肿瘤细胞治疗研究
英文原题：A novel LAG3 neutralizing antibody improves cancer immunotherapy by dual inhibition of MHC-II and FGL1 ligand binding.
LAG3 是表达于活化 T 细胞和 NK 细胞上的抑制性免疫检查点。
LAG3 是一种抑制性免疫检查点，在活化的 T 细胞和 NK 细胞上表达。阻断 LAG3 与其配体 MHC-II 和 FGL1 的相互作用，可增强 T 细胞对癌细胞的细胞毒作用。本研究通过小鼠免疫结合噬菌体展示，制备了一组 LAG3 单克隆抗体（mAb）。其中部分抗体结合 LAG3 的 D1-D2 结构域，该区域参与结合配体 FGL1 和 MHC-II。表现最佳的三种抗体 M208、M226 和 M234，在阻断 FGL1 结合方面强于 Relatlimab。此外，M234 可同时抑制 FGL1（IC50 为 20.6 nM）和 MHC-II（IC50 为 6.2 nM）与 LAG3 的结合。体外功能实验显示，M234 可显著促进活化 PBMC 细胞分泌 IFN-γ。肝细胞癌异种移植小鼠模型的体内研究表明，M234 IgG 与靶向 GPC3 的双特异性抗体联合，可显著提高疗效。此外，分泌 IL-21-M234 scFv 融合蛋白的靶向 GPC3 CAR-T 细胞，在抑制肿瘤生长方面活性增强，并显著提高小鼠生存率。综上，M234 在癌症免疫治疗中具有潜力，值得进一步临床试验。
LAG3 is an inhibitory immune checkpoint expressed on activated T and NK cells. Blocking the interaction of LAG3 with its ligands MHC-II and FGL1 renders T cells improved cytotoxicity to cancer cells. Current study generated a panel of LAG3 monoclonal antibodies (mAbs) through immunization of mice followed by phage display. Some of them bound to the D1-D2 domain of LAG3, which is known for the engagement of its ligands FGL1 and MHC-II. Three outperformers, M208, M226, and M234, showed stronger blocking activity than Relatlimab in the FGL1 binding. Furthermore, M234 showed dual inhibition of FGL1 (IC 50 of 20.6 nM) and MHC-II binding (IC 50 of 6.2 nM) to LAG3. In vitro functional tests showed that M234 significantly stimulated IFN- secretion from activated PBMC cells. In vivo studies in a mouse model of hepatocellular carcinoma xenografts demonstrated that combining M234 IgG with GPC3-targeted bispecific antibodies significantly improved efficacy. In addition, GPC3-targeted CAR-T cells secreting IL-21-M234 scFv fusion protein exhibited enhanced activity in inhibiting tumor growth and greatly increased the survival rate of mice. Taken together, M234 has potential in cancer immunotherapy and warrants further clinical trial.
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