Lilly Research Laboratories, Eli Lilly and Company, New York, New York.
Mol Cancer Ther. 2020 Apr;19(4):988-998. doi: 10.1158/1535-7163.MCT-19-0893.
The CD137 receptor plays a key role in mediating immune response by promoting T cell proliferation, survival, and memory. Effective agonism of CD137 has the potential to reinvigorate potent antitumor immunity either alone or in combination with other immune-checkpoint therapies. In this study, we describe the discovery and characterization of a unique CD137 agonist, 7A5, a fully human IgG1 Fc effector-null monoclonal antibody. The biological properties of 7A5 were investigated through and studies. 7A5 binds CD137, and the binding epitope overlaps with the CD137L binding site based on structure. 7A5 engages CD137 receptor and activates NF-κB cell signaling independent of cross-linking or Fc effector function. In addition, T cell activation measured by cytokine IFNγ production is induced by 7A5 in peripheral blood mononuclear cell costimulation assay. Human tumor xenograft mouse models reconstituted with human immune cells were used to determine antitumor activity . Monotherapy with 7A5 inhibits tumor growth, and this activity is enhanced in combination with a PD-L1 antagonist antibody. Furthermore, the intratumoral immune gene expression signature in response to 7A5 is highly suggestive of enhanced T cell infiltration and activation. Taken together, these results demonstrate 7A5 is a differentiated CD137 agonist antibody with biological properties that warrant its further development as a cancer immunotherapy. GRAPHICAL ABSTRACT: http://mct.aacrjournals.org/content/molcanther/19/4/988/F1.large.jpg.
CD137 受体通过促进 T 细胞增殖、存活和记忆，在介导免疫反应中发挥关键作用。CD137 的有效激动作用有可能单独或与其他免疫检查点疗法联合重新激活有效的抗肿瘤免疫。在这项研究中，我们描述了一种独特的 CD137 激动剂 7A5 的发现和特性，7A5 是一种完全人源 IgG1 Fc 效应子缺失的单克隆抗体。通过 和 研究研究了 7A5 的生物学特性。7A5 结合 CD137，基于结构，结合表位与 CD137L 结合位点重叠。7A5 与 CD137 受体结合并激活 NF-κB 细胞信号，而不依赖于交联或 Fc 效应子功能。此外，通过外周血单核细胞共刺激测定，7A5 在人肿瘤异种移植小鼠模型中重建的人免疫细胞中诱导 T 细胞激活，通过细胞因子 IFNγ 产生来衡量。用 7A5 进行单药治疗可抑制肿瘤生长，并且与 PD-L1 拮抗剂抗体联合使用可增强这种活性。此外，对 7A5 反应的肿瘤内免疫基因表达谱高度提示增强了 T 细胞浸润和激活。总之，这些结果表明 7A5 是一种差异化的 CD137 激动剂抗体，具有生物学特性，值得进一步开发为癌症免疫疗法。
