Urelumab

Roche ushered five Chugai assets out the door alongside one of its own candidates.\n Roche has dropped five Chugai candidates from its clinical pipeline, echoing actions the Japanese business took earlier this year.Chugai revealed (PDF) the suspension of in-house development of the drug candidates as part of its second-quarter earnings in July. However, Roche, which reported its second-quarter results on the same day, left the assets in its own pipeline when the Swiss pharma updated its list of active programs. Three months later, Roche has used its third-quarter results to remove the five candidates from its pipeline.The changes affect (PDF) four phase 1 Chugai solid tumor programs plus one phase 2 endometriosis drug candidate. Roche CEO Thomas Schinecker, Ph.D., told Fierce Biotech on a media call this morning that dropping the various Chugai cancer candidates doesn’t reflect a broader shift in the Swiss pharma\'s oncology strategy. Instead, the executive framed the actions as a continuation of Roche’s work to ensure candidates clear “the bar” before advancing. The company sets criteria assets need to meet to stay in its pipeline and continuously evaluates whether the data support continued investment, Schinecker explained. “As data comes in, data changes—it could be your own data, could be competitive data etc,” the CEO told Fierce on the call. “You constantly reassess the opportunity and likelihood of that molecule to be successful. So you constantly manage your portfolio that way.” The most advanced new molecule to fail to clear the bar in the latest review was an anti-IL-8 antibody that Chugai called AMY109. Chugai found IL-8 expression was highly up-regulated in endometriotic tissues and closely correlated with disease progression, leading it to design a long-acting antibody to neutralize the cytokine. The Japanese drugmaker began a phase 2 trial in 2023.Roche announced this morning that it had axed AMY109 alongside four phase 1 solid tumor assets. They include the pan-RAS inhibitor paluratide, also known as LUNA18. Chugai CEO Osamu Okuda commented on the decision to suspend development on an earnings call in July. The CEO said paluratide had a narrower therapeutic window than rival products, leading Chugai to shift its focus to the KRAS inhibitor AUBE00.Another axed candidate, which Chugai calls STA551, was designed to avoid the toxicities associated with early attempts to drug CD137. Bristol Myers Squibb saw liver toxicity in recipients of its CD137 candidate urelumab, leading Chugai to design its therapy to only bind to the receptor when exposed to a molecule found in the tumor microenvironment. Tsukasa Kusano, head of Chugai’s project and life cycle management unit, told investors in July that the company had confirmed the tolerability of STA551 “up to dosage levels that would likely be unattainable with CD137 antibodies without switch functionality.” Kusano added that “efficacy was confirmed to some level.”The Chugai executive also commented at the time about SAIL66, an anti-CLDN6 trispecific that Roche removed from its pipeline in the third-quarter cull. By also binding to CD3 and CD137, the candidate was designed to drive the sustained activation of exhausted T cells against tumors that express CLDN6. Chugai, which began a phase 1 trial in 2023, is planning to publish