PO.IM01.15 · 免疫学
靶向4-1BB的肿瘤定位单克隆抗体用于癌症治疗，具有卓越的安全性和疗效
Tumor-localized monoclonal antibody targeting 4-1BB for superior safety and efficacy in cancer treatment
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
4-1BB是一种强效的共刺激受体，可增强CD8⁺ T细胞活性并驱动强劲的抗肿瘤免疫。然而，传统抗4-1BB激动型抗体（Abs）引起的全身激活会导致严重毒性——包括肝毒性、血小板减少和细胞因子介导的炎症——导致多项临床试验终止。为克服这些局限性，我们工程化设计了Lock-Urelumab，一种临床抗4-1BB抗体Urelumab的肿瘤选择性前激动型。Lock-Urelumab包含一个基于自体铰链的抗体锁和一个MMP可切割肽接头，能够在正常生理条件下产生空间阻碍，并在MMP过表达的肿瘤微环境内选择性激活。生化表征显示，抗体锁使4-1BB结合降低约400倍，抑制T细胞共刺激并防止促炎细胞因子分泌。经MMP切割后，Lock-Urelumab完全恢复4-1BB激动活性。在人T细胞转移小鼠模型中，Lock-Urelumab避免了4-1BB"抗原库"效应，未表现出可检测的器官毒性，并实现了100%生存率，而所有接受Urelumab治疗的小鼠均在14天内死于治疗相关毒性。重要的是，Lock-Urelumab维持了强效抗肿瘤活性，诱导77%的肿瘤生长抑制（TGI），而Urelumab为45%，并显著增强瘤内T细胞激活。这些发现表明，肿瘤定位的4-1BB激活可以将疗效与全身毒性解耦。Lock-Urelumab代表了一种下一代免疫检查点激动剂，具有重振4-1BB靶向免疫疗法并拓宽其临床适用性的强大潜力。
查看英文原文 English abstract
4-1BB is a potent co-stimulatory receptor that enhances CD8⁺ T-cell activity and drives robust anti-tumor immunity. However, systemic activation by conventional anti-4-1BB agonist antibodies (Abs) leads to severe toxicities-including hepatotoxicity, thrombocytopenia, and cytokine-mediated inflammation-resulting in multiple terminated clinical trials. To overcome these limitations, we engineered Lock-Urelumab, a tumor-selective pro-agonist form of the clinical anti-4-1BB Ab Urelumab. Lock-Urelumab incorporates an autologous hinge-based antibody lock and an MMP-cleavable peptide linker, enabling spatial hindrance under normal physiological conditions and selective activation within the tumor microenvironment where MMP is overexpressed. Biochemical characterization showed that the antibody lock reduced 4-1BB binding by ~400-fold, suppressing T-cell co-stimulation and preventing pro-inflammatory cytokine secretion. Upon MMP cleavage, Lock-Urelumab fully restored 4-1BB agonist activity. In a human T-cell transfer mouse model, Lock-Urelumab avoided the 4-1BB “antigen sink” effect, exhibited no detectable organ toxicity, and achieved 100% survival, whereas all Urelumab-treated mice succumbed to treatment-related toxicity within 14 days. Importantly, Lock-Urelumab maintained potent anti-tumor activity, inducing 77% tumor growth inhibition (TGI) compared with 45% for Urelumab, and significantly enhanced intra-tumoral T-cell activation. These findings demonstrate that tumor-localized 4-1BB activation can uncouple efficacy from systemic toxicity. Lock-Urelumab represents a next-generation immune checkpoint agonist with strong potential to revitalize 4-1BB-targeted immunotherapy and broaden its clinical applicability.
利益披露 Disclosure
Y. Lu, None..
Y. Cheng, None..
T. Liao, None.