IL-2 is a pleiotropic cytokine that plays an essential role in the survival, expansion, and function of CD8 T cells, regulatory T cells (Tregs), and natural killer (NK) cells. Previous studies showed that binding IL-2 with an anti-IL-2 monoclonal antibody (mAb) with a particular specificity could block its interaction with IL-2Rα, which is mainly expressed on Tregs. This selectivity can enhance the anti-tumor effects of IL-2 by activating CD8 T and NK cells, while disfavoring Treg stimulation. Based on this, we newly developed a series of anti-human IL-2 (hIL-2) mAbs (TCB1-3) that selectively stimulate CD8 T and NK cells without overtly activating Tregs. Among them, the hIL-2/TCB2 complex (hIL-2/TCB2c) exerted the best efficacy by inducing a prodigious expansion of host memory phenotype (MP) CD8 T (60-fold) and NK cells (18-fold) with less efficient Treg proliferation (5-fold). As a result, there was an average eightfold increase in the ratio of MP CD8 to Tregs. Accordingly, hIL-2/TCB2c strongly inhibited the growth of B16F10, MC38, and CT26 tumors. More remarkably, hIL-2/TCB2c showed synergy with checkpoint inhibitors such as anti-CTLA-4 or PD1 antibodies, and resulted in almost complete regression of implanted tumors and resistance to secondary tumor challenge. For direct clinical use, we generated a humanized form of TCB2 that had equal immunostimulatory and anti-tumor efficacy as a murine one. Collectively, these results show that TCB2 can provide a potent immunotherapeutic modality either alone or together with checkpoint inhibitors in cancer patients.

中文翻译：

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TCB2 是一种新型抗人白细胞介素 2 抗体，可促进异二聚体 IL-2 受体信号传导并提高抗肿瘤免疫力。

IL-2 是一种多效性细胞因子，在 CD8 T 细胞、调节性 T 细胞 (Tregs) 和自然杀伤 (NK) 细胞的存活、扩增和功能中发挥重要作用。先前的研究表明，将 IL-2 与具有特定特异性的抗 IL-2 单克隆抗体 (mAb) 结合可以阻断其与主要在 Treg 上表达的 IL-2Rα 的相互作用。这种选择性可以通过激活 CD8 T 和 NK 细胞来增强 IL-2 的抗肿瘤作用，同时不利于 Treg 刺激。基于此，我们新开发了一系列抗人 IL-2 (hIL-2) mAb (TCB1-3)，可选择性地刺激 CD8 T 和 NK 细胞，而不会明显激活 Treg。其中，hIL-2/TCB2 复合物 (hIL-2/TCB2c) 通过诱导宿主记忆表型 (MP) CD8 T（60 倍）和 NK 细胞（18 倍）的显着扩增而发挥最佳功效，Treg 增殖效率较低（5倍）。结果，MP CD8 与 Treg 的比率平均增加了八倍。因此，hIL-2/TCB2c 强烈抑制 B16F10、MC38 和 CT26 肿瘤的生长。更值得注意的是，hIL-2/TCB2c 显示出与检查点抑制剂（如抗 CTLA-4 或 PD1 抗体）的协同作用，并导致植入的肿瘤几乎完全消退和对继发性肿瘤攻击的抵抗力。对于直接临床使用，我们产生了一种人源化形式的 TCB2，它具有与鼠类相同的免疫刺激和抗肿瘤功效。集体，