data on the candidate.The final axed Chugai asset is SOF10, an antibody that targets a type of TGF-β that is expressed more in tumors than other isoforms of the growth factor. Targeting the TGF-β1 isoform was intended to avoid the cardiac toxicity and bleeding associated with less-specific molecules. A phase 1 trial began in 2023.Roche ushered the Chugai assets out the door alongside one of its own candidates, RG6436. The LepB inhibitor was in phase 1 development as a treatment for complicated urinary tract infection. Roche made RG6436 the focus of its LepB work last year when it dropped its first-generation candidate RG6319.

尽管CD137激动剂在临床前模型中显示出抗肿瘤潜力，但两款CD137单克隆抗体（urelumab、utomilumab）因严重肝毒性或低疗效终止临床试验。同时，CD137L（4-1BBL）在肿瘤细胞中的表达模式与功能存在争议：在胰腺癌中促进耐药、结直肠癌中支持转移，但在黑色素瘤中的作用尚未明确。此外，CD137L的表达调控机制及能否作为ICB联合治疗靶点，均需进一步探索。     近日《Nature Communications》揭示共刺激分子CD137L在黑色素瘤中低表达，其表达受转录因子HLTF的负调控，而AMPK激动剂可通过磷酸化HLTF解除抑制，上调CD137L表达，进而激活CD8+T细胞介导的抗肿瘤免疫。更重要的是，AMPK激动剂AICAR（阿卡地新）与PD-1/CTLA-4抑制剂联合使用，在黑色素瘤模型中展现出协同抗肿瘤效果，为ICB耐药患者提供了全新治疗策略。 一：CD137L低表达与黑色素瘤ICB耐药密切相关     研究整合6个独立ICB治疗队列（涵盖黑色素瘤、肺癌、头颈癌）数据发现：肿瘤组织中CD137/CD137L（TNFRSF9/TNFSF9）高表达患者，接受ICB治疗后的OS与PFS显著延长，风险比（HR）最低达0.2。在10个独立队列中，CD137L区分ICB应答者与非应答者的ROC曲线下面积（AUC）均优于PD-L1（CD274）与CD8（CD8A/CD8B平均表达），尤其在黑色素瘤中AUC达0.76，显著高于PD-L1。     29例接受抗PD-1治疗的黑色素瘤患者中，应答者（CR/PR/SD>3个月）的肿瘤CD137L表达水平是非应答者的3.2倍，且高CD137L患者的中位PFS延长至14.2个月，显著优于低表达组（5.8个月）。      单细胞RNA测序显示，黑色素瘤细胞中CD137L阳性比例不足5%，且表达水平显著低于良性色素痣。同时发现CD137L+黑色素细胞富集免疫原性相关基因（如IFN-γ信号、抗原提呈通路），提示CD137L表达与肿瘤免疫原性正相关。同时采用TCGA-SKCM队列发现，CD137L高表达患者的5年OS率达68%，显著高于低表达组（32%），证实CD137L是黑色素瘤独立预后因子。 二：HLTF是CD137L的关键负调控因子     为解析CD137L在黑色素瘤中低表达的机制，研究通过DNA pull-down联合质谱筛选，鉴定出转录因子HLTF（解旋酶样转录因子）为CD137L的关键调控者。在TCGA-SKCM与湘雅医院黑色素瘤队列中，HLTF与CD137L的mRNA表达呈显著负相关，且该负相关在33种TCGA癌症类型中普遍存在。     ChIP-qPCR与luciferase报告基因实验也证实，HLTF通过其SNF2-N结构域直接结合CD137L启动子-1115~-996bp区域，且结合能力随HLTF表达量增加而增强，最终抑制CD137L转录。     在A375、SK-MEL-28黑色素瘤细胞中，HLTF过表达使CD137LmRNA与膜表面蛋白水平降低50%-70%，而HLTF敲低/敲除则使CD137L表达上调2.3-3.1倍。同时HLTF高表达且CD137L低表达的黑色素瘤中，CD8+T细胞浸润比例降低40%，而HLTF敲除后，肿瘤内CD8+T细胞与GZMB+CD8+T细胞比例分别增加2.1倍与2.8倍。     体外HLTF敲除使黑色素瘤细胞对T细胞介导的杀伤敏感性提升3.2倍，而HLTF过表达则使杀伤率降低60%，且该效应可被CD137L中和抗体逆转。体内HLTF敲除的B16F10细胞在C57BL/6小鼠中形成的肿瘤体积缩小58%，中位生存期延长至42天，显著优于对照组（28天），且肿瘤内CD3+、CD8+T细胞浸润显著增加。 三：AMPK磷酸化HLTF解除CD137L抑制     通过磷酸化位点数据库（Phospho Site Plus）与激酶筛选实验，研究发现AMPK（AMP依赖的蛋白激酶）是调控HLTF磷酸化的关键激酶，发现AMPK通过SNF2-N与ZFC结构域结合HLTF，且AICAR处理可增强二者核内共定位与结合强度。并通过构建HLTF serine→alanine突变体（S397A、S398A等）发现，仅S398A突变可完全阻断AICAR诱导的HLTF磷酸化，且显著抑制CD137L上调，证实Ser398是AMPK介导HLTF磷酸化的关键位点。      同时AICAR处理后，AMPK磷酸化HLTF Ser398，导致HLTF与CD137L启动子的结合能力降低60%，从而解除转录抑制。转录组分析显示，AICAR处理后黑色素瘤细胞中CD137L是上调最显著的免疫检查点分子，且其上调依赖AMPK-HLTF通路。CD137L敲除后，AICAR诱导的T细胞浸润与抗肿瘤效应完全消失。  四：AICAR联合ICBs的协同抗肿瘤效果     在B16F10黑色素瘤模型中，AICAR（300mg/kg，腹腔注射）与抗PD-1/CTLA-4抗体联合治疗的肿瘤体积较单药组（AICAR或ICBs）缩小45%-62%，终点肿瘤重量降低58%-70%，中位生存期达56天，显著优于AICAR单药组（38天）、抗PD-1组（42天）与抗CTLA-4组（40天），且20%小鼠实现肿瘤完全消退。免疫分析发现联合治疗使肿瘤内CD3+、CD8+T细胞比例分别增加，GZMB+CD8+T细胞比例提升，同时Treg与M2型巨噬细胞比例降低。      对联合治疗组小鼠的主要器官（心、肝、脾、肺、肾、皮肤）进行病理切片分析，未观察到明显炎症或组织损伤。血清肝肾功能指标（ALT、AST、肌酐）与血常规参数均在正常范围，证实该联合方案安全性良好。 总结思考     本研究揭示共刺激分子CD137L在黑色素瘤中低表达，其表达受转录因子HLTF的负调控，而AMPK激动剂可通过磷酸化HLTF解除抑制，上调CD137L表达，进而激活CD8+T细胞介导的抗肿瘤免疫。      该研究不仅阐明了CD137L在黑色素瘤中的表达调控机制，更提供了“代谢调控-免疫激活”协同的治疗新思路，为突破ICB耐药、扩大免疫治疗获益人群奠定理论基础。     CD137L promotes immune surveillance in melanoma via HLTF regulation. Nat Commun. 2025 Sep 26;16(1):8478. doi: 10.1038/s41467-025-63338-w.