Holay Nisha, Yadav Rashi, Ahn Sae Jeong, Kasiewicz Melissa J, Polovina Anya, Rolig Annah S, Staebler Thi, Becklund Bryan, Simons Noah D, Koguchi Yoshinobu, Eckelman Brendan P, de Durana Yaiza Diaz, Redmond William L
Earle A Chiles Research Institute, Providence Cancer Institute, Portland, Oregon, USA.
Oregon Health and Science University, Portland, Oregon, USA.
J Immunother Cancer. 2025 May 21;13(5):e011524. doi: 10.1136/jitc-2025-011524.
Immunotherapies targeting immune checkpoint inhibitors have revolutionized cancer treatment but are limited by incomplete patient responses. Costimulatory agonists like OX40 (CD134), a tumor necrosis factor receptor family member critical for T-cell survival and differentiation, have shown preclinical promise but limited clinical success due to suboptimal receptor activation. Conventional bivalent OX40 agonists fail to induce the trimeric engagement required for optimal downstream signaling. To address this, we developed INBRX-106, a hexavalent OX40 agonist designed to enhance receptor clustering independently of Fc-mediated crosslinking and boost antitumor T-cell responses.
We assessed INBRX-106's effects on receptor clustering, signal transduction, and T-cell activation using NF-kß reporter assays, confocal microscopy, flow cytometry, and single-cell RNA sequencing. Therapeutic efficacy was evaluated in murine tumor models and human samples. Clinical samples from a phase I/II trial (NCT04198766) were also analyzed for immune activation.
INBRX-106 demonstrated superior receptor clustering and downstream signaling compared with bivalent agonists, leading to robust T-cell activation and proliferation. In murine models, hexavalent OX40 agonism resulted in significant tumor regression, enhanced survival, and increased CD8 T-cell effector function. Clinical pharmacodynamic analysis in blood samples from patients treated with INBRX-106 showed heightened T-cell activation and proliferation, particularly in central and effector memory subsets, validating our preclinical findings.
Our data establish hexavalent INBRX-106 as a differentiated and more potent OX40 agonist, showcasing its ability to overcome the limitations of conventional bivalent therapies by inducing superior receptor clustering and multimeric engagement. This unique clustering mechanism amplifies OX40 signaling, driving robust T-cell activation, proliferation, and effector function in preclinical and clinical settings. These findings highlight the therapeutic potential of INBRX-106 and its capacity to redefine OX40-targeted immunotherapy, providing a compelling rationale for its further clinical development in combination with checkpoint inhibitors.
靶向免疫检查点抑制剂的免疫疗法彻底改变了癌症治疗方式，但患者反应不完全限制了其应用。共刺激激动剂，如OX40（CD134），一种对T细胞存活和分化至关重要的肿瘤坏死因子受体家族成员，已在临床前研究中显示出前景，但由于受体激活不理想，临床成功有限。传统的二价OX40激动剂无法诱导最佳下游信号传导所需的三聚体结合。为了解决这一问题，我们开发了INBRX-106，一种六价OX40激动剂，旨在独立于Fc介导的交联增强受体聚集并增强抗肿瘤T细胞反应。
我们使用NF-κB报告基因检测、共聚焦显微镜、流式细胞术和单细胞RNA测序评估了INBRX-106对受体聚集、信号转导和T细胞激活的影响。在小鼠肿瘤模型和人类样本中评估了治疗效果。还分析了一项I/II期试验（NCT04198766）的临床样本的免疫激活情况。
与二价激动剂相比，INBRX-106表现出优异的受体聚集和下游信号传导，导致强大的T细胞激活和增殖。在小鼠模型中，六价OX40激动作用导致显著的肿瘤消退、生存期延长和CD8 T细胞效应功能增强。对接受INBRX-106治疗的患者血液样本进行的临床药效学分析显示T细胞激活和增殖增强，特别是在中央记忆和效应记忆亚群中，证实了我们的临床前研究结果。
我们的数据表明六价INBRX-106是一种有区别的、更有效的OX40激动剂，展示了其通过诱导优异的受体聚集和多聚体结合克服传统二价疗法局限性的能力。这种独特的聚集机制放大了OX40信号传导，在临床前和临床环境中驱动强大的T细胞激活、增殖和效应功能。这些发现突出了INBRX-106的治疗潜力及其重新定义OX40靶向免疫疗法的能力，为其与检查点抑制剂联合进行进一步临床开发提供了令人信服的理论依据。
