a less potent 4-1BB agonist relative to urelumab. Both antibodies have demonstrated promising results in patients with lymphoma and are being tested in combination therapy trials with other immunomodulatory agents. In an effort to optimally leverage 4-1BB-mediated immune activation, the next generation of 4-1BB targeting strategies attempts to decouple the observed antitumor efficacy from the on-target liver toxicity. Multiple therapeutics that attempt to restrict 4-1BB agonism to the tumor microenvironment and minimize systemic exposure have emerged. 4-1BB is a compelling target for cancer immunotherapy and future agents show great promise for achieving potent immune activation while avoiding limiting immune-related adverse events.

中文翻译：

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针对 4-1BB 的免疫疗法：机制原理、临床结果和未来策略

4-1BB（CD137，肿瘤坏死因子受体超家族 9）是一种在活化的 T 细胞和自然杀伤 (NK) 细胞上表达的诱导型共刺激受体。T 细胞上的 4-1BB 连接触发信号级联反应，导致抗凋亡分子上调、细胞因子分泌和效应子功能增强。在细胞毒性能力降低的功能失调的 T 细胞中，4-1BB 连接显示出恢复效应器功能的有效能力。在 NK 细胞上，4-1BB 信号可以增加抗体依赖性细胞介导的细胞毒性。已经开发出靶向 4-1BB 的激动性单克隆抗体，以利用 4-1BB 信号进行癌症免疫治疗。各种诱导性和自发性肿瘤模型的临床前结果表明，用激动剂抗体靶向 4-1BB 可导致肿瘤清除和持久的抗肿瘤免疫。2 种激动剂抗体 urelumab 和 utomilumab 的临床试验正在进行中。尽管有初步的疗效迹象，但 urelumab 的临床开发仍受到剂量 >1 mg/kg 的炎症性肝毒性的阻碍。Utomilumab 具有优越的安全性，但相对于 urelumab 而言是一种较弱的 4-1BB 激动剂。这两种抗体都在淋巴瘤患者中显示出有希望的结果，并且正在与其他免疫调节剂的联合治疗试验中进行测试。为了优化利用 4-1BB 介导的免疫激活，下一代 4-1BB 靶向策略试图将观察到的抗肿瘤功效与靶向肝毒性脱钩。已经出现了多种试图将 4-1BB 激动作用限制在肿瘤微环境中并最小化全身暴露的疗法。